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13.3: Mutagens and Carcinogens - Biology

13.3: Mutagens and Carcinogens - Biology


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A carcinogen is any agent that directly increases the incidence of cancer. Carcinogens that act as mutagens may be biological, physical, or chemical in nature, although the term is most often used in relation to chemical substances.

Human Papilloma Virus (HPV, Figure (PageIndex{4})) is an example of a biological carcinogen. Almost all cervical cancers begin with infection by HPV, which contains genes that disrupt the normal pattern of cell division within the host cell. Any gene that leads to an uncontrolled increase in cell division is called an oncogene. The HPV E6 and E7 genes are considered oncogenes because they inhibit the host cell’s natural tumor suppressing proteins (include p53, described below). The product of the E5 gene mimics the host’s own signals for cell division, and these and other viral gene products may contribute to dysplasia, which is detected during a Pap smear (Figure (PageIndex{5})). Detection of abnormal cell morphology in a Pap smear is not necessarily evidence of cancer. It must be emphasized again that cells have many regulatory mechanisms to limit division and growth, and for cancer to occur, each of these mechanisms must be disrupted. This is one reason why only a minority of individuals with HPV infections ultimately develop cancer. Although most HPV-related cancers are cervical, HPV infection can also lead to cancer in other tissues, in both women and men.

Figure (PageIndex{4}): Electron micrograph of HPV.(Wikipedia-Unknown-PD)

Figure (PageIndex{5}): Dysplastic (left) and normal (right) cells from a Pap smear.(Flickr-Ed Uthman-CC:AS)

Radiation is a well-known physical carcinogen, because of its potential to induce DNA damage within the body. The most damaging type of radiation is ionizing, meaning waves or particles with sufficient energy to strip electrons from the molecules they encounter, including DNA or molecules that can subsequently react with DNA. Ionizing radiation, which includes x-rays, gamma rays, and some wavelengths of ultraviolet rays, is distinct from the non-ionizing radiation of microwave ovens, cell phones, and radios. As with other carcinogens, mutation of multiple, independent genes that normally regulate cell division is required before cancer develops.

Chemical carcinogens (Table (PageIndex{2})) can be either natural or synthetic compounds that, based on animal feeding trials or epidemiological (i.e. human population) studies, increase the incidence of cancer. The definition of a chemical as a carcinogen is problematic for several reasons. Some chemicals become carcinogenic only after they are metabolized into another compound in the body; not all species or individuals may metabolize chemicals in the same way. Also, the carcinogenic properties of a compound are usually dependent on its dose. It can be difficult to define a relevant dose for both lab animals and humans. Nevertheless, when a correlation between cancer incidence and chemical exposure is observed, it is usually possible to find ways to reduce exposure to that chemical.

Table (PageIndex{2}): Some classes of chemical carcinogens (Pecorino 2008)

1. PAHs (polycyclic aromatic hydrocarbons)

e.g. benzo[a]pyrene and several other components of the smoke of cigarettes, wood, and fossil fuels

2. Aromatic amines

e.g. formed in food when meat (including fish, poultry) are cooked at high temperature

3. Nitrosamines and nitrosamides

e.g. found in tobacco and in some smoked meat and fish

4. Azo dyes

e.g. various dyes and pigments used in textiles, leather, paints.

5. Carbamates

e.g. ethyl carbamate (urethane) found in some distilled beverages and fermented foods

6. Halogenated compounds

e.g. pentachlorophenol used in some wood preservatives and pesticides.

7. Inorganic compounds

e.g. asbestos; may induce chronic inflammation and reactive oxygen species

8. Miscellaneous compounds

e.g. alkylating agents, phenolics


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 Mutagen

A mutagen is an agent, either a chemical substance or radiation, which can cause mutations. That means mutations cause changes in the genetic information of an organism. Mutations may also arise by the errors in DNA replication. These type of mutations are called spontaneous mutations. Many of the mutations harm cells, causing diseases and cancers. Since mutagens modify the DNA sequence, they may cause nucleotide substitutions, insertions, deletions as well as chromosomal instability such as translocations and inversions. The mutagens that cause chromosomal instability are called clastogens. Some mutagens can change the number of chromosomes in a cell.

