Not all carcinogens are mutagens. Alcohol and estrogen, for example, does not damage DNA.
It's one of the assumptions of the Ames test that mutagenicity implies carcinogenicity, but is this always the case? I assumed that it was, but then I saw one of the comments here. I did some more research but the internet seems to be reluctant to be definitive on the subject. This guy claims 'no', but I'd prefer sources or at least a response that handles counterexamples like HPV. This paper claims 'yes', but doesn't list any specific examples. Some mutagens might be more specific to genes involved in cell cycle regulation, so I could see how a weak mutagen is a powerful carcinogen.
My question is, can you go the other way? Are there mutagens that just do not cause cancer? If they do not exist or are not known to exist, are they even possible?
All mutagens are potential carcinogens unless the mutagen is highly specific to a site. As noted in the question, carcinogens need not be mutagenic.
HPV causes oncogenic transformation of a cell because of certain proteins that it expresses. HPV is considered a carcinogen by the IARC. Some retroviruses are oncogenic: they might carry an oncogene or insert randomly near an endogenous proto-oncogene and cause oncogenic transformation; this phenomenon is called insertional mutagenesis (Coffin JM, Hughes SH, Varmus HE, editors. Retroviruses). They can also integrate within a gene and knock it out. Many of these viruses are considered carcinogens by IARC.
Hepatitis viruses (B & C) can also induce carcinogenesis but insertional mutagenesis is not the sole mechanism (Cougot et al., 2005; Fung et al., 2009; Lemon & McGivern, 2012). Hepatitis viruses are considered carcinogens by IARC.
Ethanol in alcoholic beverages is considered carcinogenic by IARC. There are many substances listed as carcinogens by IARC but they are not mutagenic. The general mechanism of carcinogenesis by these substances may be prolonged inflammation or ROS generation.
Loss of function of the tumour suppressor gene p53 leads to cancerous progression (Chiche et al., 2016; Venkatachalam et al. ISBN:978-1-59259-100-8). So an siRNA that targets p53 should be called a carcinogen. It would however not cause any mutations and is hence not a mutagen.
If you consider the tools developed for genome editing, such as ZFN, CRISPR-Cas and TALEN as mutagens then they are not carcinogenic. However the term mutagen is not used for these molecules. Mutagen almost always refers to a molecule that causes random mutagenesis thereby making it a potential carcinogen.
I'm no expert on the matter, but just quoting from Wikipedia:
Mutagens are not necessarily carcinogens, and vice versa. Sodium Azide for example may be mutagenic (and highly toxic), but it has not been shown to be carcinogenic.
It cites Toxicology And Carcinogenesis Studies Of Sodium Azide.
So it would appear the answer is no. Not all mutagens are carcinogens.
Mutagens and Carcinogens
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Good morning class, nice to see you again.
I trust you had a relaxing weekend and a Happy Halloween, whatever a Happy Halloween is. You recall that last time we were talking about the process of cell transformation, and recall, what I said was that transformation represents the conversion of a normal cell into a cancer cell.
In fact, there are a variety of traits of a cell which suggest it's a cancer cell, it changes its shape, it can get along with [foralized? growth factors. Normal cells require tethering to the bottom of a Petri dish in order to grow.
Cancer cells, you can put them into a semi-solid medium, like agar, and cancer cells will often grow like this, as colonies in suspension, without direct tethering, without direct adhesion to a solid, underlying substrate.
And that, that's a trait of cancer cells, the phenotype of cancer cells, is sometimes called, anchorage independence.
But ultimately, the best litmus test, whether a cell is truly transformed, is tumoraganisity, i.e. the ability of a cell, when plucked out of a Petri-dish like this, and implanted into a host mouse, to actually grow into a tumor.
So there are various gradations of becoming transformed, but tumoraganisity is the ultimate arbiter of whether or not a cell is truly transformed. Now, you'll recall from our conversation last time that if you put a transformed cell, a mixed a mono-layer of normal cells, that the transformed cell will overgrow the mono-layer, it will have lost contact inhibition, and that when viewed from above, such a Petri-dish yields a thick clump of cells, which is called a focus, plural, foci. And I will tell you that beginning in the late 1960's, one began to use a variety of different techniques, with which to transform cancer cells into normal cells. One of the techniques one used was to apply chemical carcinogens to cells, and keep in mind that we're reserving the word, carcinogen, for a chemical or a physical agent that causes cancer. Ultraviolet radiation is a carcinogen, as are x-rays, and there are many chemical carcinogens, such as those in tobacco smoke.
And certain experiments in the early 1970's began to reveal that one could get foci of transformed cells, by applying chemical carcinogen to the cell in-vitro, and when I say in-vitro, I mean growing here, in the Petri dish. And, in fact, one could begin to use a whole variety of different types of carcinogens, chemical carcinogens, and what seemed to be shared in common between all these carcinogens was that they were all mutagenic.
By mutagenic, I clearly mean the ability to inflict damage on the genome of the cells that were being exposed to these various compounds.
In fact, one could draw an interesting correlation because many of these mutagenic compounds had, also by chance, been tested in laboratory animals for their carcinogenicity.
And so plots were derived in the mid-1970's, between the mutagenic potential of a compound, and the carcinogenic potential of a compound. And when I say a carcinogen, how carcinogenic is a compound, I mean, how many milligrams of this compound does it take to make a tumor? And so, what one could do, is plot over a log-log scale, how many milligrams of a given compound was required, or micrograms, to make a tumor in a rat or a mouse.
And, at the same time, how mutagenic were these compounds, i.e. how potent were they in their ability to inflict damage on the genome? Because it turns out, that if this log-log scale is by orders of magnitude, powers of ten, compounds range over at least five or six orders of magnitude in their potency in inflicting mutations, and similarly, in their potency in inducing tumors in mice and rats.
And what one found was the following, that there was a log-log relationship that was roughly linear, but there was violations to this.
Some compounds were extraordinarily mutagenic, they could create mutations in very low doses, and at the same time could create tumors, they were carcinogenic in very low doses.
Other compounds required an enormous amount of material in order to induce mutations on the abscissa, and an enormous amount of material in order to induce tumors on the ordinate. And this log-log relationship over five orders of magnitude, suggested the following obvious idea, that carcinogens are mutagenic, and to the extent that carcinogens are able to induce cancer, they do so through their ability to inflict mutational damage on the cells within certain target tissues. And this, therefore, obviously suggested the notion that within cancer cells, as we said last time, there are mutant genes, and that these mutant genes are moreover instrumental in conferring the transformed phenotype on the cells that carry these mutant genes.
In the, in the late 1960's and early 1970's, a man named Howard Temin, began to use a virus called Rous sarcoma virus, which had first been discovered in 1909 by a man named Peyton Rous.
Rous was then a professor at the Rockefeller Institute, later the Rockefeller University, in New York. A Long Island chicken farmer brought in a prized hen of his who had been growing a big muscle tumor, or sarcoma, in her breast muscle, and asked Rous, the famous chicken doctor, if he could cure this chicken, and Rous said, thank you, cut off the hen's head, extracted the tumor, and ground up the tumor, and after having homogenized the tumor, passed the homogenate through a filter. And this filter would trap all cellular material, but it would allow non-cellular material, or material that was smaller than the size of a cell, to pass right through. And so, therefore, Rous took the material that passed through the filter, which you can call the filtrate, and he injected the filtrate, which passed through the filter, into a young chick. And what he observed thereafter was that chick soon came down with sarcoma after a period of some months, and when he ground up the tumor in that chick, and once again injected into another chick, he once again got a tumor.
The fact that the agent, which was inducing the cancer, and could be transmitted from one animal to another, from one chicken to the other, was filterable, suggested it was extremely small, and at the time one had already begun to appreciate the fact that there were sub-cellular infectious agents, which we now call viruses. And Peyton Rous made this very important discovery in 1909, 1910, and in 1965 he was awarded a Nobel Prize for this. It's a rather long wait, wouldn't you say? So he only had to wait 55 years, anyhow, he died a happy man, we can only presume. Now, what's interesting about this is the life cycle of Rous Sarcoma virus.
As we will discuss in greater detail later, viruses are sub-cellular particles, they don't have their own energy metabolism, and they parasitize on the macromolecular machinery of the cell that they infect. And therefore, what we can imagine here is the following scenario, which actually happens to be true.
A virus particle, which is vastly smaller than a cell, enters the cell, the virus particle carries into the cell its own genome, and this genome, in this case of Rous Sarcoma virus, is single-stranded RNA, and this genome, which is carried into the cell, carries the information for making more virus particles.
And what happens is, in the case of Rous Sarcoma virus, as Temin later speculated in a speculation that caused him ridicule and ostracism for many years, that the single-stranded RNA of Rous Sarcoma virus, once it gets into the cell, is reverse-transcribe, i.e. copied into DNA molecules.
So now we have double-stranded DNA, a double-stranded DNA copy of the viral genome, and this double-stranded DNA molecule, which came to be called a pro-virus, then became integrated into the host chromosomal DNA. So here's the host-chromosome.
And now, the pro-virus, which I'll depict here in the middle, in white, became physically inserted as a double-stranded DNA molecule, it was slipped right into the genome. We now realize that any, any of tens, of hundreds, of millions of different sites in the genome of the host cell. And this pro-virus, once established or integrated into the genome, could thereafter, function essentially like a cellular gene, i.e. from a molecular-biological perspective, it was indistinguishable from a cellular gene, it was double-stranded DNA, it had a promoter it carried in a promoter with it, and it had a polyadenylation signal, and therefore, this pro-virus thereafter, could use, or parasitize, the host-cell RNA polymerase 2, to make viral messenger RNA, on the one hand, and progeny-genomic RNA.
