Summary: A single exposure to a common fungicide during pregnancy can haunt a family line for 20 subsequent generations, according to a staggering new study. The research found that health problems—including kidney, prostate, and reproductive issues—not only persisted but actually worsened centuries later in “human time.”
By the 15th generation, the pathology became lethal, with high rates of death during birth for both mothers and offspring. This discovery of “epigenetic transgenerational inheritance” suggests that many modern chronic diseases may be rooted in the environmental exposures of ancestors who lived hundreds of years ago.
Key Facts
- The 20-Generation Span: Disease risk from a single toxic exposure remains stable for at least 20 generations, equivalent to roughly 500 years in humans.
- Lethal Progression: While disease rates stayed steady for the first 14 generations, they surged around the 15th, leading to severe abnormalities and death during the birth process.
- Germline Programming: Once a toxin alters the reproductive cells (sperm or egg), the change becomes as stable and permanent as a genetic mutation.
- Low-Dose Impact: The study used conservative toxin levels—lower than what the average person might consume in their daily diet.
- Preventative Potential: Despite the daunting timeline, researchers have identified epigenetic biomarkers that can predict these disease susceptibilities 20 years before they develop, offering a window for preventative medicine.
Source: Washington State University
A single exposure to a toxic fungicide during pregnancy can increase the risk of disease for 20 subsequent generations — with inherited health problems worsening many generations after exposure.
Those are the findings of a new Washington State University study of rats that expands the understanding of how long the intergenerational effects of toxic exposure may last, as they are passed down through alterations in reproductive cells.
The study, published this week in the Proceedings of the National Academy of Sciences, was co-authored by WSU biologist Michael Skinner, who has been studying this “epigenetic transgenerational inheritance” of disease for two decades.
The research has implications for deciphering rising disease rates among humans, Skinner said, suggesting that the reason someone has cancer today may be rooted in an ancestor’s exposure to toxins decades earlier. On the other hand, epigenetics research has also unearthed potential treatments by identifying measurable biomarkers for diseases that could eventually spur preventative treatments.
“This study really does say that this is not going to go away,” said Skinner, a professor in the School of Biological Sciences and founding director of the Center for Reproductive Biology. “We need to do something about it. We can use epigenetics to move us away from reactionary medicine and toward preventative medicine.”
Skinner first identified the epigenetic inheritance of disease in 2005 and has published scores of papers since. The effects are transmitted through alterations in sperm and egg cells—the germline—and past studies have shown that the inherited disease incidence can be greater than that arising from direct exposure to toxins.
“Essentially, when a gestating female is exposed, the fetus is exposed,” he said. “And then the germline inside the fetus is also exposed. From that exposure, the offspring will have potential effects of the exposure, and the grand offspring, and it keeps going. Once it’s programmed in the germline, it’s as stable as a genetic mutation.”
Recently, Skinner’s lab has been trying to determine how long those effects last and whether the disease risk changes over the generations.
In a study published late last year, Skinner’s team looked at 10 generations of rats following an initial exposure of vinclozolin, a fungicide used primarily in fruit crops to control blight, mold and rot. The heightened prevalence of disease persisted through those generations.
The current paper, published in the Proceedings of National Academy of Sciences, doubled the number of generations studied, showing a similar persistence of disease in the kidneys, prostate, testes and ovaries, as well as other health effects. What’s more, starting in later generations, mothers and offspring began to die in large numbers during the birth process.
“The presence of disease was pretty much staying the same, but around the 15th generation, what we started to see was an increased disease situation,” Skinner said. “By the 16th, 17th, 18th generations, disease became very prominent and we started to see abnormalities during the birth process. Either the mother would die, or all the pups would die, so it was a really lethal sort of pathology.”
Skinner said he scaled the dosage of the toxin conservatively, at a level below what the average person might consume in their diet.
The paper was co-authored by Eric Nilsson, a research professor in the School of Biological Sciences; Alexandra A. Korolenko, a previous graduate student and now postdoctoral researcher at Texas Tech University who was the lead author; and Sarah De Santos, an undergraduate research assistant in the Skinner laboratory.