Figure 1: Mutation

Physical substances such as radioactive elements, X-rays, and ultraviolet radiation can cause mutations. The chemicals that interact with DNA such as reactive oxygen species, deaminating agents, sodium azide, and benzene also cause mutations. Intercalating agents such as ethidium bromide and metals such as nickel, arsenic, cadmium, and chromium are also mutagenic. Biological agents such as transposon, virus, and bacteria also cause mutations. A mutation caused by UV is shown in figure 1.


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Mutagens and Carcinogens

Download the video from iTunes U or the Internet Archive.

So, we have another kind of very interesting piece of the course right now. We're going to continue to talk about genetics, except now we're going to talk about the genetics of diploid organisms, which apart from bacteria, most of the organisms including us are diploid. They have more than one copy of each chromosome, and so we'll go through a segment on this, and also talk about mitosis and meiosis, the central processes of cell division and the segregation of genetic material that underlie life as we know it.

And then, were going to charge into a session of recombinant DNA, and some of these technologies, PCR and various things that you see in the newspapers all the time. And then, I'll finish up with the session on the immune system, which a few of you thought was surprising that bacteria recombines. I'll tell you in that system it will feel like science fiction relative to what I've told you up to now. It's an absolutely amazing system.

So, we are going to start today with genetics of diploid organisms.

So I'm going to go back to how this was first understood.

And most of you have probably heard of Gregor Mendel, who discovered this, and surely some fraction of you have run into an exposure to this topic before. But in keeping with what I'm trying to do in this course, could you guys watch out there?

I think I'm just going to unplug, yeah, it's OK. I think I'm just going to unplug it for just a minute here. You've probably heard of Mendel. Some of you have seen these different squares.

You might have memorized it from a textbook or something like that.

I'm going to try and see if we can go through this material up another level of sophistication because, again, and I'm saying, science didn't just come down from on high and end up with facts in a textbook. What's in a textbook is somebody's effort to take a current state of understanding which is based on experimentation and come up with models. And what you're seeing in the textbooks are the models such as they were as of the time the textbook was submitted for publication. Sometimes they change even before the textbooks get out. But anyway, it's a process.

Mendel was one of the starting people who started this process, really a key figure, and a guy with an amazing intellect.

But before we start in, I just want to show you a couple of pictures because these kind of knocked me over when I saw them.

I don't know what kind of image you have of Mendel.

You probably know he was a monk, and he did something with peas, and he figured out this stuff about genetics. And most people probably carry around an image probably somewhat like this sort of romanticized drawing. He was a monk all right, but it was at an Augustine monastery in Bruno in Austria that was a very major intellectual center. They even published a scientific journal. They sent Mendel off to Vienna to go to university.

While he was there, he studied physics, math, as well as botany. So he had, in many ways, a background that is very similar to you guys, very heavy on the quantitative physical science, mathematical sort of background.

And then he went on to do some experiments in biology.

And I think you maybe can get a sense of this.

You can see a picture of what Mendel actually looked like.

Here's one picture of him. But the one that really blew me away, I have a picture of the monks. Just think of what ever image you had of the monks that Mendel was at.

Well there's a picture of them. To me, they look nothing so much like a group of university presidents or something sitting around for a portrait. And he traveled very widely.

Here he was on his way to London here. Here is a picture of him with a group of people on his way to, I think he was in Paris on his way to London. So this wasn't a little isolated monk in a garden who stumbled across stuff. He was a rather sophisticated guy going after some interesting problems.

And this was the garden in which he did his experiments.

Here's a picture of it. So this was a straightforward experimental setup for these really amazing things he did.

So, with that kind of background, Mendel was interested in a problem of inheritance. And people have been aware that traits were inherited. That was the whole principle of domesticating animals and domesticating crops, that if you took parents with certain characteristics and crossed them together, the offspring then had the traits that were associated with the parents. And so people have able to get better domesticated animals or better domesticated crops.

But up until then, this mixing was thought of sort of like blending liquids, stir together some green and red, and a little this and that. And it all stirred together.

And as you'll see, what one of Mendel's great insights was, was that it wasn't like mixing liquids. And to study this problem, then, he picked a system. It wasn't that he was just fiddling around with peas. He was a pretty sophisticated guy, and he picked peas as an experimental organisms for three reasons. And so, why peas?