Now when I say genomic, I'm not talking about the host-cell genome, I'm talking about the viral genome. How big is the virus?
Well, it's about nine or ten kilo-bases in length, so it's genome, obviously, is vastly smaller than the 3.
mega- bases that constitute the haploid human genome.
The viral mRNA, once transcribed in the nucleus, and exported to the cytoplasm, could make viral proteins, and the viral proteins could then be used to encapsidate, and when I use the word encapsidate, keep in mind, I never use a simple word when a polysyllabic one is possible. So when I, when the viral proteins encapsidate the viral-RNA, you get a virus particle like this, which has virus proteins on the outside, almost on the outside, viral RNA in the middle, single-stranded RNA, and this single-stranded RNA comes from the transcription of the pro-virus that has now been integrated into the genome.
Integration is an important concept here, i.e. it becomes covalently linked. And this suggests to us that the virus actually encodes several specialized proteins.
One set of specialized proteins is required for the reverse-transcription, and in fact, the virus actually carries with it, into the cell, not only its RNA, but also, reverse transcriptase. So if you isolate the virus particle, it has, in addition to this coat, it has within it already reversed transcriptase, molecules, so that the moment that this virion, a virion is a virus-particle.
The moment that this virion, or virus-particle, penetrates into the cytoplasm of the cell, there is then, immediately, an abundant supply of the deoxyribonucleoside triphosphates, the process of reverse-transcription can begin, the double-stranded DNA can be produced, exported to the cytoplasm, where a second viral protein is responsible for integrating the resulting double-stranded reverse transcript into the host-cell genome. Again, that's a highly specialized function. The forward transcription, we just talked about reverse-transcription, but the forward-transcription to make progeny RNA, obviously can rely on the host cell polymerase, the virus doesn't need to make that. The viral mRNA can be translated by host cell ribosomes in the cytoplasm, the virus doesn't need to make that. Some of the viral aren't, the new viral RNA, is genomic RNA, which as I say, becomes encapsidated to make progeny virus particles. And a cell, which is infected in this way, can suffer two fates. It could be, as is in the case with many viruses like this, that the viruses, that the cell is not actually killed by this infection, i.e.
that the cell can tolerate an infectious, an infection like this, and therefore, if you look at such a cell, for days and weeks later, it will be producing virus particles, which are being released from the cell, continuously, continually released from the cell, and are able then, to pass and infect yet other cells.
The alternative to this is what is called a cytopathic effect, and the truth of the matter is, many kinds of viruses, when they go and infect a cell, and they produce their progeny, they end up killing the cell that they've infected.
So, for example, when we get infected by a cold virus, which has a different metabolism than this one, by the way, then the cells that are infected and produce progeny-virus particles are rather quickly killed, as a consequence of the infection, which is why we have damage to our nasal mucosa.
But in this case, in the case of Temin's virus, actually RSV, Rous Sarcoma Virus, that isn't the case. And therefore, in fact, one has RSV particles that are continually being released from the cell. If one looks under the electron microscope, at the surface of a virus-infected cell, one sees structures like this.
Where here is in the green is the lipid by-layer, the plasma membrane of the cell. And here, in the middle, is a viral-protein capsid, a protein capsid like this, encoded by the virus, and carried in the capsid is actually, are actually, the viral-RNA molecules, and the reverse-transcriptase molecule. And in saying that, what I mean to suggest to you, is that actually the viral particle, the virion, is slightly more complicated than I represented it to be. As the virus, as progeny particles are made, they are pushed out through the plasma membrane of the infected cell, on which occasion, they become enveloped with a layer of plasma membrane.
And this layer of plasma membrane is actually stolen as a patch from the plasma membrane of the infected cell. So in truth, actually, a virus particle like RSV, has some membrane around it, it has a protein-capsid encoded by the viral mRNA, and in the middle it has RNA and reverse transcriptase molecules.
Note, by the way, that most viruses actually, everything that the virus carries, the virus has encoded in it's own genome, in this case, the virus has stolen, has absconded, with a patch of plasma membrane from the infected cell.
Now what Temin observered, several other people before him had done so, was that when he infected a mono-layer of chicken cells with Rous Sarcoma virus, he was able to in fact, observe the appearance of foci of transformed cells.
And he observed that these foci of transformed cells actually released Rous Sarcoma Virus. So, the infection by Rous Sarcoma Virus, had led to the production of progeny virus particles, which we kind of expect of a virus. Keep in mind that if a virus can't produce progeny, it's out of business.
Or, to put it another way, the only thing a virus is really interested in, is making more copies of itself.
So, the cells in these foci of transformants were transformed, but they were also releasing progeny virus particles.
And if you took these virus particles, and he could isolate them away from any contaminating cell, the way Peyton Rous did, just by filtering them, or the filter will trap all of the cells, and allow the much tinier virus particles to pass through, then he could take these virus particles and infect another plate of cells, and once again, he would get foci of transformants.
And therefore, this virus was actually bipotential, it could do two things. It could replicate, here I've been talking about the life cycle or the replication-cycle of the virus, on the one hand, and on the other hand, it could transform cells. And subsequent work demonstrated that actually, the replicated functions of Rous Sarcoma Virus, on the one hand, and the transforming functions of Rous Sarcoma Virus, on the other hand, were encoded in separable genes.
For example, Howard Temin was able to demonstrate, and others later, that one could get mutants of RSV that had lost the ability to transform cells, but could still replicate perfectly well.
And there were yet other mutants that had lost the ability to replicate, but could transform perfectly well.
And so there were two classes of specialized genes, one involved in replication, the other in transformation. In 1975 and 1976, the laboratories of Harold Varmus and Mike Bishop, at University of California, San Francisco, or UCSF, as it's called in the trade, began to exam the origin of the viral transforming gene.
Now the viral transforming gene, because it was assumed there was only one of them, the genome is so small, it only has about ten kilo-basis, and only enough room for three, or four, or five, genes in it, not a hundred or a thousand, the viral transforming gene came to be called SRC, S-R-C. And what they observed was the following, they made a radio-labeled probe, which was specific for the SRC gene.
And they could use the radio-labeled probe to anneal to two kinds of viruses, wild-type Rous Sarcoma Virus, and a deletion mutant, I'll use the Greek -delta, a version of Rous Sarcoma Virus, which was lacking, which apparently through process of genetic deletion, was lacking the ability to transform cells. And that loss of ability to transform cells was ostensibly due to the lesion of it's genome of the SRC gene.
And what they observed is that the SRC, the radio-labeled SRC probe, as one would've hoped, was able to anneal to this wild-type genome, but it couldn't anneal to the deletion mutant of RSV, which had lost the SRC gene through a process of genetic deletion.
So, so far, so good. By the way, the fact that the SRC gene could transform cells, led to it's being called, an oncogene. The term "oncos" in Greek means, a tumor or a lump, an oncogene therefore, was a cancer-causing gene.
And therefore, Rous Sarcoma Virus possessed at least one cancer-causing gene, or oncogene. Now the mind-blowing result that happened shortly thereafter, was the following.
People in the Varmus-Bishop lab began to look for the origins of the SRC oncogene of Rous Sarcoma Virus. It turns out that the vast majority of genes that have been in virus, that are present in viral genomes, have been in viral genomes, as far as we know, for the last billion years. i.e. we have every reason to think that the evolutionary origins of viruses can be traced into the distant past. It could even be the case, some people think, some perfectly sane people think, that this whole retro-virus life cycle that I just told you about, recapitulates one of the earliest stages of cellular evolution on the planet. People believe now, with ever-increasing conviction, and keep in mind, class, people who are convinced of something are usually wrong, in a loud voice.
But people believe with ever-increasing conviction, that the first cells on earth actually had RNA genomes, rather than DNA genomes, and that the invention of double-stranded DNA genomes in cellular life forms, came later. And if it did, then the conversion from an RNA to a DNA state is reflected in the modern life cycle of Rous Sarcoma Virus, and similar viruses, which as you may know, have come to be called retroviruses, simply because they transcribe their nucleic acid backwards.
So, Varmus and Bishop were interested in the origins of the SRC oncogene that was carried by Rous Sarcoma Virus.
I say, well it probably, the Rous Sarcoma Virus, had antecedents, which existed thousands and millions of years ago, and carried the SRC oncogene. But the fact of the matter is, the SRC, the Rous Sarcoma Virus, had only been isolated once in the 20th century, when this very trusting, and caring, Long Island chicken farmer came in to Peyton Rous, hoping that Rous would cure his chicken, rather than cutting the chicken's head off. So what happened, then, was the following. They used this radiolabeled probe to look at the DNA of infected, RSV-infected chicken cells, and uninfected chicken cells. So they probed the DNA of the infected chicken cells, with this radiolabeled probe, and they probed the DNA with uninfected chicken cell, of uninfected chicken cells, once again with this radiolabeled probe. And what they, what they expected to find was the following, it's obvious, in uninfected chicken cells you don't find any SRC, and in infected chicken cells, you do find SRC, because the SRC gene has been brought into the infected cells by the infecting viral genome. Stands to reason, right? Shouldn't be any in the uninfected cells, after the cell's infected, now they have a SRC, at least one copy, they may have multiple copies of the SRC oncogene, because I haven't really dictated how many pro-viruses should be integrated into the genome of an infected cell. And what they found was puzzling, and eventually mind-blowing. Because they found that in the DNA of uninfected chicken cells, they could find a SRC gene, and these uninfected chicken cells had never experienced Rous Sarcoma Virus in any form, whatsoever. And as a consequence, they began to develop a theory, a model, which turned out, actually, to be right on, and the model was as follows, that there was a retrovirus, like Rous Sarcoma Virus, that was the precursor of RSV, and this retrovirus had replication genes, but it lacked a transforming oncogene.
