Vinclozolin induced epigenetic transgenerational inheritance of pathologies and sperm epimutation biomarkers for specific diseases

Abstract

Exposure to vinclozolin has been shown to induce the epigenetic transgenerational inheritance of increased susceptibility to disease, and to induce transgenerational changes to the epigenome. In the current study, gestating F0 generation rats were exposed to vinclozolin, and the subsequent F1, F2 and transgenerational F3 generations were evaluated for diseases and pathologies. F1 and F2 generation rats exhibited few abnormalities. However, F3 generation rats showed transgenerational increases in testis, prostate, and kidney disease, changes in the age of puberty onset in males, and an increased obesity rate in females. Overall there was an increase in the rate of animals with disease, and in the incidence of animals with multiple diseases. The objective of the current study was to analyze the sperm epigenome of F3 generation rats with specific abnormalities and compare them to rats without those abnormalities, in an effort to find epigenetic biomarkers of transgenerational disease. Unique signatures of differential DNA methylation regions (DMRs) in sperm were found that associated with testis disease, prostate disease and kidney disease. Confounding factors identified were the presence of multiple diseases in the analysis and the limited number of animals without disease. These results further our understanding of the mechanisms governing epigenetic transgenerational inheritance, and may lead in the future to the use of epigenetic biomarkers that will help predict an individual’s susceptibility for specific diseases.

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

“…Therefore, the transgenerational inheritance of increased ovarian disease can occur after exposure to a variety of environmental toxicants. There was no increase in ovarian disease in direct fetal exposed F1 or germline exposed F2 generation vinclozolin or DDT lineage rats compared to controls [30,31]. Therefore, as previously observed with most exposures, negligible ovarian disease is present following direct exposure [25,27–29], with the exception of BPA and phthalates [26].…”

Pesticides and transgenerational inheritance of pathologies: Designing, analysing and reporting rodent studies

“…(iii) To generate F2 offspring, F1 rodents from all the experimental groups are either mated with rodents from different litters but from the same F0 experimental group ('dual breeding') [2][3][4][5][6], or exposed females are mated with unexposed males from outside the study ('matriline') [9], or exposed males are mated with unexposed females from outside the study ('patriline') [16]. All or some of these offspring are measured.…”

“…Turning to the design of the WSU studies [2][3][4][5][6], a careful reading of them indicates that they did not use random assignment; there is an imbalance between the numbers of treatment and control rats at F1 and some controls appear in the same three studies (S1 Table, note 5). This overlap between the control groups -and the fact that each of the five studies address essentially the same research question in the same way -means that it is both reasonable and efficient to combine the five studies into a single re-analysis with a set of outcomes defined in S1 Appendix.…”

“…An important, and widely ignored, issue in the analysis of these studies is the lack of independence between observational units after the first generation, an occurrence which is often referred to as the 'litter effect'. This is addressed by reanalysing data from five papers from the Center for Reproductive Biology, Washington State University (WSU), USA [2][3][4][5][6]. Each of these WSU papers analyses, in essentially the same way, epigenetic transgenerational inheritance after rats have been exposed to a pesticide (two herbicides, two insecticides and one fungicide).…”

“…Their advice on how to estimate treatment effects when the treatment is allocated to a litter is, however, rather ambiguous. A similar paper [14] describes how litter effects are 5 ignored in behavioural neuroendocrinology. These two papers focus on the implications of ignoring litter effects on statistical inference, both in terms of generating false positive treatment effects (i.e.…”