Well one, they were easy to grow, and that's still a major consideration of any model system that you want to use and science today. It's really tricky to grow, it's very hard to work with. It was easy to pollinate in a controlled way.

Just the structure of the pea flower makes it very easy to make sure to either put the pollen right on the pistol of that same flower, which is a kind of self fertilization, or to make sure that the pollen goes from one flower to another, which is basically cross-pollination. And the third thing, and this was a really important thing, was the system had worked on before. And there were a number of what were called pure breeding lines. If he had just grabbed peas out of the wild it would be sort of like me starting to do genetics by crossing a couple of you guys. We'd get offspring, all right, and we'd cross those offspring, we'd keep getting things, people that look different and different, maybe something like the parents, but what had happened with peas is people had taken a pea, and then they continually inbred it until it finally sort of settled down. It always had white flowers.

It always had wrinkled seeds. It always had whatever the particular trait was. And so, I think I showed you the slide earlier. This shows two things.

You can see there are smooth seeds and then wrinkled seeds.

And it may be a little hard to tell in this light, but there is sort of two colors here. One's kind of greenish and one's sort of yellowish. So there, you see two of the traits right there. There were also flower colors, and height, and other things that had the characteristic.

They were pure breeding. Every time you took that line and if you self crossed it and put out its progeny, you'd see the same characteristic each time. So, this was the system that Mendel started to study this problem of inheritance. And how does blending come together when two organisms brought pollen?

Or, if it was other animals like us, it would be sperm and egg.

But somehow, you did something that ended up giving you an egg that got fertilized. And out of that came the progeny. So, what Mendel did, the term that's used, they say he carried out a cross. This is genetic-speak here now. So he took pollen from one plant.

And used it to fertilize another plant, collected the seeds that came out of this, and he examined the progeny. And I think an interesting way of thinking about this is a UROP project.

You'd come into Mendel's lab and wanted to do a UROP project, it was pretty easy. I could probably show you all the techniques you needed to know, and this is it. You'd show how you pollinate, collect seeds, and then we'd look at the characteristics. So, it's just some fairly simple manipulations and some observational stuff. So, let's suppose you're doing Mendel's thing as a UROP project, and let's just see where that will take us. So, what Mendel did to begin with, he took one of these pure breeding lines that was smooth or all abbreviated as a capital S. And he pollinated it with something that was wrinkled. I'll do that as little S.

And then he collected the seeds from what's known as the first generation, starting with something like this.

And geneticists use the term F1 for this first generation in a cross like this, and what he found was everything, all the seeds, were smooth. So, the wrinkled trait had, if you will, disappeared.

That's your first UROP experiment.

[Time doesn't?] submit to nature, or science, or something, and read a little paper like Watson and Craig that turns the world on its end. What would you do next? No gels, no Whitehead Sequencing Facility. Anybody got any ideas? I've showed you all the techniques that he knew about. Pardon? Cross it again?

What's your thinking? Do you think the traits disappear, or do you think it's hiding? It might be hiding, right?

I don't know what he thought, but I think that's a reasonable to think about it is he's probably trying to figure out, did this wrinkled trait just disappear from the face of the Earth, or is it hiding in those first-generation seeds?

So, let's put that up here. So, that's exactly what he did.

So, he took these seeds, now, that were the smooth F1.

These are not the same smooth as the parental up here.

Just to make clear, you guys understand these are pure breeding.

These are the ones that people have been breeding for a long time, this one and this one. In this case, even though I'm trying it in circles, this is a smooth F1, smooth F1. And, this time when he did the experiment he looked at the second generation, or the F2 generation as a geneticist would call it. What he found, he got some smooth and he got some wrinkled.

So, the wrinkled trait reemerged in the F2. So it wasn't really gone.

It was hiding. OK, time to submit to nature's science cell. Got it? He didn't try and publish it at that point. He did something else. He had the same kind of background you guys have. Can he think what he might've done?

He could cross again. There's something else he did with this experiment, though. Well, you're thinking of new experiments. He's got a little data processing he can do here. What did you say? I'm not able to hear, sorry.

