Environmental toxins permanently alter genetics
Evidence that the genes of developing fetuses can be permanently changed by exposure to compounds that act like hormones and that this effect is then passed on to future generations is sending shock waves through the ecotoxicology community. A study reported this week in June at the annual Endocrine Society meeting in San Diego, Calif., found that if pregnant rats were dosed with the fungicide vinclozolin or the pesticide methoxychlor, their young later suffered fertility problems. Further, this defect was passed on to future offspring, evidence that the chemicals had permanently reprogrammed the animals’ genetics.
“This is a really extraordinary find,” says Frederick vom Saal, a professor of biology at the University of Missouri–Columbia. “It’s the sort of effect that we’ve been looking for in endocrine disrupters, and it shows that we may be missing some subtle effects from some chemicals.”
“Extraordinary claims require extraordinary evidence,” says John Sumpter, a professor of biology and biochemistry at Brunel University (U.K.) and a leading authority in the field of endocrine disrupters. “I would like to see this study replicated.”
In the study, scientists dosed pregnant rats with a pesticide as the fetuses’ sexual organs were forming. At birth, the pups appeared normal, but at puberty 90% of the males had problems such as high rates of sperm death, decreased sperm count, and low sperm motility. These poor fertility traits were passed on for at least three more generations, even though these rats were never exposed to the pesticides.
“We don’t think this [response] is happening only with the population that is exposed to pesticides,” says study author Michael Skinner, the director of the center for reproductive biology at Washington State University. “Reprogramming the germ line so that your grandkids have the same [trait] makes for a big impact from the biohazards of some of these compounds.”
Skinner rules out a mere change in genetic sequence to explain the frequency of the poor fertility. “We couldn’t explain this effect through a genetic mutation, because you would normally only have affected less than 1% of the population,” he says. “Even in a hot-spot mutation site, the highest rate ever recorded is between 10 and 15%.”
Instead, Skinner argues that the pesticides must have changed the methylation pattern of the rat pups’ DNA. Most genes are methylated, and the more methyl groups a gene has, the more likely that gene is to remain silent.
About one week into normal male fetal development, as the testes are forming, methyl groups are stripped off DNA; these are later reattached. Skinner believes that vinclozolin and methoxychlor can disrupt the fetuses’ hormone system. Since hormones influence the cellular program that reattaches the methyl groups, the methylation pattern is altered. So, even after the pesticide disappears and hormone levels normalize, the toxic effects are permanently captured by DNA in the cells. And if those cells produce sperm DNA, then the altered methylation pattern can be passed on to offspring.
Skinner has found two genes in affected males that show this altered methylation pattern and is investigating 25 other candidate genes. “We have unpublished data showing that other disease states are popping up in the older animals,” he says, adding that about 10% of the males later become completely infertile, while others show signs of kidney disease and tumors.
Earl Gray, a research biologist with the U.S. EPA who studies endocrine disrupters, says that vinclozolin and methoxychlor are known to block the effects of male hormones. “There was a recent Federal Register notice that the [government] intended to cancel all use of methoxychlor,” Gray says. He adds that during the past 10 years, vinclozolin use has been restricted to controlling fungi on certain crops.
“Nobody has ever seen anything like this,” Gray comments on the study. “I think people are guardedly enthusiastic about the results. You want to see this sort of breakthrough replicated.”
Skinner says that these results build on previous studies that have shown a correlation between toxin exposure and generational effects. For instance, recent research discovered that women whose mothers smoked during pregnancy were more likely to have asthmatic children. Frank Gilliland, a professor of preventive medicine at the University of Southern California, says that this grandmaternal effect occurs even after environmental variables are controlled for, and he suggests that some environmental toxins may have consequences for multiple generations.
Skinner cautions that this study proves little about environmental risks of either chemical because the doses were very high. The importance, he says, is in uncovering a mechanism by which a pregnant female’s environment can alter gene expression in her progeny. He even speculates that this mechanism may drive evolution.
Evolutionary biologists find the results interesting but not necessarily indicative of a need to change current evolutionary theory. “This doesn’t surprise me at all,” writes Arthur Shapiro, professor of evolution and ecology at the University of California, Davis, in an email. He notes that methylation effects are well known and debated in evolutionary biology but that experts view these examples as “weird, special cases with no broader implications.”
However, Skinner says that this apparent anomaly does raise concerns for medicine. “If some disease states are due to transgenerational effects, we could have a disease such as prostate or breast cancer, and it could be due to what your grandmother was exposed to,” he says.
