Alterations in sperm DNA methylation, non-coding RNA expression, and histone retention mediate vinclozolin-induced epigenetic transgenerational inheritance of disease

Abstract

Epigenetic transgenerational inheritance of disease and phenotypic variation can be induced by several toxicants, such as vinclozolin. This phenomenon can involve DNA methylation, non-coding RNA (ncRNA) and histone retention, and/or modification in the germline (e.g. sperm). These different epigenetic marks are called epimutations and can transmit in part the transgenerational phenotypes. This study was designed to investigate the vinclozolin-induced concurrent alterations of a number of different epigenetic factors, including DNA methylation, ncRNA, and histone retention in rat sperm. Gestating females (F0 generation) were exposed transiently to vinclozolin during fetal gonadal development. The directly exposed F1 generation fetus, the directly exposed germline within the fetus that will generate the F2 generation, and the transgenerational F3 generation sperm were studied. DNA methylation and ncRNA were altered in each generation rat sperm with the direct exposure F1 and F2 generations being distinct from the F3 generation epimutations. Interestingly, an increased number of differential histone retention sites were found in the F3 generation vinclozolin sperm, but not in the F1 or F2 generations. All three different epimutation types were affected in the vinclozolin lineage transgenerational sperm (F3 generation). The direct exposure generations (F1 and F2) epigenetic alterations were distinct from the transgenerational sperm epimutations. The genomic features and gene pathways associated with the epimutations were investigated to help elucidate the integration of these different epigenetic processes. Our results show that the three different types of epimutations are involved and integrated in the mediation of the epigenetic transgenerational inheritance phenomenon.

Intergenerational Effects of Alcohol: A Review of Paternal Preconception Ethanol Exposure Studies and Epigenetic Mechanisms in the Male Germline

“…Retained histones are concentrated at promoter regions of key genes for embryo development, thereby well positioned to influence initial zygotic gene expression (Brykczynska et al., ; Hammoud et al., ). Moreover, adult exposure to the environmental toxin DDT or gestational exposure to vinclozolin leads to ectopic histone retention sites in sperm, showing that environmental exposures can influence germline histone displacement mechanisms (Ben Maamar et al., ; Skinner et al., ).…”

“…The earliest evidence of intergenerational/transgenerational phenotype associated with environmentally induced epigenetic mechanisms in sperm showed that transient exposure of pregnant rats to endocrine disruptors (e.g., vinclozolin) imparts reduced fertility to males across multiple generations through the male germline (Anway et al., ; Nilsson and Skinner, ). This phenomenon was associated with altered DNA methylation patterns in sperm (Anway et al., ; Nilsson and Skinner, ), and those effects have more recently been found to expand to histone retention and altered small RNA content (Ben Maamar et al., ; Schuster et al., ).…”

Direct evidence for transport of RNA from the mouse brain to the germline and offspring

“…The mode of transportation of RNAs may be via membrane-bound vesicles that are expelled from cells and contain an abundance of small RNAs [15][16][17], including miRNAs [18]. Long non-coding RNAs have also been indirectly postulated to be transferred to offspring due to experience-dependent alterations in the sperm [19][20][21][22]. We, therefore, postulated that somatically expressed RNAs may be transported to the germline allowing real-time heritability of somatic, experience-dependent alterations.…”

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

“…Small noncoding RNAs are known to regulate gene expression by affecting transcript stability and have been shown to be abundant in sperm with a single spermatozoon containing above 20,000 long and short noncoding RNAs [21,22]. Recently, concurrent alterations of DNA methylation, ncRNA, and histone alterations have been identified in sperm mediating the epigenetic transgenerational inheritance of pathology [23,24]. Therefore, the current study investigates alterations in both DNA methylation, ncRNA expression and gene expression.…”