Abstract
Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures.
Highlights
Epigenetic transgenerational inheritance is defined as the germline transmission of epigenetic information and phenotypic change across generations in the absence of any direct environmental exposure or genetic manipulation [1,2]
Transgenerational adult-onset disease analysis The epigenetic transgenerational actions of methoxychlor administered to female rats during day 8 to 14 of gestation were investigated
The body weights of the F1 and F3 generation methoxychlor lineage females were unaltered compared to controls
Summary
Epigenetic transgenerational inheritance is defined as the germline transmission of epigenetic information and phenotypic change across generations in the absence of any direct environmental exposure or genetic manipulation [1,2]. The environmental insults promote an apparent permanent alteration in the germline epigenome (DNA methylation) that escapes epigenetic reprogramming after fertilization, similar to an imprinted gene [4]. This germline epigenetic inheritance will alter the embryonic stem cell epigenome such that all cell types derived will have an altered epigenome and transcriptome and those somatic cell types sensitive to this altered epigenome and gene expression will be susceptible to develop adult onset disease across generations [5,6]. The transgenerational epigenetic alterations (epimutations) in sperm appear exposure specific and may be useful as biomarkers of ancestral toxicant exposure and susceptibility to develop transgenerational adult onset disease [12]
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