Statistics, OK. I'll simplify it even slightly before that. I've got some of each. Count them, right, exactly. So that's what he did, and I think the numbers were, if I remember, five, four, seven, four in 1850.

So, what should I do now? Ratio: absolutely. We could count another million of them, but that probably would not be terribly productive. And what he found out is that when he did that, he found that he got a ratio that was pretty close to 3:1. And, so that was sort of what he found out from this by doing this sort of thing over again was a pattern. A trait disappeared in the F1. The trait reemerged in the F2, and the two traits had this. The ratio of the two traits would be about 3:1. If you don't think this is sort of like a UROP project or something, that's a page out of some of Mendel's actual notes while he was doing his crosses. And what he did next, then, was to take some other traits. Yeah? Sorry? Excuse me?

Reemerged in F2. So, he took some other traits, white and purple flowers, tall, short, I found that there were at least certain other traits. It didn't work for everything he studied, but some of them he could see the same pattern.

One of the traits disappeared. It reemerged in the F2, and when he counted them, he'd find that the trait that reemerged was at one, and the other one there were three times as many.

So, he'd seen a pattern. And all he's done at this point is to cross flowers and count the progeny. So, at that point Mendel tried to explain his data. So, he had to, now, take the next part of the scientific process. And what's kind of nice about thinking about Mendel, in this sense, is we are not overwhelmed by complicated techniques.

You can see, I think, the scientific process.

And it's a very bare bones thing marching along.

So now he's got some data. He's quantitated his stuff.

He's founded reproducible. It's not only for seeds.

It seems to be some general feature. And the thing about this, I guess, I don't know what he thought but it seems to be likely that he could see that this didn't fit very well with the blending idea.

Like, you'd pour together two liquids, and you'd stir them all up. Instead, he really made this monumental leap in thinking that genetic information must come in some sort of particular form, come in particles, or units, or quanta if you want to think about if it if you're a physicist.

We know those units as genes right now. We grow up with it right now, but to go from the idea that genetic information was kind of like two liquids blending to the idea it was a little particle, so it was just about the same kind of leap as thinking that energy comes in particles instead of a continuous sort of thing.

So, that was the kind of insight that Mendel had.

And so genetic info comes in particles, units.

I was going to say, we now call these genes, and if that was what it was then he started to think about these traits as particles that had a different character associated with each of them. That would mean there would be one particle that was a big S, and that was smooth. There was some other particle that was specified.

The wrinkled character, that would be called a small s.

So, what was happening in these crosses, then, he was now mixing particles instead of liquids. Again, I don't know how he got to, how many particles there had to be of each per organism. It could have been anywhere from two upwards. He had to have two in order to explain the sort of stuff he was working with. There's no reason he couldn't have thought of 12 or something. But I assume you start with the very simplest thing, number that you can think of, and see if you can make this work. So, what he hypothesized, then, was that each organism had two copies of each of these particles.

So, two copies of each particle, so this would mean that there were two types of particles. So, there would be the S and the smooth. So, he can get three types of things. He could get one that was both big S or smooth. Or you could have the ones that were the two little S's. And these would be wrinkled.

Or, if you had the other combination, what he figured out, what fit with this model is these would have to be smooth.

That would have to mean that one of them is dominant over the other when you put them in combination. So, in this thing, the big S would be said to be dominant. And the little s Would be said to be recessive. There's another little term here that I'm going to introduce because it'll help us talk about this stuff over the next few days, terms geneticists use all the time. Because these both have two of the same, they're said to be homozygous, do the same.

And this one, with one of each, is said to be heterozygous.

OK, so there is, I think, sort of the setup for Mendel's model. He had to contend with one other issue, though, and that was if every organism has two, and two parents get together and each donate something, unless you did something, the offspring would have four.

When those offspring got together, the next one would have twice as many, and so on. So, from probably, I don't know whether it was just from first principle, but I would imagine he figured out that if organisms had sex with pollen and whatever, or egg and sperm, that something had to be done to get around this problem of an ever increasing number of particles. So, he envisioned that when there were specialized cells for sex, and that they have the number so that the sex cells would have half the number of particles so that when each parent donated one, you'd be back up to two.

