Epigenetic transgenerational inheritance. Say that again? Those three "little" words refer to environmental exposures causing genetic changes that can be passed on to future generations.
These effects appear to be transferred via modification of DNA — modifications that can sometimes increase the risk of disease. As a study released last week shows, the increased disease risk can keep showing up through multiple generations.
This basic concept has been unpacked in previous blogs here on GroundTruth, when earlier research linked pesticides and other synthetic chemicals to epigenetic transgenerational inheritance. Last week's study found that rats exposed to the pesticide methoxychlor had a higher likelihood of multiple diseases — including kidney disease and obesity — and this increased risk lasted for three generations after the original exposure.
Methoxychlor is an organochlorine insecticide that was introduced as a replacement for DDT, and is a known endocrine disrupting chemical. Methoxychlor's last registered product in the U.S. was canceled in 2003 — but this study shows that its health harms may keep showing up for many years to come.
Disease in a never-exposed generation
Here's how they conducted this latest study: Pregnant adult female rats (filial generation zero, or "F0") were exposed to methoxychlor during the time that fetal gonads are known to develop. The offspring of those exposed rats were called F1, and the beginning of the "methoxychlor lineage." They then crossed (or bred) the offspring from this lineage up to generation F3. Generation F3 was the first generation with no potential exposure.
The F4 generation was also examined, and this generation was "outcrossed" by breeding F3 males or females with animals from outside of the methoxychlor lineage. In human terms, the F4 generation is the great-grandchild of first generation exposed.
What did they find? The results indicated that the animals displayed increased incidence of kidney disease, ovarian disease and obesity in the F1 and F3 generations.
In the F4 generation, they found increased disease incidence among the females. This result indicates that genetic changes increasing the risk of disease were primarily inherited through the female's eggs.
Changes to the genetic blueprint
How do such changes get inherited? Changes to DNA can occur via a process called "methylation," a chemical change resulting in stretches of genetic material being expressed in a certain way. Our gene expression is controlled in part via chemical changes and modifications to proteins that are packed around our DNA.
This is the "epigenetic" part — a change that sits on top of our genetic material. These epigenetic patterns are supposed to get "reset" during gonadal development in the cells that will generate sperm and eggs.
This genetic reset button might be intended to remove any epigenetic changes resulting from environmental exposures that the parent acquires over the course of a lifetime. But as these recent studies show, some chemicals seem to be overriding the reset button, so that epigenetic changes are inherited.
What's the risk?
The growing evidence that increased risk of diseases can be inherited in subsequent generations after "ancestral chemical exposure" means this is yet another aspect of exposure that policymakers need to consider when assessing risk. While still relevant, traditional toxicology endpoints (such as liver toxicity) clearly don't capture all of the potential adverse effects stemming from exposure to pesticides.
The authors of this study specifically stated that although their study was not designed for risk assessment,
... these results have implications for the human population that is exposed to methoxychlor that may experience declines in fertility and increases in adult onset diseases with a potential to transmit these to subsequent generations... Future work ... can now use the current information to more efficiently do risk assessment.
If we want to evaluate the risks of pesticide exposure in a manner that's more likely to protect human health, we need to use all the information we have at hand. This means it's time to incorporate the possibility that exposure to chemicals in one generation might increase risk of disease in generations to come.