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The global tissue-specific RNA transcription dysregulation effects in the third generation after embryonic exposure to the widely used herbicide atrazine are mediated via inherited histone trimethylation [ChIP-Seq]

ABSTRACT: We report the effect of histone trimethylation on transgenerational inheritance. We exposed outbred pregnant CD1 mice to herbicide atrazine and progeny of these mice were crossed for a three generations. First (F1) and third (F3) generation of males were analyzed by using genome-wide sequencing analysis. We analyzed the RNA expression level in liver, brain (hypothalamus) and testis in F3 generation males. The testis samples of F1 and F3 generations’ males were analyzed by ChIP-seq using antibody against H3K4me3. We find that subset of H3K4me3 marks altered in F1 was also detected in F3 males progeny. This subset is enriched in genes of stem cell differentiation. We found that embryonic exposure to atrazine globally affects the RNA transcription in testis: we found the tissue-specific transcription deregulation, increased number transcripts with altered transcription start site, alternatively spliced and polyadenylated mRNA transcripts in a F3 generation males. This study provides a new knowledge of mechanisms of transgenerational inheritance exposed to toxic compounds.

ORGANISM(S): Mus musculus

PROVIDER: GSE81056 | GEO | 2016/09/01

SECONDARY ACCESSION(S): PRJNA320390

REPOSITORIES: GEO

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Project description: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. Methylated sperm DNA was isolated from rats ancestrally exposed to methoxychlor. Three independent samples from each treatment group were obtained. Differential DNA methylation between treatment groups was determined using Nimblegen microarrays. Treated samples were paired with control samples and hybridized together on arrays, resulting in three arrays for the treatment.

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The global tissue-specific RNA transcription dysregulation effects in the third generation after embryonic exposure to the widely used herbicide atrazine are mediated via inherited histone trimethylation [ChIP-Seq]

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