It's pretty simple, straightforward thinking once you've gotten the idea that these things are coming in a particular form.

So, with this, could he now explain his results?

Let's do it over here. So, what happened in the first cross? He had a smooth, pure breeding line crossed with, so the sex cells from this, each one would have been a big S, and the sex cells from each one of this would have been a little s.

And as you recall, what he got was all smooth, right? Remember?

So, if we try and figure out what's happening here, a way of representing this would be to think what happens if all of the combinations that you could get, so if we paired them in all possible ways, then every combination would be identical from that first cross, one from one parent, one from the other.

And, if one was dominant over the other, it's going to look like this.

This is really the word I introduced you to.

That's the genotype. That's what's going on down at the genetic level. What you're seeing up here is the observable characteristics of the organism.

That would be the phenotype. So, then what would happen then with this if he crossed the F1's? Well, as you recall, they were smooth, but he was now seeing them as being like this.

So that means that the sex cells that are generated from this, each one will generate one big S, and one little s.

And then, if you put them together to see how this would work out, well, this one's two big S's. This is a big S and a little s, a big S and a little s, and two little s's. So, what he's got over here is SS, SS, and a ratio of 1:2:1.

But when you look at the phenotype, what would we expect? Well, this would be smooth, big S and little s.

That's smooth. Big S, little s, smooth again, and two little s's, that's wrinkled. There's his ratio of 3:1.

Has he proved anything? It works. Beautiful. The model must be right?

What do you think? Are you ready to publish?

Why is that? Why did the model work?

Has the model predicted anything yet? No, it works because it describes the data. To some extent, it's kind of like hitting a curve.

You said it, but you don't really know yet. Of course it's going to work, because if you got different data it would've had a different model. So, you're putting your finger on a really important point, and that is that you can do an experiment. You can get data.

It doesn't have to involve DNA sequencing or fancy technique.

You're getting data out of a biological system.

You've come up with a hypothesis that explains it.

But of course it's going to explain it because you wouldn't publish a model that didn't explain your own data. But what he hasn't done is tested it. Will his model predict the outcome of something that he hasn't already done? So, the suggestion was that he should carry out another cross. And that's what Mendel then did again. This is what he had to work with.

He could cross, and he could count, and he could do some calculating and some thinking. But, those were the techniques.

I really like thinking about this, because you can sort of put yourself in his shoes. So, what would you guys like to cross?

We haven't got much, right? One, he did. One cross he did, the F1 with the homozygous dominant parent, the pure breeding lines.

So, he's got this smooth, that's a big S and a little s, and he's crossing it with something, two big S's. So, the sex cells that you'll get out of this, so if you set this one up and see what happens, there's the two. You will get to big S's, big S, little S, the big S, little S. This is sort of uninformative. If you want to look at your notes afterwards, and have this be consistent, let me just flip this slightly. I put the two big S's up here, and this is our F1 down here. That way I'll be following the same pattern as I did before. OK, so there we are. In any case, they're all smooth, but that's not particularly helpful.

He's seen that result before. It hasn't really proven out. Given the sort of unexpected result that's predicted by his model.

But he tried another one that's very, very similar.

And in this case, he crossed the F1 with the homozygous recessive parent. This is a really important process in genetics. And the reason, because it's so important, it's given a special term that's called a test cross. Let's see what happens with this one, because this one's more interesting. So, we take the F1. So, this is the F1. He's now crossing it with this homozygous recessive, so a parent that's got two particles that are little s. And so, will the sex cells look like this, a big S little s as before, to little S's here? So, if we set up this, as we've done, there are the sex cells from this F1.

Here are the sex cells from the homozygous, recessive parent.

Up here, we get a big S and a little s for each of those.

But here, we get two little s's. So, if we look at the phenotype, if you're out on the field or out in the garden sitting in the kitchen, after you brought your seeds in or wherever he was working, what would you predict you'd see in a cross like this?

These would be both smooth, but these would both be wrinkled.

So, here at the genotypic level, we've got a ratio, now, of 1:1. And here as well, there's now a ratio of 1:1. So, there you have a result that you haven't seen before. And, if you do that cross and get that result, again, it doesn't prove your model.

