Abstract
Environmental BPA exposure has been shown to impact human sperm concentration and motility, as well as rodent spermatogenesis. However, it is unclear whether BPA exposure is associated with alteration in DNA hydroxymethylation, a marker for epigenetic modification, in human sperm. A genome-wide DNA hydroxymethylation study was performed using sperm samples of men who were occupationally exposed to BPA. Compared with controls who had no occupational BPA exposure, the total levels of 5-hydroxymethylcytosine (5hmc) increased significantly (19.37% increase) in BPA-exposed men, with 72.69% of genome regions harboring 5hmc. A total of 9,610 differential 5hmc regions (DhMRs) were revealed in BPA-exposed men relative to controls, which were mainly located in intergenic and intron regions. These DhMRs were composed of 8,670 hyper-hMRs and 940 hypo-hMRs, affecting 2,008 genes and the repetitive elements. The hyper-hMRs affected genes were enriched in pathways associated with nervous system, development, cardiovascular diseases and signal transduction. Additionally, enrichment of 5hmc was observed in the promoters of eight maternally expressed imprinted genes in BPA-exposed sperm. Some of the BPA-affected genes, for example, MLH1, CHD2, SPATA12 and SPATA20 might participate in the response to DNA damage in germ cells caused by BPA. Our analysis showed that enrichment of 5hmc both in promoters and gene bodies is higher in the genes whose expression has been detected in human sperm than those whose expression is absent. Importantly, we observed that BPA exposure affected the 5hmc level in 11.4% of these genes expressed in sperm, and in 6.85% of the sperm genome. Finally, we also observed that BPA exposure tends to change the 5hmc enrichment in the genes which was previously reported to be distributed with the trimethylated Histone 3 (H3K27me3, H3K4me2 or H3K4me3) in sperm. Thus, these results suggest that BPA exposure likely interferes with gene expression via affecting DNA hydroxymethylation in a way partially dependent on trimethylation of H3 in human spermatogenesis. Our current study reveals a new mechanism by which BPA exposure reduces human sperm quality.
Highlights
Bisphenol A (BPA) is an endocrine disrupting chemical used mainly in epoxy resin and polycarbonate plastic industry
Our analysis revealed that 44.6% (895/2,008) of the genes with BPA-responsive differential 5hmc regions (DhMRs) bind H3K4me3, while only 28.5% (573/2,008), 23.6% (474/2,008) and 15.2% (306/ 2,008) of them binds with H3K4me2, H3K27me3 and H3K4me3/H3K27me3, respectively (The p-value between H3K4me3 and H3K4me2 was 2.2E-16, between H3K4me3 and H3K27me3 was 2.2E-163H) (Fig 4A–4D)
Given more than 100 LINE-1-mediated insertions which result in genetic diseases have been reported [57] and derepression of LINE-1 along with complete male sterility is linked to azoospermia [58], upregulated 5hmc rate in LINE-1 likely raises genomic instability, eventually making a contribution to reduced sperm concentration in the men exposed to BPA
Summary
Bisphenol A (BPA) is an endocrine disrupting chemical used mainly in epoxy resin and polycarbonate plastic industry. Human studies have shown that BPA exposure is associated with sexual function as well as sexual hormones among males [2, 3]. We identified an inverse association between total urinary BPA levels and semen concentration, total sperm count, sperm vitality and sperm motility among factory workers [4]. Male rodents exposed to various levels of BPA displayed several reproductive and developmental impacts, including decreased serum testosterone levels and sperm quality [8]. BPA has been shown to impact sperm motility in vivo and in vitro [9, 10]. Paternal BPA exposure of mice resulted in a global alteration of DNA methylation in offspring’s sperm which is associated with an impaired spermatogenesis [17] and heart problems[18] observed in offspring
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