A few years ago, David Crews decided to put his laboratory rats at the University of Texas, Austin under an inordinate amount of stress. Beyond testing what might happen to minds and bodies under strain, Crews had a more exotic goal: He wanted to discover how ancestral histories might cast a shadow on the lives of descendants, beyond just inherited genes.
Crews dosed half of his rats with a toxic chemical, and then bred all the rats down to the fourth generation. Half of the 4th generation rats were restrained so they were unable to move around for six hours a day.
The most notable effect from the experiment: The rats put under restraint whose great-grandparents were exposed to toxic chemicals fared much worse than the rats who were restrained but whose legacy was toxic-free. Rats with toxicity in their ancestry and who got restrained suffered altered brain anatomy and performed poorly on anxiety tests.
The experiment falls within the field of epigenetics; this is the study of molecular changes that don't alter DNA code but, rather, influence which genes get turned on or off—in other words, which genes get expressed.
Gene expression governs how the genetic code gets translated into proteins, which are the worker bees of the body. These proteins include enzymes vital for life functions, and hormones that act as messengers, traveling throughout the body to direct bodily function and even mood.
Tipping these finely tuned systems out-of-balance can lead to disease.
Epigenetic researchers have discovered that environmental stress is a key factor behind harmful molecular changes. The stress can run the gamut from poor diet and noxious chemicals to psychological strain.
Animal studies have established that harmful epigenetic changes can be caused by chemicals in cigarettes or pesticides, for example, and other studies now abound pointing to environmental stresses as a trigger for damaging cells and causing disease—PCBs, arsenic, air pollution from fossil fuels, and endocrine disruptors being some of the main culprits.
What's striking about recent research is the discovery that epigenetic tags can be transmitted across generations, potentially harming descendants long after the fact. This discovery shook up a century-old paradigm that said an individual's DNA code essentially determines how traits are passed on. Epigenetics is now saying there’s more than just the code that can be inherited.
Systems biologist Michael Skinner’s lab at Washington State University discovered these transgenerational effects almost by accident a decade ago. Skinner showed that the great-grandchildren of lab animals dosed with pesticides suffered sperm abnormalities that had nothing to do with mutations in the genes themselves.
In another example, studies of World War II famine survivors who endured the Dutch Hunger Winter showed that starvation of the fetus at very early stages of development may have predisposed the children to obesity as adults, their bodies compensating for the early deprivation.
“The implications for understanding our connection with the environment are profound, dramatic, and sweeping,” says Shea Robison, a research fellow at City University of Hong Kong.
Passing Down the Harm
Epigenetics has created controversy over the possibility that harmful chemicals could predispose our descendants to all sorts of illnesses, even if they are never exposed themselves. The legal and societal ramifications could be significant—Robison can imagine a time when the science has evolved enough that the great-grandchildren of people who lived next to a chemical plant might sue the company because cancer has appeared three generations down.
The chemical industry, including the German manufacturer of the agricultural fungicide vinclozolin, has funded studies that could not replicate the intergenerational effects in animals in Skinner’s original research. Industry studies, though, used a different breed of rats and exposed them to the chemical in a different manner.
Skinner says the evidence is strong, and not just for vinclozolin.
"We’ve repeated the studies with more than six or eight environmental toxicants, partly because this is very relevant to the human population being exposed to many different chemicals that impact many of the diseases we see today,” he says. “[Epigenetic changes occur] in all organs, all cell types in the body, including the brain.”
The most prominently studied type of epigenetic change is DNA methylation, which generally silences expression of a particular gene. These molecular changes can get passed on to offspring if they are not erased as a normal part of early fetal development. Researchers have linked DNA methylation to diseases such as cancer, obesity, aging and cardiovascular disease.
Can Psychological Trauma Affect Your Genes?
There is a growing body of research that shows psychological stress can result in epigenetic changes that have negative effects on the body. Medical professionals have long understood there's a link between stress and disease, but haven't known how that link works. The evidence currently points to epigenetics as a mechanism for bringing on chronic disease.
One 2016 paper based on data from the Department of Veterans Affairs found a molecular signature linking psychological states to coronary heart disease. The Boston-based researchers found that positive and negative mental states affect DNA methylation, switching on or off the genes that cause hardening of the arteries.
The research showed negative states like anxiety and depression affected genes involved in inflammatory processes—bad news for the arteries and heart. Meanwhile, those who reported being content showed epigenetic patterns that made them less prone to the same processes. The study’s findings were based on mostly older white male veterans.
"These changes may represent underlying common biological pathways for the effects of psychological factors on chronic diseases, including coronary heart disease,” says lead researcher Daniel Kim, a social epidemiologist from Northeastern University.
Scientists are studying whether a traumatic event can cause molecular changes that get passed through generations in the same way that toxic exposures might. But this is difficult to prove.
In a study published last year, Mt. Sinai Hospital researchers looked at the molecular profiles of the children of Holocaust survivors. Their claim that parental stress and trauma could be passed down generationally by way of epigenetic marks was criticized for its small sample size and inconsistent findings.
Crews says there's "very clear evidence" the children of Holocaust survivors were affected psychologically by their parents, but no evidence the effects of trauma went beyond that generation.
The psychological effect is distinct from a germline effect, he says, "where exposure of the mother is incorporated into the germline, and even if the offspring never experience that event again, [future generations] will still express the effects.”
An Ecology of Health
Rates of obesity, cancer and other chronic diseases have risen dramatically over the past decades. In the U.S., heart disease and cancer account for nearly half of all deaths. Skinner believes “the susceptibility to disease today is in large part due to ancestral exposures,” to chemicals. He says this epigenetic cycle will continue to impact future generations.
If research can identify these epigenetic biomarkers, then it may be possible to intervene by changing habits and lifestyles when people are young, before they start developing disease.
Epigenetics has cast the nature-versus-nurture debate in a new light, revealing a much more intricate relationship between an individual's genes and their environment than was previously understood.
"You can’t understand a higher-order thing like an organism by looking just at the genes. The organism is an emergent process that is much more than its elements,” Crews says.