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DNA methylation changes in fetal germ cells exposed to endocrine disruptors and in the next generation [methylation set 2]

ABSTRACT: According to recent reports, exposure to environmental endocrine disrupting chemicals (EDs) during pregnancy may harm multiple subsequent generations. We hypothesized that EDs must directly alter DNA methylation and/or transcription in the exposed fetal germ cells to affect the grandchild. In addition, the aberrant pattern must be retained in the germ cells of the grandchild -- withstanding global epigenome remodeling -- to affect the great-grandchild. To test this hypothesis, we extensively searched for immediate and persistent epigenetic effects in purified germ cells of the exposed fetus and those of the next generation. We treated gestating female mice with previously validated doses of vinclozolin (VZ), bisphenol A (BPA), di-(2-ethylhexyl) phthalate (DEHP), or control oil, during the time when the prospermatogonia of the exposed fetus undergo global de novo DNA methylation. Using genome-wide assays, we detected changes in transcription and DNA methylation in the exposed prospermatogonia but these did not persist into the prospermatogonia of the next generation. There was no evidence for transgenerational inheritance of these epigenetic aberrations. Our results suggest that EDs exert direct epigenetic effects in the exposed fetal germ cells, but the germline corrects against deleterious effects in the next generation.

ORGANISM(S): Mus musculus

PROVIDER: GSE59542 | GEO | 2015/02/18

SECONDARY ACCESSION(S): PRJNA255527

REPOSITORIES: GEO

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Project description:A number of environmental factors (e.g. toxicants) have been shown to promote the epigenetic transgenerational inheritance of disease and phenotypic variation. Transgenerational inheritance requires the germline transmission of altered epigenetic information between generations in the absence of direct environmental exposures. The primary periods for epigenetic programming of the germ line are those associated with primordial germ cell development and subsequent fetal germline development. The current study examined the actions of an agricultural fungicide vinclozolin on gestating female (F0 generation) progeny in regards to the primordial germ cell (PGC) epigenetic reprogramming of the F3 generation (i.e. great-grandchildren). The F3 generation germline transcriptome and epigenome (DNA methylation) were altered transgenerationally. Interestingly, disruptions in DNA methylation patterns and altered transcriptomes were distinct between germ cells at the onset of gonadal sex determination at embryonic day 13 (E13) and after cord formation in the testis at embryonic day 16 (E16). A larger number of DNA methylation abnormalities (epimutations) and transcriptional alterations were observed in the E13 germ cells than in the E16 germ cells. These observations indicate that altered transgenerational epigenetic reprogramming and function of the male germline is a component of vinclozolin induced epigenetic transgenerational inheritance of disease. Insights into the molecular control of germline transmitted epigenetic inheritance are provided. The F0 generation females were exposed to a vehicle (dimethylsulfoxide DMSO) as control or to vinclozolin, as described in the Methods. The F1 generation offspring were bred to generate the F2 generation and the F2 generation offspring were bred to generate the F3 generation offspring. The timed pregnant F2 generation females were used to isolate the F3 generation control and vinclozolin lineage fetal gonads at the E13 and E16 time points. The F3 generation E13 PGC and E16 prospermatogonia were isolated. DNA was isolated from the freshly isolated cells to examine DNA methylation by methylated DNA immunoprecipitation (MeDIP) followed by analysis on a genome-wide promoter tiling array (Chip) using a comparative hybridization MeDIP-Chip analysis between control and vinclozolin lineage samples as described in Methods. This allowed a comparison of the epigenome alterations in F3 vinclozolin lineage germ cells at E13 and E16. Three separate experimental comparisons of control and vinclozolin-lineage animals involving different germ cell isolations were analyzed with three different MeDIP-Chip analyses at each time point.

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DNA methylation changes in fetal germ cells exposed to endocrine disruptors and in the next generation [methylation set 2]

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