The Chemical Exposure That Keeps Going and Going and Going

The Chemical Marketplace: More than 80,000 chemicals are produced, used, and present in the United States. This is one of their stories.

Roll over, Darwin -- what you eat or touch may spell bad news for your grandchild.

It's About Epigenetics

agouti mice in epigenetic study
The epigenomic system regulates the expression of our genes, turning them on or off. Studies with mice have shown the environment can affect the epigenome, having profound implications for our health and, it turns out, our offspring's. (Photo: Randy Jirtle/Duke)

By now everyone is familiar with the concept of DNA and genes. The human body has about 20,000-25,000 genes. Each gene is made up of DNA, the genetic code we get from our parents that contains the instructions for how each gene should operate (e.g., what type of protein to generate and when). For many years it was thought that our genes were the whole game -- the stuff that determined our appearance, our aptitudes, and even our susceptibility to disease.

But we now know it's more complicated than that. It turns out that not all of our genes are active. Some are turned "on" and others are turned "off."

The turning on and off of genes is the job of another system called the epigenome -- the prefix "epi" coming from the Greek for "above." Depending on the specific gene or genes and when they can get turned on or off, the epigenome can have a profound effect on an individual. In one seminal example of the role epigenomes play, adding BPA (a compound traditionally added to some plastic containers) to the diet of mice was able to turn on the agouti gene, a gene that makes mice yellow, sickly and obese. The mice whose agouti gene had been turned on tended to be more obese, yellow and sickly than their genetically identical siblings (see photo). The clear implication: our epigenome and our genome play a profoundly important part of determining who we are.

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     Epigenetics and chemical exposure

Lamarck's Inheritance of Acquired Characteristics

You might remember Jean Baptiste Lamarck from a biology class way back when. He's the late 18th - early 19th century scientist who is most often credited with the idea that the skills and talents a person obtains in his or her lifetime could be passed on to subsequent generations -- the theory of the inheritance of acquired characteristics. An extreme application might be: if you want your children to have a musical proclivity, you should study music. But with the work of Darwin and others all that Lamarckian stuff was largely discarded.

And Along Comes Epigenetics

While it is difficult, but not impossible (for example via carcinogenesis), for the environment to alter our DNA, the same cannot be said for our epigenetics. In particular, research has shown that exposure to various chemicals, like the BPA example described above, can alter one's epigenetics. What types of chemicals? Lots, including any number of synthetic compounds in consumer products -- think pesticides, additives to plastics, additives to cosmetics (the kinds of compounds we've covered right here in TheGreenGrok's Chemical Marketplace series).

Epigenetic alterations can be especially profound when the epigenetic changes occur in the womb. Consider this scenario:

  • A mother is exposed to a chemical while pregnant;
  • The chemical reaches the fetus, altering its epigenome turning on or off critical genes that are directing the baby's development;
  • The changes, for good or bad, are set for the rest of that baby's life.

That may sound rather fantastical, but that's what the research is telling us, at least when it comes to mice. For example, remember the experiment with those agouti mice? Adding BPA led to more sickly offspring. But when the BPA exposure was accompanied with a methylating substance like folic acid, the offspring tended toward less obesity and browner coats. In short we have a quasi Lamarckian situation: an environmental condition before birth altering the characteristics of an individual.

And Down Through the Generations Go Changes From in Utero Exposures

Now there's more. New research suggests that epigenetic alterations can be passed down from one generation to the next. Even more fantastical?

Here's how scientists speculate this so-called epigenetic transgenerational inheritance occurs. Imagine that a fetus is exposed to a chemical that affects its epigenome at a point in its gestation that sexual development is occurring. It's possible for the epigenetic change to affect the fetus' developing germline -- that is, the genetic material in the fetus that can be passed on to its own offspring. If that happens, those alterations would now be programed to potentially appear in subsequent generations of that fetus without any additional exposures.* Note, not all epigenetic changes are inheritable, only those that affect the germline.

OK, so that's the theory. But does it actually happen? Two recent papers suggest that it does in rats.

Last February Mohan Manikkam of Washington State University and colleagues reported results in the journal PLoS ONE that hint that transgenerational endocrine disruption can be triggered in rats by fetal exposure to a wide variety of chemicals. These include a pesticide mixture (permethrin and insect repellant DEET), a plastic mixture (bisphenol A and phthalates), dioxin (TCDD) and a hydrocarbon mixture (jet fuel, JP8).

In each case the authors found effects through three generations descended from pregnant rats exposed to the mixtures. The types of changes seen were earlier onset of puberty in the female rats and lower fertility in both males and females of subsequent generations -- changes  associated with earlier onset of disease in adulthood.

Last week we learned of other effects from transgenerational inheritance. David Crews of the University of Texas at Austin and colleagues reported in the Proceedings of the National Academy of Sciences that this type of inheritance can change not just the propensity for disease in rats but even how they respond to stress. The researchers carried out a series of behavioral experiments on third-generation male rats descended from females who had been exposed while pregnant to a single dose of vinclozolin [pdf], a commonly used fungicide and known hormone disruptor. The researchers found that the adolescent rats descended from the exposed rats were more sensitive to stress and had increased stress behaviors as compared to rats descended from unexposed rats.

Just Rats in a Cage?

The implications give me pause. The way my great grandchild responds to disease, accumulates weight, and handles stress may be traceable to one of the no-doubt thousands of chemicals my wife and I blithely brought into our home while she was pregnant. Of course the experiments were done on rats and we're... well, humans. Do the rat findings apply to humans? Think of it this way: they've done the experiment on rats and now they're waiting on the results from the experiment on us.


End Note

*To be sure that the epigenetic change is in fact inherited rather
than deriving from a direct exposure, scientists look to the first "great"
generation (referred to by geneticists as F3) because all prior
generations have direct exposure via the originally exposed pregnant
female. When she (F0) is exposed, the embryo (F1) and the germline (F2)
inside the embryo are also exposed.