Unique DNA methylation and histone retention signatures associated with obesity and kidney and prostate disease were seen in the third generation after brief periods of glyphosate exposure, new study reports on Sprague Dawley rat models. These inherited signature biomarkers, the researchers noted, if replicated in human studies, may result in epigenetic diagnoses that will facilitate preventive medicine in future generations.
The study, led by Michael K. Skinner, director of the Center for Reproductive Biology School of Biological Sciences, Washington State University, and reported in Epigenetics, in an article titled “Epigenome-wide association study for glyphosate-induced transgenerational sperm DNA methylation and epigenetic biomarkers of histone retention for disease”, builds on on an earlier 2019 study by the same research group that showed that epigenetic changes induced by the herbicide glyphosate may increase disease transmission in great-young offspring.
Glyphosate is widely used in agriculture and therefore commonly found in human food. Previous studies show that glyphosate has a short half-life and is broken down quickly in the body. Despite these indications of limited toxicity, Skinner’s team and other animal studies confirm that the phenotypic effects of glyphosate can be inherited by subsequent generations.
âWhile we can’t figure out what’s wrong with the exposed person, we can potentially use it to diagnose if someone is at higher risk for kidney or prostate disease later in life,â then prescribe a therapeutic or lifestyle change to help alleviate or prevent the disease, âsaid Skinner, who is also a professor of biological sciences at Washington State University.
DNA Differential Methylation Regions (DMR) and Differential Histone Retention (DHR) are molecular factors and processes around DNA that regulate genome activity without altering DNA sequences and are called epimutations. These epimutations are involved in the epigenetic inheritance of the disease and other phenotypic variations. Genes associated with DMR and DHR have been identified and correlated with established and disease-specific genes.
Less than 1% of the patient population with common human diseases such as prostate disease, kidney disease, obesity and multiple pathologies can be associated with causative genetic mutations. In contrast, several studies, including this report, show a higher frequency of changes in epigenetic sites, the biomarkers of epimutation, in people with these diseases. By the time the third and fourth generation rats whose predecessors had been briefly exposed to glyphosate were middle-aged, 90% had one or more of the three diseases studied, a significantly higher rate than the control group.
The study shows that for third generation men (great-grandsons) with these diseases, the number of regions with altered DNA methylation exceeded 200, with little overlap between pathologies of the prostate, kidneys, obesity and multiple diseases, at a strict statistical threshold. At a more flexible statistical threshold, 30-50% of regions with altered methylation status overlap among the different diseases studied. This suggests that certain epimutations are common among these diseases, while a unique set of disease-specific biomarkers show disease-specific susceptibility.
The team further investigated epigenetic changes in rat sperm caused by glyphosate. Despite replacing histones with protamines to compact DNA in the heads of mature sperm, some histone retention sites are retained in semen. Skinner and his colleagues found that glyphosate promotes the inheritance of differential histone retention (DHR) in semen over generations. This is the association’s first report for these DHR sperm with specific diseases. Therefore, the retention of histones in sperm can potentially be used as a biomarker for specific diseases, the authors noted.
The aim is to replicate these studies in humans and to develop epigenomic diagnostic tests. But a major obstacle to achieving this goal is the almost ubiquitous presence of glyphosate in our diets.
âRight now it’s very difficult to find a population that is not exposed to glyphosate to have a control group for comparison,â Skinner said.
Skinner added, âWe need to change the way we think about toxicology. Today, worldwide, we only assess the toxicology of direct exposure. We do not consider subsequent generational toxicity. We have a certain responsibility towards our future generations.