This retrovirus went into a chicken cell, and when it emerged from the chicken cell, it carried not only the replication genes, but now the SRC oncogene. It had acquired a new gene, which it could then use to subsequently transform other cells that it had infected. And this, itself, turned out to be absolutely right. This SRC gene was of cellular origin, and in fact, homologs of the SRC gene, were present in all vertebrates, in all chordates, in all metazoan, there's even a distant homolog of the SRC gene that's present in sponge cells, which are obviously rather primitive.
So this SRC gene is not a recent invention, it's been sitting around in the eukaryotic genome, at least in the genome of metazoan and its precursors, for a very long time.
It was kidnapped, picked up by the Rous Sarcoma Virus, and subsequently exploited by the virus to transform cells that it happened to infect. And this acquisition and activation of a gene was obviously a rare event, because RSV, as I've just told you, was only picked up once, was only generated once.
It didn't exist in nature, and Rous Sarcoma Virus was never seen to, go from one chicken flock to the other, like most infectious agents. The ecology of Rous Sarcoma Virus is not so much of interest to us, what is of greatest interest to us in our discussion today, is the following notion that, within the normal genome of a chicken cell, there exists a normal gene which came to be called a proto-oncogene, a precursor of the, A proto-oncogene which resides in normal chicken DNA, and the fact that the proto-oncogene is highly conserved, evolutionary, dictates to us that this proto-oncogene, this SRC proto-oncogene, must mediate essential functions, otherwise it wouldn't long ago been lost. In fact, just to repeat myself, virtually identical copies of the SRC oncogene, proto-oncogene, excuse me, lie, can be found in the genomes of all vertebrates. So, a proto-oncogene is a normal cellular, growth-regulating gene, which, on this occasion, became activated, and subverted, and converted into an active transforming gene, i.e. an oncogene. So the term -proto in this case, implies a normal gene, which has the potential, under certain circumstances, to become an active oncogene. In the years that followed, it's been almost 30 years now, more than 30 proto-oncogenes have been discovered, by looking at retroviruses like RSV.
SRC is not the only proto-oncogene that lies in our genome, and therefore, we begin to appreciate on the basis of this, that our genome carries a whole repertoire of these growth-regulating genes that, when a retrovirus happens to swoop in, can be activated into active oncogenes, they can be converted into active oncogenes, and thereafter, they can induce cancer. And this obviously leads to the suggestion that the seeds of human cancer don't lie, necessarily, on the outside of cells because most kinds of human cancers are not caused by infecting viruses. That was a puzzle that was already apparent in the late-1970's. If Rous Sarcoma Virus, or similar viruses, could not be invoked to explain many kinds of viruses, how could one get cancer? And this work suggested an obvious solution.
Let's imagine that there are a repertoire of a dozen, or two-dozen, or three-dozen, proto-oncogenes that reside in our normal genome, their purpose there is not to create cancer, their purpose is to regulate normal cell proliferation.
These genes, being genes, are subject to damage, to mutation, and therefore we can imagine that in cases of human cancer, where there are no viruses involved, there can be genetic alteration of the DNA sequences of a proto-oncogene that converted into an oncogene. i.e chemical changes to the DNA, mutagenic changes to the DNA, can mimic the conversion of a proto-oncogene to an oncogene, without any virus. There are other ways by which you can skin this cat. And one experiment to demonstrate that is the following. Did we talk at the end of last time about the guy who got a bladder carcinoma after 40 years of smoking?
I'm glad we did. Good. So, let's say this person gets a, has a bladder carcinoma, and he got the bladder carcinoma, and it was called an EG bladder carcinoma, and he got it for reasons we described last time, and I can't imagine you have any illusions about whether smoking is good or bad for you, after last time. But anyhow, so, EG bladder carcinoma, pig DNA from the tumor, so we make tumor DNA.
And now, and by the way, we presume correctly that viruses have nothing to do with this particular cancer, with the development of this cancer, and by the way, the development of a disease is another wonderful polysyllabic Greek word, pathogenesis. Pathogenesis means the study of how a disease is caused, what generates the disease.
So the pathogenesis of bladder carcinoma has nothing whatsoever to do with any viruses. Maybe it had to do with the fact that cigarette smoke mutated genes, mutated, proto-oncogenes in the DNA of Mr. Jones, that happens to have been his name, or his pseudonym, who knows, Mr. Jones' bladder cells.
So one takes tumor DNA here, and one uses the procedure of transfection, where you take the DNA, make a DNA, and you put it into normal cells, by a gene transfer, or a transfection procedure. So, this is transfection, or gene transfer, these are equally applicable names, and what was found on this occasion was, that one got foci of transformed cells. And these foci, for all practical purposes, looked just like the foci that Howard Temin had gotten years earlier, by infecting monolayers of chicken cells, with Rous Sarcoma Virus. And therefore, that suggested very strongly, that the DNA of the bladder carcinoma, carried within it, an oncogene that was capable of transforming these recipient cells, into which the DNA had been introduced by the transfection procedure. It remained, of course, to actually find that. I'll mention to you in passing, that one does a control experiment here.
If you take normal DNA, you do the exact same experiment you never get foci. So that means, it's not as if all human DNA carries oncogenes in it. The normal DNA doesn't give you foci, the DNA from the bladder carcinoma does give you foci.
And so, about 20 years ago, one actually looked at the normal DNA and the tumor DNA, and one came up with the following, that the bladder carcinoma oncogene, was about, let's say, 6KB long, there was a corresponding, normal proto-oncogene.
It was also 6 kilobasis long. This was a normal DNA, this was extracted by cloning, gene cloning, from the genome of the bladder carcinoma. And having extracted it, one then began to look at how different these two genes were from one another. This transformed cells, this did not transform cells.
If one did restriction enzyme mapping, one found the identical array of restriction enzyme sites. So it was clear that even though these two genes, we can call the normal one a proto-oncogene, these two genes were structurally identical, they couldn't be absolutely identical, because biologically, they were behaving very differently.
And so, when the sequence analyses were done, it was discovered that the difference between the normal proto-oncogene and the oncogene, was a single point mutation, a single-base pair change.
And that single-base pair change created a potent oncogene.
And that single-based pair change, one could show in comparable tumors, was a somatic mutation. Remember, we said somatic mutations are mutations that strike the genomes of cells in our soma, rather than the germ line. That somatic mutation had almost surely had struck one of the epithelial cells lining the bladder of Mr. Jones' urinary bladder. How did this work?
Well, let's go back to our discussion of growth factor receptors, you recall we talked about them last time.
Let's say, here's a growth factor receptor at the cell surface, the growth factor receptor sends signals into the cell, and such a sequence of signals, where you go from a to b, to c to d, is sometimes called a signaling pathway, sometimes it's called a signaling cascade, It's a molecular bucket brigade where a passes signals to b, passes signals to c, to do, and so fourth, and they cross-communicate with one another to process this incoming signal from the growth factor activated receptor.
Now it turned out that the protein product of this, of a normal proto-oncogene, and the bladder carcinoma oncogene, sat right down here, in the signaling cascade, downstream in the signaling cascade of the growth factor receptor.
And the protein product was a very interesting protein, it was a protein, which came to be called RAS, in fact, the original proto-oncogene had previously been associated with a retrovirus. But in this case, it was clear that the activation of the proto-oncogene to the oncogene had nothing to do whatever, with the intervention, by a retrovirus, or by the acquisition of a retrovirus, by a normal proto-oncogene.
So RAS has the normal, the following normal lifestyle.
RAS normally exists in a quiet state, an inactive state, so here's RAS, and while it's in the quiet state it binds GDP, guanosine diphosphate, GDP. What happens, then, is that RAS on occasion, gets an incoming signal from some upstream activator, and you can imagine what the upstream activator is from here.
Keep in mind, I'm only focusing now on, let's say, component c of this signaling cascade, so an upstream activator comes in, and impinges on RAS. And in so doing, it wants to switch RAS from a quiet to an activated state. So what happens, when RAS gets a signal from, an upstream signal from here, RAS will shed its GDP, and will instead, allow a GTP to jump aboard. So now a GTP can jump aboard, and now RAS is in its active state up here. And while it's in its active state, it can emit growth stimulatory signals into the cell, like that. I'm not showing you exactly what it looks like, but it can emit signals. And this is, by the way, called a signal transducing protein, a protein that tranduces signals receives signals from higher up in the cascade, and passes them on lower into the cascade. So it's transducing these signals, and so RAS is put, here I should've capitalized RAS here, so RAS is now in its active state.
It's received upstream signals, it's shed its GDP, its bound GDP, and while it's there, RAS passes signals on further downstream in the pathway. So, if want to relate it to the signaling cascade, and we imagine that RAS is component c of this cascade, it receives signals from b, and then RAS passes signals onto d, it's sitting in-between them, it's an intermediary, it's a member of this molecular bucket-brigade.
Now what happens is that RAS is in this active state for only a period of usually milliseconds, and after it's in a period of this active stage, and it's emitting growth stimulatory signals, downstream, for a period of milliseconds, RAS does something very interesting. It hydrolyzes the GTP, and when it hydrolyzes the GTP into GDP, obviously an inorganic phosphate comes out, RAS switches itself off, i.e. RAS has an intrinsic GTPase activity, GTPase means it can cleave GTP. So it's as if there was a switch here, and I could turn it on, well I'm not going to mess with it since I still haven't figured out how the switches work, but it's as if there was a light switch here that I could switch on, and the lights would be on for a short period of time, and then the switch would automatically shut itself off.
