Abstract
Exposure to environmental factors during fetal development may lead to epigenomic modifications in fetal germ cells, altering gene expression and promoting diseases in successive generations. In mouse, maternal exposure to di(2-ethylhexyl) phthalate (DEHP) is known to induce defects in spermatogenesis in successive generations, but the mechanism(s) of impaired spermatogenesis are unclear. Here, we showed that maternal DEHP exposure results in DNA hypermethylation of promoters of spermatogenesis-related genes in fetal testicular germ cells in F1 mice, and hypermethylation of Hist1h2ba, Sycp1, and Taf7l, which are crucial for spermatogenesis, persisted from fetal testicular cells to adult spermatogonia, resulting in the downregulation of expression of these genes. Forced methylation of these gene promoters silenced expression of these loci in a reporter assay. These results suggested that maternal DEHP exposure-induced hypermethylation of Hist1h2ba, Sycp1, and Taf7l results in downregulation of these genes in spermatogonia and subsequent defects in spermatogenesis, at least in the F1 generation.
Highlights
A wide variety of environmental influences have been shown to greatly impact human health, with the effects persisting through multiple generations (Daxinger & Whitelaw, 2012; Taouk & Schulkin, 2016)
We used histological evaluation to examine spermatogenesis in the F1 of dams exposed to Di (2-ethylhexyl) phthalate (DEHP) and in the F2 resulting from mating of these maternally exposed F1 males with untreated C57BL/6 females
Testicular abnormalities, including vacuoles in tubules (Type A), no lumen in tubules (Type B), and apoptotic cells (Type C), were observed in F1 males of the DEHP group, while few abnormal tubules were found in the oil group as vehicle control (Fig 1A), as previously reported (Doyle et al, 2013)
Summary
A wide variety of environmental influences have been shown to greatly impact human health, with the effects persisting through multiple generations (Daxinger & Whitelaw, 2012; Taouk & Schulkin, 2016). Studies on the Dutch famine of 1944 indicated that poor maternal nutrition during pregnancy was associated with low birth weight as well as a greater risk of metabolic and cardiovascular diseases in offspring (Painter et al, 2005). Those studies showed that maternal nutritional conditions resulted in changes in offspring in DNA methylation patterns in the promoters of genes related to metabolic diseases and cardiac diseases (Tobi et al, 2009), suggesting the involvement of epigenetic modifications in germ cells in inter-/transgenerational influences of the maternal environment. Concerning nutritional influences, paternal prediabetes has been shown to alter DNA methylation of sperm genes encoding components of the insulin signaling pathway, leading to glucose intolerance and insulin resistance in the offspring (Wei et al, 2014)
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