Scientific proof is never a QED.

Somebody can always come up with an experiment tomorrow that disproves it. It tends to work more. You just keep shoveling on evidence, and finally someone says, enough, enough, I believe you.

So, this was at least a test of the model, and the model survived this task. Now, he did one other experiment. Of the things that we've got on our plate right now, is there anything else we might do you can think of? He did another cross.

Pardon? Two of the heterogeneous ones, we did the F1's against each other. That's where we got the 3:1. We've already crossed the F1's, but I like your idea. What if we took the F2's?

In this case, it's going to be pretty complicated because they've got this 2:1:1, but one of the things you can do with peas is you can self fertilize them as well as cross them with their neighbors because they've got the ability to make the eggs.

It'll become the seeds, and they have the pollen, which would be equivalent to the sperm. So it got both.

So, as long as there's some plants that you can self fertilize and some you can't, one of the really nice things about peas, they have the property that you can self fertilize them.

So, another kind of experiment that Mendel did, then, was to self fertilize another test of the model, self fertilize the F2's. Well, the model predicts, if we look back over there, that what you'll have there is a mix of things in a ratio of 1:2:1.

So, if you were to take seeds from that F2, and then cross them with themselves, you could figure out all the different outcomes, and then sum them up. You'd have a prediction for what this model would suggest. All right, so let me just take you through the pieces. Let's think about a quarter of them, according to the model, a quarter are that. So, if we self cross those, what we should get is all wrinkled because the only thing we're dealing with is the wrinkled trait.

So, that would be a quarter of the F2 seeds would be expected to give that outcome. So, three quarters of them are smooth, but it's tricky because there's two types of them in there, right? So, of these, one third are this, and two thirds have that.

So, what would happen if we thought about each of those individually, and thought about the outcome? Well, if we take the SS type, and we've self crossed them, what we're going to get is all smooth because all we've got in the cross are the traits for the smooth characteristic. And, if we take these guys and we've self-crossed them, we've already done that.

We know what we will get is we will get smooth to wrinkled in a ratio of 3:1. So, again, you could now sit down with that and figure out in total what you would predict in terms of smooth and wrinkled if you self crossed the F2, and if the model is correct.

So, that was basically [your? first UROP project, or the end of the first term, or the first year, or something like that. And he did publish those results that were published in 1866, which was the same year as those, about the same time as those results that Pasteur was publishing that I told you about earlier on. So, it was a very impressive in retrospect, a truly major intellectual leap.

But, it had almost no impact at all on the world. And there's a theme here that it sort of tried to hit up several times.

And we saw it, to some extent, with the early work on DNA, that someone can get evidence for an idea. But if the scientific community is ready to accept it, it can take quite awhile before that idea becomes credible even if it's correct. The data was there. The DNA was genetic material quite a bit before the general scientists thought it was, and it just seemed like it was too simple a molecule, too boring a molecule to be possibly able to encode anything.

And the same sort of thing happened here. It was some geneticists picked up on this but not until about 1900.


Somatic mutation theory of carcinogenesis: why it should be dropped and replaced

The somatic mutation theory of carcinogenesis has been the dominant force driving cancer research during the 20th century. In brief, it proposes that successive DNA mutations in a single cell cause cancer (monoclonality). This theory places carcinogenesis at the cellular and subcellular hierarchical levels of biological complexity. Its basic premises are that (1) cancer is a defect of the control of cell proliferation and (2) the default state of metazoan cells is quiescence. These two premises have recently been contradicted by evidence. Supporters of the theory have dealt with these lacks of fit by incorporating ad hoc explanations similar to the use of epicycles in pre-Copernican astronomy. We propose the adoption of an alternative theory, the tissue organization field theory of carcinogenesis and neoplasia. Its basic premises are that (1) proliferation is the default state of all cells and (2) carcinogenesis and neoplasia are defects of tissue architecture. Carcinogens would act initially by disrupting the normal interactions that take place among cells in the parenchyma and stroma of an organ (the equivalent of the "morphogenetic fields" of developing organisms). Stroma appears as the primary target of carcinogens. Carcinogenesis and neoplasia occur entirely through emergent (supracellular) phenomena. Neoplastic cells may be reprogrammed to behave like "normal" cells within normal tissues. We argue that it is necessary to abandon the somatic mutation theory. Researchers will then become free to adopt alternative reliable premises to build a theory that explains carcinogenesis as another outcome, aberrant as it may be, of biological organization.