A negative-feedback control to ensure that the period of activation of the RAS protein is only a period of milliseconds, and that the pulse of downstream signals that are released is finite, circumscribed, limited, it's only a quantum of signals that are released. After which occasion, RAS hydrolyzes it's GTP and shuts itself off. It's a nice system, and it actually works because, as I've told you before, we go through ten of the sixteenth cell divisions, with RAS proteins in our cells, and rarely, if we lead virtuous lives and listen to everything I've said in the last lecture, do we ever get cancer. So, what happens when the RAS encoding gene becomes mutated in cancer? That's another one of those questions that I'm really glad I asked, because what happens is that the ability of the GTPase activity to function, is knocked out.
The GTPase can no longer operate, and therefore, the ability of RAS to shut itself off, by cleaving GTP down to GDP, is now compromised, and as a consequence, RAS is trapped for extended periods of time, for minutes and hours, and maybe even days, in this excited signal-emitting configuration, on which occasion, it sends out a continuous flood of signals.
In fact, we now know that the point-mutation, which happens in the gene here, and is seen, by the way, in about 20% of human cancers that have virtually identical point-mutations, those, that point mutation is in the GTPase domain of the RAS protein, that is normally responsible for cleaving GTP into GDP.
So now we can begin to get a very concrete and specific understanding, an insight, into the mechanism by which a point mutation, a somatic mutation, can have a dramatic effect on the ability of a cell to grow. Note, by the way, that if RAS is sending signals constitutively down here, and you may recall that the word constitutive means, at a constant and unrelenting fashion. So the ability of RAS, which I depicted as residing right in here in the signaling cascade, to send out signals unrelentingly down like this, means that the signals up here are no longer so important.
RAS might require a brief stimulus to get into this activated state, but then it can sit around for hours and days, pushing the cell to proliferate. And the subsequent exposure of a cell carrying a RAS oncogene is now gratuitous, it's unnecessary, because this downstream signal emitter has gone wild, and is firing and pushing the cell to grow unrelentingly. Interestingly, that signal is very critically important in pushing cells to move through the G1 phase of their growth and division cycle.
In other words, it's during that phase of the division cycle, that RAS is actually able to send it's signals that perturb cell cycling, and push the cell to move from G1 up to the restriction point, and then into the remaining part of the cell cycle. So now we see how somatic mutations, and we now know about dozens of such genes, can convert proto-oncogenes to oncogenes, without the intervention of any retrovirus.
There are yet another class of genes, which are called, tumor suppressor genes, and these tumor suppressor genes operate in exactly the opposite way as proto-oncogenes and oncogenes.
The proto-oncogenes and oncogenes, from what I've told you, you can imagine are functioning analogously to accelerator pedals on a car, they push the cell to proliferate and, when you have a cancer, the accelerator pedal gets stuck to the floor. In other words, it's no longer well regulated. The tumor suppressor genes work in an opposite fashion, as a breaking system to slow down cell proliferation. And, as such, tumor suppressor genes operate to counteract, and counterbalance, and limit, the growth stimulatory signals that are coming from the RAS gene, and other growth promoting genes. So there's two sides to the coin, indeed as you can imagine from circuit theory, any positive signal must be counter balanced by a negative signal, so that you end up having some kind of physical balance that is compatible with normal, biological function.
So these tumor suppressor genes are normally functioning as break, break linings of a cell, if you will, and that also describes how they become involved in cancer. The mutation that struck the RAS gene caused a hyper-activation of the proto-oncogene.
The proto-oncogene was hyper-activated, and now it began sending out an unrelenting stream of growth-stimulatory signals. As you can imagine, as it is intuitively obvious, in the case of tumor suppressor genes, when they became involved in cancer, what kind of mutations affect them? Inactivating mutations. So there's a very interesting gene, it's called the retinoblastoma gene, and the retinoblastoma gene, the retinoblastoma is a rare eye-tumor of children, it happens about 1/20,000 kids, and the retinoblastoma gene, if you look at the retinoblastoma gene in the genomes of tumor cells, these are the eye cells that form the precursors, the rods and the cones, and other neuronal cells lining the retina. Here's the normal retinoblastoma gene, and it's 190 kilo basis long. So it's a pretty nice size gene, it's not the biggest, it's not the smallest.
If you look at many retinoblastoma tumors, what you find is that there are major portions of the gene that have been just deleted.
Here I'll show you one deletion, here's another deletion, here's a third deletion, sometimes the whole gene is deleted, and cut out. Obviously such deletions are not enhancing the function of the retinoblastoma gene, obviously they're wiping it out. And therefore, we can begin to imagine that the way that the tumor suppressor genes are recruited into the process of forming cancer is through their elimination, rather than through their hyper activation. In fact, as you might also imagine, a cell, which has the following genotype, RB+, RB-, actually grows normally.
Why? Because one of the two alleles has been inactivated, the minus, but the other allele is still, is still active, and still functional, and still able to create an adequately functional break lining. Only when a cell becomes RB- like this, homozygous minus, does it begin to grow uncontrollably, because now it lacks all ability to manufacture the normally required break lining. And this begins, as well, to explain certain kinds of hereditary cancers, because in certain individuals, they inherit a defective allele of the RGB, and therefore, at the moment of conception, they have the following genotype.
Well, you'll say that's all, that's fine, because each of their cells has a wild-type copy of their RB gene, and a mutant, defective copy. And the wild-type copy, as you will correctly say, suffices to template, to orchestrate, to program, normal cell behavior.
Why do they then get retinoblastomas?
Because the surviving wild-type gene, or the gene copy, the wild-type allele, can be lost with a certain, finite probability per cell generation, through chromosomal mistakes, accidents, or through crossing-over.
And so roughly, one in ten to the sixth cells, one has an event, a genetic accident, which causes the accidental loss of the surviving RB allele, leaving, RB wild-type allele, leading now to a genotype that looks like this, homozygous mutant, or homozygous inactive, and now a rare cell in which that has happened, now begins to proliferate uncontrollably because of the absence of the RB break lining, which is normally required to control cell proliferation. By the way, I'll tell you in passing, without describing the gory details, that the RB protein works at the end, at the restriction point. We talked about the restriction point last time, you remember? The RB protein actually prevents the cell from advancing through the restriction point gate, unless it becomes inactivated, and then the cell can sail through into the rest of the cell cycle.
In cells that lack the RB protein, the guardian of the restriction point gate is no longer there, and therefore the gate is held open, and cells can sail all the way through G1, in an unimpeded fashion, without the RB protein standing at the restriction point gate and saying, advance no further, unless and until, certain conditions have been satisfied. And so we can begin to understand that the tumor suppressor gene, the RB gene, is able to act as a quality control, to ensure that cells don't inadvertently, inappropriately, pass through the restriction point gate into the rest of the cell cycle.
And by now, there are 40 or 50 different kinds of tumor suppressor genes that are found to be inactivated through various mechanisms, in human cancers. This was only the progenitor, the harbinger, of those. How many tumors does a child who's born like, this get in his eyes, or her eyes?
Well, it might get two or three or four, in both eyes, but that reflects the fact that there maybe a million or two million cells in each of the retina, which are susceptible to this loss of the surviving wild-type gene copy. Having heard all that, you will ask me, well why don't they get tumors all over the body, since it is the fact that the RB protein regulates the restriction point gate in all cells throughout the body?
So therefore, why isn't the child who's born constitutionally, whose genetic makeup is this, why isn't a child like this sensitive to developing tumors all over his or her body?
In fact, children who are born genetically with this genotype, get retinoblastoma's with high probability early in life, and as teenagers, they often come down with osteosarcomas, which are tumors of the bones. But otherwise, they don't get many kinds of cancer, and the answer to your question is, I haven't the vaguest idea. No one knows why loss of this critical gene that plays a key role in the biology, in the metabolism, of all cells throughout the body, can be lost to yield cancer in the eye and in the bone, whereas when the same gene, which must be lost elsewhere in other tissues in the body are lost, tumors do not arise. And on that puzzling note, I wish you a pleasant day, another happy Halloween, and see you on, oh yes, tomorrow is election day.
Don't forget to vote. And remember what the mayor of Boston once said, vote early and often.
Mutagens and carcinogens
A mutagen is a substance or agent that induces heritable change in cells or organisms. A carcinogen is a substance that induces unregulated growth processes in cells or tissues of multicellular animals, leading to cancer. Although mutagen and carcinogen are not synonymous terms, the ability of a substance to induce mutations and its ability to induce cancer are strongly correlated. Mutagenesis refers to processes that result in genetic change, and carcinogenesis (the processes of tumor development) may result from mutagenic events. See Mutation, Radiation biology
A mutation is any change in a cell or in an organism that is transmitted to subsequent generations. Mutations can occur spontaneously or be induced by chemical or physical agents. The cause of mutations is usually some form of damage to DNA or chromosomes that results in some change that can be seen or measured. However, damage can occur in a segment of DNA that is a noncoding region and thus will not result in a mutation. Mutations may or may not be harmful, depending upon which function is affected. They may occur in either somatic or germ cells. Mutations that occur in germ cells may be transmitted to subsequent generations, whereas mutations in somatic cells are generally of consequence only to the affected individual.
Not all heritable changes result from damage to DNA. For example, in growth and differentiation of normal cells, major changes in gene expression occur and are transmitted to progeny cells through changes in the signals that control genes that are transcribed into ribonucleic acid (RNA). It is possible that chemicals and radiation alter these processes as well. When such an effect is seen in newborns, it is called teratogenic and results in birth defects that are not transmitted to the next generation. However, if the change is transmissible to progeny, it is a mutation, even though it might have arisen from an effect on the way in which the gene is expressed. Thus, chemicals can have somatic effects involving genes regulating cell growth that could lead to the development of cancer, without damaging DNA.
