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A mouse walks into a bar…

ResearchBlogging.orgHave you ever wondered how drunk mice act? Whether they stumble up to another sexy mouse and incoherently mumble “cani*squeak*buyyouadrink*squeak*maybeplease?” or pass out on the floor of their cage after attempting a rather daring acrobatic maneuver? Me too! But sadly the paper I’m covering today didn’t go into the behavioral consequences of murine overindulgence. Instead it looked at how alcohol consumption affects DNA damage and repair during fetal development and adulthood.

Photo credit: David Jones/PA Wire
Photo credit: David Jones/PA Wire
Binge drinking is rapidly becoming one of the biggest public health problems in first world countries. In America, a binge is defined as the consumption of 10 or more drinks over a period of two to three hours, with the explicit intention of getting drunk. And these binges can be damaging in a number of ways: 10% of men and 19% of women have reported being assaulted while intoxicated, one third of traffic accidents in adolescents (aged 15-20) are alcohol related, and it is estimated that one in 25 pregnant woman binge drink, often seriously damaging the baby they are carrying. All of these examples reflect the immediate, short-term impact of being drunk on decision-making and emotional responses. But there are long term effects too, including neurological damage, particularly when teenagers binge.

In this recent study by Langevin et al, the authors set out to understand the symptoms of the hereditary disease Fanconi’s anemia, and in the process discovered how excessive alcohol consumption might have more of an impact on our cellular physiology than we thought. Before we carry on with the new science, it’s background time.

DNA: Structure, Function, and Maintenance

DNA is basically a cellular hard drive. It contains a bunch of information, which has to be read to be used. As we all know, hard drives are susceptible to corruption. Anyone who’s tried to recover data from a fried computer can appreciate how frustrating this can be, and also how important it is that the information is retrieved with as few errors as possible. Data full of mistakes is misleading at best, useless at worst. All of these hard drive analogies can be applied when thinking about how DNA is preserved within the millions of cells of our bodies.

DNA is susceptible to damage in a number of ways, and has to deal with this damage at a seemingly alarming frequency: Between 1,000 and 1,000,000 chemical modifications can occur in a single cell every day. However given that our genome is made up of six million bases (or bits of information), that’s only 0.000165% of our DNA that is affected. But biology is precise, and if one of those lesions occurs in a critical gene and is left unrepaired it can have disastrous consequences. Some common DNA lesions are diagrammed here (click for a larger version):

These changes can be induced in our cells by a variety of mechanisms. Our own metabolic pathways produce harmful byproducts, including reactive oxygen species and aldehydes. These molecules can directly damage DNA and so we have evolved mechanisms to neutralize them. For example, the enzyme superoxide dismutase (SOD) is responsible for the conversion of superoxide (the most common reactive species we produce and a byproduct of basic respiration) to oxygen and hydrogen peroxide, thus rendering it harmless. However if this enzyme does not do its job, the free radical tendencies of superoxide allow it to oxidize certain DNA components. The importance of SOD function is highlighted by the fact that mutations in the gene result in a marked increase in the risk for developing various cancers.

Environmental factors can also cause significant DNA damage, and as such are considered carcinogenic. Exposure to various types of radiation (UV, x-rays, gamma-rays), chemicals, and viruses represent a few well-studied examples. Paradoxically, various cancer treatments induce carcinogenic DNA lesions. While this might seem a little ass-backwards, the rationale is sound. Cancer cells generally reproduce at a much faster rate that normal cells, and therefore this induced damage is a much bigger problem for them. Part of the cellular DNA-damage response involves cellular suicide, and chemically pushing a cell to give up all hope of repairing accumulating damage triggers this mechanism.

Regardless of the source of DNA damage, all are dealt with by a discrete set of proteins known as the DNA repair machinery. This is where the double-stranded nature of DNA becomes really important. (You could think of it as a data back-up system, or a set of mirrored hard-drives.) If only one strand of the DNA molecule is damaged, the DNA repair machinery can use the opposing strand as a template to correct the error (for a refresher on DNA structure see my earlier post here). If both strands are damaged, in what is referred to as a double-stranded break, the repair proteins do their best to put the broken DNA back together, but the chances of introducing potentially harmful genomic rearrangements are dramatically increased. Importantly, DNA damage is the first step a cell takes along the road to becoming cancerous.