Contents

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. [1] 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, [2] 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. [3] 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. [4] In 1915, Yamagawa and Ichikawa showed that repeated application of coal tar to rabbit's ears produced malignant cancer. [5] Subsequently, in the 1930s the carcinogen component in coal tar was identified as a polyaromatic hydrocarbon (PAH), benzo[a]pyrene. [2] [6] 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. [7] Georgii Nadson and German Filippov were the first who created fungi mutants under ionizing radiation in 1925. [8] [9] 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, [10] [11] visible due to the presence of enlarged "polytene" chromosomes in fruit fly salivary glands. [12] His collaborator Edgar Altenburg also demonstrated the mutational effect of UV radiation in 1928. [13] Muller went on to use x-rays to create Drosophila mutants that he used in his studies of genetics. [14] He also found that X-rays not only mutate genes in fruit flies, [10] but also have effects on the genetic makeup of humans. [15] [ better source needed ] Similar work by Lewis Stadler also showed the mutational effect of X-rays on barley in 1928, [16] and ultraviolet (UV) radiation on maize in 1936. [17] 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. [18]

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. [19] 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. [20] [21] Early studies by Ames showed around 90% of known carcinogens can be identified in Ames test as mutagenic (later studies however gave lower figures), [22] [23] [24] and

80% of the mutagens identified through Ames test may also be carcinogens. [24] [25] 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. [26]

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. [27]

Different mutagens act on the DNA differently. Powerful mutagens may result in chromosomal instability, [28] 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. [29]

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. [30] [10] 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. [31]

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. [32] 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). [33] 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, [34] may be converted by metabolic processes into the active mutagen or carcinogen. and some compounds that contain bromine in their chemical structure. [35] , 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

    , which can substitute for DNA bases during replication and cause transition mutations.some examples are 5 bromo uracil and 2 amino purine

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.

Metals Edit

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. [36] 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. [37]

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, [38] and 1911 by Peyton Rous who discovered the Rous sarcoma virus. [39] – 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. [40] 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, [41] however, the effectiveness of antioxidant supplements in cancer prevention in general is still the subject of some debate. [41] [42]

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. [43] Others that may be effective against cancer include indole-3-carbinol from cruciferous vegetables and resveratrol from red wine. [44]

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. [45] [46]

In 1981, human epidemiological analysis by Richard Doll and Richard Peto indicated that smoking caused 30% of cancers in the US. [47] 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. [48] 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 [49] 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). [40] Overly-browned starchy food such as bread, biscuits and potatoes can generate acrylamide, a chemical shown to cause cancer in animal studies. [50] [51] 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. [52]

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. [53]

Many different systems for detecting mutagen have been developed. [54] [55] 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.

Bacterial Edit

  • 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 repairE. 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.

Yeast Edit

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.

Drosophila Edit

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.


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For use in screening for environmental mutagens and carcinogens, a highly fluorescent derivative of guanosine, 2′-deoxy-2′-(2",3"-dihydro- 2",4"-diphenyl-2"-hydroxy-3"-oxo-1"-pyrrolyl) guanosine (FG), was synthesized. When incubated with FG in aqueous solution, mutagens form adducts that can be analyzed with an HPLC-fluorescence detector-system. By this method, mutagens such as glyoxsl, methylglyoxal, 2-(2-furyl)-3-(5-nitrofuryl)acryl-amide and 4-nitroquinoline-N-oxide, used as model compounds, were detected rapidly with high sensitivity.

Reaction with isopropylideneguanosine (IPG), followed by isolation and characterization of the mutagen-IPG-adduct was found to be a useful method for identifying unknown mutagens in crude samples. This method was success fully applied in identification of the mutagens in heated glucose (200°C, 20 min) glyoxal-IPG and 8-hydroxy-IPG were identified in the reaction mixture.


Watch the video: Mutagens and carcinogens. Biomolecules. MCAT. Khan Academy (July 2022).


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