Cancer arises because of the loss of growth control by dearrangement of regulatory signals. Included in the phenotypic consequences of mutations are alterations in gene regulation brought about by changes either in the regulatory region or in proteins involved with coordinated cellular functions. Altered proteins may exhibit novel interactions with target substrates and thereby lose the ability to provide a regulatory function for the cell or impose altered functions on associated molecules. Through such a complex series of molecular interactions, changes occur in the growth properties of normal cells leading to cancer cells that are not responsive to normal regulatory controls and can eventually give rise to a visible neoplasm or tumor. While mutagens can give rise to neoplasms by a process similar to that described above, not all mutagens induce cancer and not all mutational events result in tumors.
The identification of certain specific types of genes, termed oncogenes, that appear to be causally involved in the neoplastic process has helped to focus mechanistic studies on carcinogenesis. Oncogenes can be classified into a few functionally different groups, and specific mutations in some of the genes have been identified and are believed to be critical in tumorigenesis. Tumor suppressor genes or antioncogenes provide a normal regulatory function by mutation or other events, the loss of the function of these genes may release cells from normal growth-control processes, allowing them to begin the neoplastic process.
There are a number of methods and systems for identifying chemical mutagens. Mutations can be detected at a variety of genetic loci in very diverse organisms, including bacteria, insects, cultured mammalian cells, rodents, and humans. Spontaneous and induced mutations occur very infrequently, the estimated rate being less than 1 in 10,000 per gene per cell generation. This low mutation rate is probably the result of a combination of factors that include the relative inaccessibility of DNA to damaging agents and the ability of cellular processes to repair damage to DNA.
Factors that contribute to the difficulty in recognizing substances that may be carcinogenic to humans include the prevalence of cancer, the diversity of types of cancer, the generally late-life onset of most cancers, and the multifactorial nature of the disease process. Approximately 50 substances have been identified as causes of cancer in humans, but they probably account for only a small portion of the disease incidence. See Cancer (medicine), Human genetics, Mutation, Radiation biology
What is a Carcinogen
Any physical, chemical or biological substance, which can cause or promote cancer is referred to as a carcinogen. Five categories of cancer forming agents can be identified. They are the tobacco smoke, pathogens, radiation, environmental hazard, and the diet. Smokers and victim of secondhand smoke can easily be subjected to cancers. Smoking cause cancers in lungs, respiratory tract, and the esophagus. Smoking indirectly causes cancers in the stomach, kidney, and the liver. Air, water, and soil pollution also cause cancers in bladder and lungs. Other cancer forming agents and examples are shown in table 1.
What's the difference between a mutagen and a carcinogen?
I work with ethidium bromide in the lab, and was told that it was a mutagen by my professor. He said he's not sure why it's not considered a carcinogen, as cancers are caused my mutations, and the mutagen causes mutations. Can anyone clarify?
To adapt some biological terminology, a mutagen is classified based on its genotypic effects (does it cause mutations), while a carcinogen is classified based on its phenotypic effects (does it cause cancer). While many mutagens are indeed carcinogens, not all of them are. Without evidence clearly connecting exposure to a chemical and increased cancer rates, it cannot be properly called a carcinogen.
On the subject of ethidium bromide specifically, there isn't any conclusive evidence showing it to be a carcinogen, and even the evidence for mutagenicity is somewhat lackluster - the U.S. National Toxicology Program states that it's only been shown to induce mutations in Salmonella, and not in mice or rats. Furthermore, ethidium bromide is used in much higher concentrations as a trypanosomiasis treatment in cattle, with little evidence of ill effects.
The perceived dangers of ethidium bromide is a persistent myth in life sciences research. As a former bench scientist starting a career in environmental health & safety, many researchers are surprised when I tell them that most gels and solutions containing ethidium bromide can be disposed of as regular trash.
Just to be clear on this, have they tested it in multiple things and only found that it induces mutations in Salmonella, or have they only tested it in Salmonella? Also, did they test it to see if it's carcinogenic and not found the results to be statistically significant, or have they not tested it?
On the subject of ethidium bromide specifically, there isn't any conclusive evidence showing it to be a carcinogen, and even the evidence for mutagenicity is somewhat lackluster
Wew. Nice to read this. Dropped a few drops of EthBr on my underarm years and years ago. Have been watching them ever since for possible tumors. Plus of course have been testing myself regularly to see whether I developed new powers.
Am I right in that Mutegens are determined using the AMES test, and if a substances is AMES positive then it is classified as a mutagen?
( An AMES test is where a special strain of bacteria cannot survive if they do not mutate. So these bacteria and the substance to be tested are mixed, if the bacteria survive then the substance can mutate DNA.)
A mutagen is any factor that has the potential to cause mutations.
A carcinogen is a mutagen that has the potential to cause mutations in oncogenes, anti-oncogenes, apoptosis regulating genes, DNA reparation regulating genes and cellular senescence regulating genes. Basically, any gene involved with growth, differentiation and the regulation thereof.
The subset isn't sharp - in theory any mutagen with non-specific action can induce cancer. One would have to be looking at things specifically targeting certain parts of the DNA but not cancer-related genes in order to call it a mutagen but not a carcinogen. An example of this is viral gene therapy.
Hard to imagine that there are any small molecule mutagens in humans which are not also carcinogenic.
Any mutagen has the potential to cause cancer, when it comes down to it cancer is a game of chance in terms of if a mutation lands in a particular gene capable of starting the cancer process. The tag "carcinogen" is more of an industrial term to indictate the more potent mutagens that have the highest risk in handling. DNA mutation is fairly non-specific at the level of genes, as far as I'm aware theres no mutagen/carcinogen that specifically targets the keystone cancer-starting genes, p53 etc.
As any wet-lab researcher will know the danger of EtBr is really down to peoples opinions, particuarly the older generation have no problem swilling it as mouth-wash, and will actively encourage people to not wear gloves on the principle that there is "no hard evidence".
Personally I have always worn gloves with DNA gels, just because "why not". In my mind any DNA-binding compound, which I work with many as a microbiologist, just isn't worth the risk in handling without protection, as whether the evidence for it inducing cancer is significant or not, why take the risk?
A mutagen is a substance or agent that induces heritable change in cells or organisms. A carcinogen is a substance that induces unregulated growth processes in cells or tissues of multicellular animals, leading to the disease called cancer. Although mutagen and carcinogen are not synonymous terms, the ability of a substance to induce mutations and its ability to induce cancer are strongly correlated. Mutagenesis refers to processes that result in genetic change, and carcinogenesis (the processes of tumor development) may result from mutagenic events.
The top answer is good, but on a more basic level, a carcinogen is such due to its phenotypic effects, a mutagen is a mutagen based on its chemical genotype can effects. It's a subtle distinction, but makes sense if you walk through it.
Ethidium bromide can certainly intercolate between DNA bases, which can evidently cause mutation in salmonella (probably some other bacteria to). This is probably caused by polymerase screwing up somehow due to the bulge from the EtBr.
Now consider a cattle. Ethidium bromide can certainly still intercolate, but first it would have to penetrate the cell membrane (not by any means certain based on a glance at that molecule), it would have to cross the nuclear membrane, after that. I don't know if it would have any issue with the packaging of the DNA (chromatin etc.), but it very well could.
The most likely difference is that even if it intercolated into the genome, the very obvious bulge it would make would provide an easy target for the sophisticated proofreading apparatus present in cattle (or a human). Or maybe it is the other way, and the bulkier human polymerase apparatus would be unaffected by its presence.
Even though the chemical properties of the mutagen haven't changed, there are plenty of chemical and biochemical reasons it may be harmless. And ethidum bromide is pretty harmless, I believe that I would have to drink 10s-100s of thousands of gallons of my DNA gel solution to match a single dose of EtBr used as an anti-parasitic in cows.
Mutagens, teratogens and carcinogens
Gen means birth or origin, as in the book of Genesis, which explains the origin of the Earth “Muta” means change “terato” means monster and “carcino” means crab. Thus, all three “gens”-are physical or chemical agents that cause or originate malformations.
Mutagens cause changes (mutations) in the genetic material of cells. Teratogens cause irreversible, deleterious structural malformations in fetuses. Some congenital malformations are so severe they result in grossly deformed fetuses. Carcinogens cause cancerous tumors with a characteristically crablike appearance.
Mutagens, teratogens and carcinogens are similar in that each causes some form of mutation. Congenital malformations can be caused by mutations, which may occur in the parent germ cell (sperm or ovum), in the resulting embryo (mutagenic effect), or in some cells of a fetus after development has begun (teratogenic effect). Mutations in somatic (body) cells can cause certain cancers (carcinogenic effect). One hypothesis for determining the etiology of chemically induced cancer involves the concept of somatic mutation, which is based on the fact that several chemicals capable of causing cancer in animals also are capable of causing mutations in microorganisms.
Mutagens. The most significant mutagenic event is transmission of heritable effects through germ cells to the next generation. Germ cells are comprised of complex structures called chromosomes. Chromosomes are composed of molecules of deoxyribonucleic acid (DNA) and are contained in cell nuclei. A gene is the smallest unit of a germ cell considered to carry a genetic message one gene exists for each characteristic. Genes are linked together in long chains to form chromosomes.
When sufficient evidence establishes a causal connection between human exposure to a chemical and heritable genetic effects, the substance is classified as a mutagen. Mutations may occur either in somatic (body) cells or germ (reproductive) cells. Somatic mutations are inherited by other somatic cells formed from a changed cell, but they are not inherited by offspring of organisms in which a somatic mutation resides. Chemicals that can produce this type of mutation are referred to as “genotoxic.” Although these agents do not damage future generations, they may initiate a biochemical rampage in cells of an affected organism. The result is a cancerous growth.