Fanconi Anemia

One in 350,000 children born today are affected by this genetic disorder. A total of thirteen genes have been implicated in causing the disease, and all of them are involved in a specific DNA repair pathway. The Fanconi anemia (FA) pathway genes work together to sense and repair damage, and if just one of the components of this pathway is defective the whole thing stops working. As a result, FA patients are highly susceptible to both metabolic and environmental insults to their DNA. While developmental defects such as small heads, mental difficulties, and the absence of digits are seen in a variety of cases, the predominant symptom of FA is bone marrow failure. Bone marrow produces all the different kinds of blood cells we need to survive, and due to this constant production demand is particularly sensitive to DNA damage. Without a bone marrow transplant, patients generally develop acute myeloid leukemia, and the median life expectancy of a FA sufferer is around 30 years.

So what does this have to do with drunk mice?

The authors of this paper began by looking at sources of DNA-damaging agents that are produced by our own bodies. Specifically they focused on aldehydes, which are highly reactive chemicals that are produced in large amounts as a metabolic byproduct. Aldehydes are generally removed from cells by aldehyde dehydrogenases, however recent work in cell culture models has shown that if aldehydes are not neutralized by these enzymes they can attack DNA.

So here’s where the drunken mice come into play. Acetaldehyde, as well as being a common metabolic byproduct, is a break down product of ethanol. Ethanol has recently been shown to cause DNA damage in mice. The natural question arising from these observations is “are these two occurrences causally linked?” In other words, is ethanol being converted into acetaldehyde, which in turn damages DNA?

To answer this question the researchers began by assessing the effects of aldehydes on a variety of cells that had specific genetic mutations, including those found in patients with Fanconi anemia. As predicted, cells expressing mutated FA pathway genes were hypersensitive to ethanol. They next engineered mice that carried the same mutations and looked at their alcohol sensitivity by spiking their drinking water (15% alcohol for 5 days, then 20% alcohol for 5 days). Their blood was analyzed for to test bone marrow function, and indeed mice with FA pathway mutations showed a decrease in all types of blood cell and an increase in DNA damage when exposed to ethanol, when compared to none-inebriated control mice.

They also did a similar test to assess the effects of alcohol consumption on a pregnant mouse’s unborn pups. This time, rather than having the mouse get as drunk as she liked on boozy water, the authors injected a specific amount of alcohol into her body cavity (5g/kg of 28% ethanol). I suspect alcohol administered this way might bypass the liver, and thus access a developing fetus more readily, but I could not find much information to back that up (comments very welcome). The result was that pups carrying FA mutations were far more likely to abort, and those that didn’t displayed dramatic developmental defects, primarily in the formation of the head.

For those interested in how this all relates to a human “binge”, I did a little math:

If a binge is defined as 10 or more drinks in 2-3 hours, and you assume the drinker is imbibing beer at 5% alcohol content, that is a total of 170g of 100% ethanol.

An average American male weighs 190 lbs or 86.2 kg.

Therefore a binge is the consumption of 7g per kg in body mass of 28% ethanol over a period of 2-3 hours.

So the pregnant mice were receiving roughly the equivalent of a human alcohol binge in one dose. When it comes to the spiked drinking water, it’s not as easy to draw a direct comparison, as we don’t know how much the mice drank. They may have been less tempted to drink ethanol-laced water than regular water, or equally they may have gorged on it. But imagine drinking wine all day, every day, for ten straight days, and you can probably imagine how the mice felt (mild anthropomorphism, sorry).

Does this mean you should stop drinking?

If you have Fanconi anemia, definitely. The study demonstrated that mice with a decreased ability to fix aldehyde-induced DNA damage were extremely sensitive to the carcinogenic effects of alcohol. If you are one of the 8% of the worlds population that carry a mutation in ALDH2 (an aldehyde dehydrogenase that breaks down acetaldehyde in the blood stream before it can get to your DNA) you too might want to consider cutting back, as a lack of this enzyme has been linked to stomach and intestinal cancers. This study has also raised the possibility that fetal alcohol syndrome is caused by DNA damage in utero, thus emphasizing the importance of extreme caution when it comes to alcohol consumption during pregnancy.

But it’s not all doom and gloom; there is also the potential for new therapies contained within this work. Perhaps increasing the activity of aldehyde dehydrogenases can compensate for the loss of DNA-repair activity in FA patients. This can be done through administering low doses of ethanol, as the body compensates for their presence through increasing the amount of enzymes produced. (You probably experienced this effect first hand in college as your alcohol tolerance increased with each crazy night out.)

And what about the rest of us? Enjoy those brewskis in a responsible manner and you should be fine. Cheers!

Langevin, F., Crossan, G., Rosado, I., Arends, M., & Patel, K. (2011). Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice Nature, 475 (7354), 53-58 DOI: 10.1038/nature10192



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