Skinner said epigenetic disease inheritance could help explain the rising rates of chronic disease in humans, an increase that paralleled the rising use of pesticides, fungicides and other environmental chemicals in agriculture and other industries. More than three-quarters of Americans now deal with a chronic disease such as heart disease, cancer or arthritis, and more than half have two diseases, according to the U.S. Centers for Disease Control.
Research by Skinner and others has found epigenetic alterations in human germlines that correspond with mammal studies, and the increased incidence of human disease tracks with the transgenerational results found in animal studies.
The scale of the time period involved is daunting. Twenty generations in rat populations cover a few years; in human beings, it’s more like 500. With such a long stretch of time between the potential cause and effect, how might the impacts of the exposures be mitigated?
Skinner pointed to another product of epigenetic research as a possible answer: the discovery of epigenetic biomarkers that predict susceptibility to specific diseases. Developing the use of epigenetic biomarkers to drive preventative treatments in humans could offer a valuable strategy for offsetting the long-term effects.
“In humans, we’ve actually got epigenetic biomarkers for about 10 different disease susceptibilities,” he said.
“It doesn’t say you have the disease now, it says 20 years from now, you’re potentially going to get this disease. There’s a whole series of preventative medicine approaches that can be taken before the disease develops to delay or prevent the disease from happening.”
Key Questions Answered:
A: It means your baseline risk might be higher, but it’s not a destiny. The study highlights that while the “programming” is there, we are now discovering biomarkers that can tell us which diseases we are susceptible to decades before they show up. This turns “reactionary” medicine into “preventative” medicine.
A: This is the most shocking part of the study. It suggests that epigenetic changes don’t just “fade out”; they can reach a tipping point where the accumulated cellular stress becomes lethal. In the rat models, this manifested as a “lethal pathology” during birth.
A: The researchers used vinclozolin, a fungicide commonly used on fruit crops to control rot and mold. They purposefully used a dose scaled below average human dietary consumption to show how sensitive the germline is to environmental chemicals.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this epigenetics research news
Author: Shawn Vestal
Source: Washington State University
Contact: Shawn Vestal – Washington State University
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Stability of epigenetic transgenerational inheritance of adult-onset disease and parturition abnormalities” by Alexandra A. Korolenko, Eric E. Nilsson, Sarah De Santos, and Michael K. Skinner. PNAS
DOI:10.1073/pnas.2523071123
Abstract
Stability of epigenetic transgenerational inheritance of adult-onset disease and parturition abnormalities
Previous research on the generational stability of epigenetic transgenerational inheritance was conducted through a ten-generation study of all transgenerational generations in mammals.
This study demonstrated both the stability of epigenetic inheritance across generations and demonstrated a generational increase incidence of disease pathology. Building on this research, the present study follows the same lineage of rats with ancestral vinclozolin exposure through twenty generations.
The findings offer important insights into long-term mammalian models of epigenetic transgenerational inheritance. Observations demonstrate an increase in differential DNA methylated regions across multiple generations. This indicates a persistent and stable transmission of epigenetic alterations.
Additionally, deoxyuridine triphosphate (dUTP) transferase-mediated nick end labeling apoptosis assays revealed elevated levels of germline apoptosis in the male rats of the maternal and paternal lineages. This suggests a potential consequence of epigenetic dysregulation in spermatogenesis.
Ancestrally exposed rats to vinclozolin showed significant parturition abnormalities in both the maternal and paternal lineages after 16 generations. This included maternal deaths during labor and stillbirths. Pathological assessments revealed abnormalities across multiple tissue types and an increased incidence of disease.
This suggests the physiological consequences of the generational stability of epigenetic inheritance. Observations establish the generational stability of epigenetic inheritance over twenty generations in a mammalian model system; however, new pathology in later generations involving parturition abnormalities was also observed.
The generational stability of transgenerational effects observed in this study has implications for human health, particularly regarding environmental toxicant exposures, reproductive health disorders, and disease susceptibility.