Recent studies show chemicals can cause mutations by generating rapid cell division, or mitogenesis. “A dividing cell is much more at risk of mutating,” explains Bruce Ames, a research scientist at the University of California, Berkeley. “These mutations can transform normal cells into cancer cells.” Non-genotoxic, or epigenetic, chemicals generally cause mutations only when administered in enormous doses. The best example is saccharin.
Saccharin is a synthetic, non-caloric sweetener developed in the 1960s. Scientists administered saccharin to 200 mice for 13 months. The mice developed sarcomas and carcinomas. However, the dosage given the test animals is equivalent to the amount of saccharin ingested by a human consuming about 800 cans of saccharin-sweetened soda a day for life.
When given to a test animal in large enough quantities, genotoxic chemicals, such as formaldehyde, and non-genotoxic chemicals, such as saccharin, can trigger cell mutations. These chemicals may pose no risk in lower doses. This dose-response relationship determines a substance’s relative toxicity. This premise is central to the study of toxicology.
Mutations are not rare. Everyone normally carries some mutated cells. The causes, nature and significance of such mutations are not well understood and open to speculation. All organisms have certain biochemical repair mechanisms to protect against mutations. The process is complex, but, in the simplest terms, errors in the genetic code (DNA) are identified and corrected by the repair systems. The fact that everyone carries some mutated cells indicates such systems are not fail-safe.
Teratogens. Teratogens are agents that cause abnormalities in developing organisms in the womb. When a fetal abnormality is manifested in progeny, the infant is born with a congenital defect, anomaly or malformation. Congenital abnormalities also may result from other factors. Human congenital abnormalities may stem from diseases mothers may have during the first trimester of pregnancy, particularly such viral diseases as German measles (rubella).
Hereditary abnormalities result from mutation and are expressed in the offspring of those who carry the associated train in their genes. Such nutritional factors as vitamin deficiencies or excesses also can interfere with normal fetal development, and maternal age at the time of conception is related to congenital anomalies. Finally, such physical factors as ionizing radiation also may cause malformations. X-rays, for example, are potent mutagens and teratogens.
For a teratogenic agent to produce a congenital abnormality, the agent must contact the developing organism. In the case of ionizing radiation, an embryo or fetus must be in the path of radiation. On the other hand, viruses or chemicals must be able to cross the placental barrier. A teratogen causes a malformation when it reaches a fetus during the critical phase of gestation when organs are developing. In humans, this stage occurs during the first trimester of pregnancy. The type of abnormality caused depends on which organ system is most rapidly developing at the time of exposure.
Few chemicals are known to be human teratogens. Among these are certain anti-cancer drugs and thalidomide, a drug used to combat nausea during pregnancy. Thalidomide causes an aberration by interfering with the fetal development of limbs, resulting in the hands being directly appended to the body at the shoulder.
Carcinogens. Carcinogens can cause malignant tumors. However, a distinction between benign and malignant tumors is not always possible. Nevertheless, the mark of carcinogenicity is an increase in malignant tumors. For a chemical to be considered a human carcinogen under expected conditions of exposure, it also must be genotoxic.
Studies show that up to 90 percent of all mutagens are carcinogens. The theory that mutation sets the stage for cancer development is based on the fact that many mutagenic physical and chemical agents also are carcinogenic. Mutations giving rise to cancer usually occur in somatic cells. If a change caused by such mutations is minor, it probably never will be discovered. However, if there is a major change, the cell may die.
If a mutated cells does not die but divides, and other similarly mutated cells are present, the cells may group together to form a benign or malignant tumor. Cancer experts generally agree that a minimum number of cells in close proximity must undergo mutation before a tumor can form.
Epigenetic chemicals, a second major category of carcinogens, may increase the mutation rate by some mechanism other than genetic-tissue or cellular damage. Saccharin is one example.
Mutagenic studies. Mutagens, teratogens and carcinogens are agents that cause chronic toxicity, the ability to cause illness or death after related exposures to low doses or after a latency period. For example, asbestos may cause mesothelioma, lung cancer or asbestosis but these diseases typically are not manifested for 20 or more years after initial exposure and may never occur.
Because no single test can adequately predict mutagenic risk for humans, batteries of tests are run to evaluate the potential mutagenicity of chemicals. Mutagenicity studies employ a variety of other mammals, as well as animal tissues, insects or other lower animal forms, plants or microorganisms.
The most widely used mutagenicity test for preliminary screening of chemicals is the Ames test, named for its developer, Brice Ames. Used in more than 3,000 laboratories worldwide, it involves exposing bacterial cultures to suspect chemicals, then checking for mutations. More potent mutagens cause a higher incidence of change in the genetic material. The Ames test has unmasked a variety of potential carcinogens. However, relatively little is yet known about the “gen family.”
Aside from exhaust, polluted outdoor air contains dust and traces of metals and solvents that can lead to cancer. Experts know this from looking at data from over 1.2 million people across the U.S.
You can't avoid pollution, but you can do your part to avoid contributing to it by walking or biking instead of driving. Follow local public health warnings and stay indoors on days when air quality is bad.
American Cancer Society: "Known and Probable Human Carcinogens," "Harmful Chemicals in Tobacco Products," "Diesel Exhaust and Cancer," "How to Test Your Home for Radon," "Asbestos and Cancer Risk," "World Health Organization Says Processed Meat Causes Cancer," "Talcum Powder and Cancer," "Does UV Radiation Cause Cancer?" "Can I Avoid Exposure to UV Radiation?" "Menopausal Hormone Therapy and Cancer Risk," "World Health Organization: Outdoor Air Pollution Causes Cancer," "Cancer Prevention Study II (CPS-II)."
Cancer Research UK: "How Smoking Causes Cancer," "How Air Pollution Can Cause Cancer."
Environmental Protection Agency: "Health Risk of Radon," "How do I get a radon test kit? Are they free?"
National Cancer Institute, "Acrylamide and Cancer Risk," "Alcohol and Cancer Risk," "Formaldehyde and Cancer Risk."
FDA: "Acrylamide: Information on Diet, Food Storage and Food Preparation."
Cancer Council: "How ultraviolet (UV) radiation causes skin cancer."
Reviews on Environmental Health: "Skin cancer: role of ultraviolet radiation in carcinogenesis."
Breastcancer.org, "Do Hormonal Contraceptives Increase Breast Cancer Risk?"
North American Menopause Society: "Hormone Therapy: Benefits and Risks."
Fred Hutchinson Cancer Research Center: "Links between air pollution and cancer risk."
Literature Review-Compare And Contrast A Carcinogen That Is A Mutagen To A Carcinogen That Is Not A Mutagen
This unit&rsquos assigned reading focuses on chemical-induced mutagens. As you are aware from the reading, not all carcinogens are mutagens. For this assignment, compare and contrast a carcinogen that is a mutagen to a carcinogen that is not a mutagen. Find at least four peer-reviewed journal articles published within the last 7 years that discuss the carcinogens and the cancer that each causes.
Compare the means of exposure of each chemical and the type of cancer each causes. Be sure to integrate the perspective and information gathered from each article into a discussion in your own words.
Your literature review must include the following components:
- an introduction of your topic of choice (include some background information on the origins of exposure and cancer),
- the methods used to search for the articles,
- the results of the articles,
- a discussion and conclusion with your own opinion, and
- APA references and in-text citations for the article.
The literature review must be four pages in length and follow APA formatting.
The first mutagens to be identified were carcinogens, substances that were shown to be linked to cancer. Tumors were described more than 2,000 years before the discovery of chromosomes and DNA in 500 B.C., the Greek physician Hippocrates named tumors resembling a crab karkinos (from which the word "cancer" is derived via Latin), meaning crab.  In 1567, Swiss physician Paracelsus suggested that an unidentified substance in mined ore (identified as radon gas in modern times) caused a wasting disease in miners,  and in England, in 1761, John Hill made the first direct link of cancer to chemical substances by noting that excessive use of snuff may cause nasal cancer.  In 1775, Sir Percivall Pott wrote a paper on the high incidence of scrotal cancer in chimney sweeps, and suggested chimney soot as the cause of scrotal cancer.  In 1915, Yamagawa and Ichikawa showed that repeated application of coal tar to rabbit's ears produced malignant cancer.  Subsequently, in the 1930s the carcinogen component in coal tar was identified as a polyaromatic hydrocarbon (PAH), benzo[a]pyrene.   Polyaromatic hydrocarbons are also present in soot, which was suggested to be a causative agent of cancer over 150 years earlier.
The association of exposure to radiation and cancer had been observed as early as 1902, six years after the discovery of X-ray by Wilhelm Röntgen and radioactivity by Henri Becquerel.  Georgii Nadson and German Filippov were the first who created fungi mutants under ionizing radiation in 1925.   The mutagenic property of mutagens was first demonstrated in 1927, when Hermann Muller discovered that x-rays can cause genetic mutations in fruit flies, producing phenotypic mutants as well as observable changes to the chromosomes,   visible due to the presence of enlarged "polytene" chromosomes in fruit fly salivary glands.  His collaborator Edgar Altenburg also demonstrated the mutational effect of UV radiation in 1928.  Muller went on to use x-rays to create Drosophila mutants that he used in his studies of genetics.  He also found that X-rays not only mutate genes in fruit flies,  but also have effects on the genetic makeup of humans.  [ better source needed ] Similar work by Lewis Stadler also showed the mutational effect of X-rays on barley in 1928,  and ultraviolet (UV) radiation on maize in 1936.  The effect of sunlight had previously been noted in the nineteenth century where rural outdoor workers and sailors were found to be more prone to skin cancer. 
