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Perturbed adult sperm methylome after in utero undernutrition is associated with transmission of metabolic disease

ABSTRACT: The pre and postnatal environment can affect both an individual’s risk of adult onset metabolic disease and that of subsequent generations. Although animal models and epidemiological data implicate epigenetic inheritance, little is known of the mechanisms involved. In a robust intergenerational model of developmental programming we demonstrate that the nutritional environment experienced in utero by F1 generation embryos alters the DNA methylome of the F1 adult male germ line in a locus-specific manner, without affecting overall methylation levels. Differentially methylated regions are mostly hypomethylated and are enriched in nucleosome retaining regions in adult sperm. A substantial fraction is resistant to early embryo methylation reprogramming, and thus have the potential to alter F2 generation development. Altered expression of transcripts neighbouring differentially methylated regions are evident in tissues of F2 offspring despite lack of persistence of differential methylation. Transmitted methylation variation in the germline at key regulatory loci may therefore contribute to the development of metabolic disease in the subsequent generation.

ORGANISM(S): Mus musculus

PROVIDER: GSE58747 | GEO | 2014/07/16

SECONDARY ACCESSION(S): PRJNA253334

REPOSITORIES: GEO

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Project description:Environmental factors during fetal development can induce a permanent epigenetic change in the germ line (sperm) that then transmits epigenetic transgenerational inheritance of adult-onset disease in the absence of any subsequent exposure. The epigenetic transgenerational actions of various environmental compounds and relevant mixtures were investigated with the use of a pesticide mixture (permethrin and insect repellant DEET), a plastic mixture (bisphenol A and phthalates), dioxin (TCDD) and a hydrocarbon mixture (jet fuel, JP8). After transient exposure of F0 gestating female rats during the period of embryonic gonadal sex determination, the subsequent F1-F3 generations were obtained in the absence of any environmental exposure. The effects on the F1, F2 and F3 generations pubertal onset and gonadal function were assessed. The plastics, dioxin and jet fuel were found to promote early-onset female puberty transgenerationally (F3 generation). Spermatogenic cell apoptosis was affected transgenerationally. Ovarian primordial follicle pool size was significantly decreased with all treatments transgenerationally. Differential DNA methylation of the F3 generation sperm promoter epigenome was examined. Differential DNA methylation regions (DMR) were identified in the sperm of all exposure lineage males and found to be consistent within a specific exposure lineage, but different between the exposures. Several genomic features of the DMR, such as low density CpG content, were identified. Exposure-specific epigenetic biomarkers were identified that may allow for the assessment of ancestral environmental exposures associated with adult onset disease. Environmental factors during fetal development can induce a permanent epigenetic change in the germ line (sperm) that then transmits epigenetic transgenerational inheritance of adult-onset disease in the absence of any subsequent exposure. The epigenetic transgenerational actions of various environmental compounds and relevant mixtures were investigated with the use of a pesticide mixture (permethrin and insect repellant DEET), a plastic mixture (bisphenol A and phthalates), dioxin (TCDD) and a hydrocarbon mixture (jet fuel, JP8). After transient exposure of F0 gestating female rats during the period of embryonic gonadal sex determination, the subsequent F1-F3 generations were obtained in the absence of any environmental exposure. The effects on the F1, F2 and F3 generations pubertal onset and gonadal function were assessed. The plastics, dioxin and jet fuel were found to promote early-onset female puberty transgenerationally (F3 generation). Spermatogenic cell apoptosis was affected transgenerationally. Ovarian primordial follicle pool size was significantly decreased with all treatments transgenerationally. Differential DNA methylation of the F3 generation sperm promoter epigenome was examined. Differential DNA methylation regions (DMR) were identified in the sperm of all exposure lineage males and found to be consistent within a specific exposure lineage, but different between the exposures. Several genomic features of the DMR, such as low density CpG content, were identified. Exposure-specific epigenetic biomarkers were identified that may allow for the assessment of ancestral environmental exposures associated with adult onset disease. Methylated sperm DNA was isolated from rats ancestrally exposed to plastics (Bip), vinclozolin (Vip), pesticides (Pip), dioxin (Hip), jet fuel (Jip) or control vehicle (Cip). Three independent samples from each treatment group were obtained. Differential DNA methylation between treatment groups was determined using Nimblegen microarrays. For each treatment, treated samples were paired with control samples and hybridized together on arrays (Bip1/Cip1, Bip2/Cip2, Bip3/Cip3, Vip1/Cip1, etc.), resulting in three arrays per treatment group.

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Perturbed adult sperm methylome after in utero undernutrition is associated with transmission of metabolic disease

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