Chemical mutagens were not demonstrated to cause mutation until the 1940s, when Charlotte Auerbach and J. M. Robson found that mustard gas can cause mutations in fruit flies.  A large number of chemical mutagens have since been identified, especially after the development of the Ames test in the 1970s by Bruce Ames that screens for mutagens and allows for preliminary identification of carcinogens.   Early studies by Ames showed around 90% of known carcinogens can be identified in Ames test as mutagenic (later studies however gave lower figures),    and
80% of the mutagens identified through Ames test may also be carcinogens.   Mutagens are not necessarily carcinogens, and vice versa. Sodium azide for example may be mutagenic (and highly toxic), but it has not been shown to be carcinogenic. 
Mutagens can cause changes to the DNA and are therefore genotoxic. They can affect the transcription and replication of the DNA, which in severe cases can lead to cell death. The mutagen produces mutations in the DNA, and deleterious mutation can result in aberrant, impaired or loss of function for a particular gene, and accumulation of mutations may lead to cancer. Mutagens may therefore be also carcinogens. However, some mutagens exert their mutagenic effect through their metabolites, and therefore whether such mutagens actually become carcinogenic may be dependent on the metabolic processes of an organism, and a compound shown to be mutagenic in one organism may not necessarily be carcinogenic in another. 
Different mutagens act on the DNA differently. Powerful mutagens may result in chromosomal instability,  causing chromosomal breakages and rearrangement of the chromosomes such as translocation, deletion, and inversion. Such mutagens are called clastogens.
Mutagens may also modify the DNA sequence the changes in nucleic acid sequences by mutations include substitution of nucleotide base-pairs and insertions and deletions of one or more nucleotides in DNA sequences. Although some of these mutations are lethal or cause serious disease, many have minor effects as they do not result in residue changes that have significant effect on the structure and function of the proteins. Many mutations are silent mutations, causing no visible effects at all, either because they occur in non-coding or non-functional sequences, or they do not change the amino-acid sequence due to the redundancy of codons.
Some mutagens can cause aneuploidy and change the number of chromosomes in the cell. They are known as aneuploidogens. 
In Ames test, where the varying concentrations of the chemical are used in the test, the dose response curve obtained is nearly always linear, suggesting that there may be no threshold for mutagenesis. Similar results are also obtained in studies with radiations, indicating that there may be no safe threshold for mutagens. However, the no-threshold model is disputed with some arguing for a dose rate dependent threshold for mutagenesis.   Some have proposed that low level of some mutagens may stimulate the DNA repair processes and therefore may not necessarily be harmful. More recent approaches with sensitive analytical methods have shown that there may be non-linear or bilinear dose-responses for genotoxic effects, and that the activation of DNA repair pathways can prevent the occurrence of mutation arising from a low dose of mutagen. 
Mutagens may be of physical, chemical or biological origin. They may act directly on the DNA, causing direct damage to the DNA, and most often result in replication error. Some however may act on the replication mechanism and chromosomal partition. Many mutagens are not mutagenic by themselves, but can form mutagenic metabolites through cellular processes, for example through the activity of the cytochrome P450 system and other oxygenases such as cyclooxygenase.  Such mutagens are called promutagens.
Physical mutagens Edit
- such as X-rays, gamma rays and alpha particles cause DNA breakage and other damages. The most common lab sources include cobalt-60 and cesium-137. radiations with wavelength above 260 nm are absorbed strongly by bases, producing pyrimidine dimers, which can cause error in replication if left uncorrected. , such as 14 C in DNA which decays into nitrogen.
DNA reactive chemicals Edit
A large number of chemicals may interact directly with DNA. However, many such as PAHs, aromatic amines, benzene are not necessarily mutagenic by themselves, but through metabolic processes in cells they produce mutagenic compounds.
- (ROS) – These may be superoxide, hydroxyl radicals and hydrogen peroxide, and large number of these highly reactive species are generated by normal cellular processes, for example as a by-products of mitochondrial electron transport, or lipid peroxidation. As an example of the latter, 15-hydroperoxyicosatetraenocic acid, a natural product of cellular cyclooxygenases and lipoxygenases, breaks down to form 4-hydroxy-2(E)-nonenal, 4-hydroperoxy-2(E)-nonenal, 4-oxo-2(E)-nonenal, and cis-4,5-epoxy-2(E)-decanal these bifunctional electophils are mutagenic in mammalian cells and may contribute to the development and/or progression of human cancers (see 15-Hydroxyicosatetraenoic acid).  A number of mutagens may also generate these ROS. These ROS may result in the production of many base adducts, as well as DNA strand breaks and crosslinks. agents, for example nitrous acid which can cause transition mutations by converting cytosine to uracil. (PAH), when activated to diol-epoxides can bind to DNA and form adducts. agents such as ethylnitrosourea. The compounds transfer methyl or ethyl group to bases or the backbone phosphate groups. Guanine when alkylated may be mispaired with thymine. Some may cause DNA crosslinking and breakages. Nitrosamines are an important group of mutagens found in tobacco, and may also be formed in smoked meats and fish via the interaction of amines in food with nitrites added as preservatives. Other alkylating agents include mustard gas and vinyl chloride. and amides have been associated with carcinogenesis since 1895 when German physician Ludwig Rehn observed high incidence of bladder cancer among workers in German synthetic aromatic amine dye industry. 2-Acetylaminofluorene, originally used as a pesticide but may also be found in cooked meat, may cause cancer of the bladder, liver, ear, intestine, thyroid and breast. from plants, such as those from Vinca species,  may be converted by metabolic processes into the active mutagen or carcinogen. and some compounds that contain bromine in their chemical structure.  , an azide salt that is a common reagent in organic synthesis and a component in many car airbag systems combined with ultraviolet radiation causes DNA cross-linking and hence chromosome breakage. , an industrial solvent and precursor in the production of drugs, plastics, synthetic rubber and dyes.
Base analogs Edit
Intercalating agents Edit
- , such as ethidium bromide and proflavine, are molecules that may insert between bases in DNA, causing frameshift mutation during replication. Some such as daunorubicin may block transcription and replication, making them highly toxic to proliferating cells.
Many metals, such as arsenic, cadmium, chromium, nickel and their compounds may be mutagenic, but they may act, however, via a number of different mechanisms.  Arsenic, chromium, iron, and nickel may be associated with the production of ROS, and some of these may also alter the fidelity of DNA replication. Nickel may also be linked to DNA hypermethylation and histone deacetylation, while some metals such as cobalt, arsenic, nickel and cadmium may also affect DNA repair processes such as DNA mismatch repair, and base and nucleotide excision repair. 
Biological agents Edit
- , a section of DNA that undergoes autonomous fragment relocation/multiplication. Its insertion into chromosomal DNA disrupts functional elements of the genes. – Virus DNA may be inserted into the genome and disrupts genetic function. Infectious agents have been suggested to cause cancer as early as 1908 by Vilhelm Ellermann and Oluf Bang,  and 1911 by Peyton Rous who discovered the Rous sarcoma virus.  – some bacteria such as Helicobacter pylori cause inflammation during which oxidative species are produced, causing DNA damage and reducing efficiency of DNA repair systems, thereby increasing mutation.
Antioxidants are an important group of anticarcinogenic compounds that may help remove ROS or potentially harmful chemicals. These may be found naturally in fruits and vegetables.  Examples of antioxidants are vitamin A and its carotenoid precursors, vitamin C, vitamin E, polyphenols, and various other compounds. β-Carotene is the red-orange colored compounds found in vegetables like carrots and tomatoes. Vitamin C may prevent some cancers by inhibiting the formation of mutagenic N-nitroso compounds (nitrosamine). Flavonoids, such as EGCG in green tea, have also been shown to be effective antioxidants and may have anti-cancer properties. Epidemiological studies indicate that a diet rich in fruits and vegetables is associated with lower incidence of some cancers and longer life expectancy,  however, the effectiveness of antioxidant supplements in cancer prevention in general is still the subject of some debate.  
Other chemicals may reduce mutagenesis or prevent cancer via other mechanisms, although for some the precise mechanism for their protective property may not be certain. Selenium, which is present as a micronutrient in vegetables, is a component of important antioxidant enzymes such as gluthathione peroxidase. Many phytonutrients may counter the effect of mutagens for example, sulforaphane in vegetables such as broccoli has been shown to be protective against prostate cancer.  Others that may be effective against cancer include indole-3-carbinol from cruciferous vegetables and resveratrol from red wine. 
An effective precautionary measure an individual can undertake to protect themselves is by limiting exposure to mutagens such as UV radiations and tobacco smoke. In Australia, where people with pale skin are often exposed to strong sunlight, melanoma is the most common cancer diagnosed in people aged 15–44 years.  
In 1981, human epidemiological analysis by Richard Doll and Richard Peto indicated that smoking caused 30% of cancers in the US.  Diet is also thought to cause a significant number of cancer, and it has been estimated that around 32% of cancer deaths may be avoidable by modification to the diet.  Mutagens identified in food include mycotoxins from food contaminated with fungal growths, such as aflatoxins which may be present in contaminated peanuts and corn heterocyclic amines generated in meat when cooked at high temperature PAHs in charred meat and smoked fish, as well as in oils, fats, bread, and cereal  and nitrosamines generated from nitrites used as food preservatives in cured meat such as bacon (ascobate, which is added to cured meat, however, reduces nitrosamine formation).  Overly-browned starchy food such as bread, biscuits and potatoes can generate acrylamide, a chemical shown to cause cancer in animal studies.   Excessive alcohol consumption has also been linked to cancer the possible mechanisms for its carcinogenicity include formation of the possible mutagen acetaldehyde, and the induction of the cytochrome P450 system which is known to produce mutagenic compounds from promutagens. 
For certain mutagens, such as dangerous chemicals and radioactive materials, as well as infectious agents known to cause cancer, government legislations and regulatory bodies are necessary for their control. 
Many different systems for detecting mutagen have been developed.   Animal systems may more accurately reflect the metabolism of human, however, they are expensive and time-consuming (may take around three years to complete), they are therefore not used as a first screen for mutagenicity or carcinogenicity.
- Ames test – This is the most commonly used test, and Salmonella typhimurium strains deficient in histidine biosynthesis are used in this test. The test checks for mutants that can revert to wild-type. It is an easy, inexpensive and convenient initial screen for mutagens.
- Resistance to 8-azaguanine in S. typhimurium – Similar to Ames test, but instead of reverse mutation, it checks for forward mutation that confer resistance to 8-Azaguanine in a histidine revertant strain.
- Escherichia coli systems – Both forward and reverse mutation detection system have been modified for use in E. coli. Tryptophan-deficient mutant is used for the reverse mutation, while galactose utility or resistance to 5-methyltryptophan may be used for forward mutation.
- DNA repair – E. coli and Bacillus subtilis strains deficient in DNA repair may be used to detect mutagens by their effect on the growth of these cells through DNA damage.
Systems similar to Ames test have been developed in yeast. Saccharomyces cerevisiae is generally used. These systems can check for forward and reverse mutations, as well as recombinant events.
Sex-Linked Recessive Lethal Test – Males from a strain with yellow bodies are used in this test. The gene for the yellow body lies on the X-chromosome. The fruit flies are fed on a diet of test chemical, and progenies are separated by sex. The surviving males are crossed with the females of the same generation, and if no males with yellow bodies are detected in the second generation, it would indicate a lethal mutation on the X-chromosome has occurred.
Plant assays Edit
Plants such as Zea mays, Arabidopsis thaliana and Tradescantia have been used in various test assays for mutagenecity of chemicals.
Cell culture assay Edit
Mammalian cell lines such as Chinese hamster V79 cells, Chinese hamster ovary (CHO) cells or mouse lymphoma cells may be used to test for mutagenesis. Such systems include the HPRT assay for resistance to 8-azaguanine or 6-thioguanine, and ouabain-resistance (OUA) assay.
Rat primary hepatocytes may also be used to measure DNA repair following DNA damage. Mutagens may stimulate unscheduled DNA synthesis that results in more stained nuclear material in cells following exposure to mutagens.
Chromosome check systems Edit
These systems check for large scale changes to the chromosomes and may be used with cell culture or in animal test. The chromosomes are stained and observed for any changes. Sister chromatid exchange is a symmetrical exchange of chromosome material between sister chromatids and may be correlated to the mutagenic or carcinogenic potential of a chemical. In micronucleus Test, cells are examined for micronuclei, which are fragments or chromosomes left behind at anaphase, and is therefore a test for clastogenic agents that cause chromosome breakages. Other tests may check for various chromosomal aberrations such as chromatid and chromosomal gaps and deletions, translocations, and ploidy.
Animal test systems Edit
Rodents are usually used in animal test. The chemicals under test are usually administered in the food and in the drinking water, but sometimes by dermal application, by gavage, or by inhalation, and carried out over the major part of the life span for rodents. In tests that check for carcinogens, maximum tolerated dosage is first determined, then a range of doses are given to around 50 animals throughout the notional lifespan of the animal of two years. After death the animals are examined for sign of tumours. Differences in metabolism between rat and human however means that human may not respond in exactly the same way to mutagen, and dosages that produce tumours on the animal test may also be unreasonably high for a human, i.e. the equivalent amount required to produce tumours in human may far exceed what a person might encounter in real life.
Mice with recessive mutations for a visible phenotype may also be used to check for mutagens. Females with recessive mutation crossed with wild-type males would yield the same phenotype as the wild-type, and any observable change to the phenotype would indicate that a mutation induced by the mutagen has occurred.
Mice may also be used for dominant lethal assays where early embryonic deaths are monitored. Male mice are treated with chemicals under test, mated with females, and the females are then sacrificed before parturition and early fetal deaths are counted in the uterine horns.
Transgenic mouse assay using a mouse strain infected with a viral shuttle vector is another method for testing mutagens. Animals are first treated with suspected mutagen, the mouse DNA is then isolated and the phage segment recovered and used to infect E. coli. Using similar method as the blue-white screen, the plaque formed with DNA containing mutation are white, while those without are blue.
Many mutagens are highly toxic to proliferating cells, and they are often used to destroy cancer cells. Alkylating agents such as cyclophosphamide and cisplatin, as well as intercalating agent such as daunorubicin and doxorubicin may be used in chemotherapy. However, due to their effect on other cells which are also rapidly dividing, they may have side effects such as hair loss and nausea. Research on better targeted therapies may reduce such side-effects. Ionizing radiations are used in radiation therapy.
In science fiction, mutagens are often represented as substances that are capable of completely changing the form of the recipient or granting them superpowers. Powerful radiations are the agents of mutation for the superheroes in Marvel Comics's Fantastic Four, Daredevil, and Hulk, while in the Teenage Mutant Ninja Turtles franchise the mutagen is a chemical agent also called "ooze", and for Inhumans the mutagen is the Terrigen Mist. Mutagens are also featured in video games such as Cyberia, The Witcher, Metroid Prime: Trilogy, Resistance: Fall of Man, Resident Evil, Infamous, Freedom Force, Command & Conquer, Gears of War 3, StarCraft, BioShock, Fallout, and Maneater. In the "nuclear monster" films of the 1950s, nuclear radiation mutates humans and common insects often to enormous size and aggression these films include Godzilla, Them!, Attack of the 50 Foot Woman, Tarantula!, and The Amazing Colossal Man.
Are all mutagens carcinogens? - Biology
A mutation is a change that occurs in a DNA sequence, either due to mistakes when the DNA is copied or as the result of environmental factors it can occur during DNA replication if errors are made and not corrected in time.
Mutations contribute to genetic variation within species, and can also be inherited, particularly if they have a positive effect. However, a mutation can also disrupt regular gene activity and cause diseases, like cancer. Cancer is the most common human genetic disease it is caused by mutations occurring in several growth-controlling genes. Sometimes faulty, cancer-causing genes can exist from birth, increasing a person’s chance of getting cancer.
Errors during DNA replication are not the only reason why mutations arise in DNA. Mutations, variations in the nucleotide sequence of a genome, can also occur because of damage to DNA. Such mutations may be of nine types:
- Random mutation occurs when there are accidental changes in the DNA sequence that are due to radiation, chemicals, replication error, etc.
- Translation and transcription errors cause the expression of a mutant phenotype.
- Base substitution is a mutation involving a DNA base (ATGC) changing to a different base.
- Inversion is a type of mutation where a stretch of DNA (a segment of a chromosome) breaks off, then reattaches in the opposite orientation.
- Addition, happens when an extra DNA base is added/inserted into the DNA sequence.
- Deletion is a type of mutation when a DNA base is taken out of the DNA sequence.
- Translocation mutation occurs when a stretch of DNA (a segment of a chromosome) breaks off, then reattaches somewhere else.
- Mispairing is a type of mutation that mispairs the DNA such that A does not pair with T or G with C.
Mutations can also be classified as harmful or beneficial. A harmful or deleterious mutation decreases the fitness of the organism. One example is a mutation that causes an organism to be sterile. Common mutations lead to changes in the triplet base pair code which means the codons of the mRNA do not match up to the anticodons of the tRNA this results in the incorrect translation and incorrect amino acid structure. Often this will result in misfolded proteins and inactive enzymes and hormones.
A favourable or advantageous mutation increases the fitness of the organism. For instance, the mutation that causes flies to become wingless is beneficial in a very windy environment.
Mutations are often caused by chemicals, radiation or dangerous substances. These are known as mutagens, which can be defined as an agent which causes mutations in the DNA of the cell. Carcinogens are those agents that lead to cancer, i.e. converts a normal cell to cancerous cell. Mutagens are often also carcinogens, agents that cause cancer. However, whereas nearly all carcinogens are mutagenic, not all mutagens are necessarily carcinogens.
Mutations that cause Crohn’s Disease
MCAT Official Prep (AAMC)
Biology Question Pack, Vol. 1 Passage 9 Question 59
Biology Question Pack, Vol 2. Passage 16 Question 104
Biology Question Pack, Vol 2. Passage 16 Question 106
Sample Test B/B Section Passage 2 Question 9
Sample Test B/B Section Passage 4 Question 20
Sample Test B/B Section Passage 10 Question 53
Practice Exam 1 B/B Passage 1 Question 3
• Mutation can occur during DNA replication if errors are made and not corrected in time.
• Most mistakes are corrected, but if they are not, they may result in a mutation defined as a permanent change in the DNA sequence.
• Mutations can be of many types, such as random mutation, translation error, transcription error, base substitution, inversion, addition, deletion, addition/insertion, deletion, translocation, and mispairing.
• Mutations can be classified as deleterious or advantages which decreases or increases the fitness of the organism, respectively.
• Inborn errors of metabolism are rare genetic (inherited) disorders in which the body cannot properly turn food into energy.
• Mutations often lead to the misfolding of proteins as the amino acid sequence is different.
• Almost all carcinogens are mutagens, but not all mutagens are carcinogens.
DNA base : a unit of the DNA AGTC adenine (A), guanine (G), thymine (T), and cytosine (C)
Mutagens : anything that causes a mutation
Carcinogens: any substance or radiation that promotes the formation of cancer
Species: a group of living organisms consisting of similar individuals capable of exchanging genes or interbreeding.
Mutation: the changing of the structure of a gene, resulting in a variant form that may be transmitted to subsequent generations, caused by the alteration of DNA
Deleterious mutation: decreases the fitness of the organism
Advantageous mutation: increases the fitness of the organism.
Gene: A section of DNA that codes for a characteristic
DNA replication: is the process by which DNA makes a copy of itself during cell division