Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men

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.

Melatonin protects prepuberal testis from deleterious effects of bisphenol A or diethylhexyl phthalate by preserving H3K9 methylation

“…The exposure of BPA and DEHP leads to oxidative stress in cells and has been recently associated with epigenetic changes . In particular, BPA alters global DNA and H3 histone methylation in human cell lines, and causes DNA hydroxymethylation, partially dependent on trimethylation of histone H3, during spermatogenesis . Similarly, in the mouse, pubertal exposure to DEHP resulted in defects in spermatogenesis attributed to the inhibition of G9a‐mediated histone methylation .…”

“…23,24 In particular, BPA alters global DNA and H3 histone methylation in human cell lines, 25 and causes DNA hydroxymethylation, partially dependent on trimethylation of histone H3, during spermatogenesis. 26 Similarly, in the mouse, pubertal exposure to DEHP resulted in defects in spermatogenesis attributed to the inhibition of G9amediated histone methylation. 11 The activity of the G9a (a histone methyltransferase) or Meisetz methyltransferases on H3K9me1 (histone 3 [H3] lysine 9 [K9] trimethylation [me1]) and H3K9me2 and H3K4me3 are essential for activation of meiotic genes and meiotic progression.…”

DNA hydroxymethylation rate in the AChE and HoxC4 promoter associated with human sperm quality

“…Alteration in 5hmc has been found to exist widely in globozoospermia spermatozoa (Wang et al., ) and the spermatozoa from infertile men (Efimova et al., ). We recently reported the presence of genome‐wide alteration of 5hmc in the spermatozoa from the men exposed to bisphenol A (BPA; Zheng et al., ), a widely studied endocrine‐disrupting chemical (EDC) which has a power to reduce human sperm quality, according to the human epidemiologic studies (Li et al., ). These studies suggest that 5hmc has a potential to be a new biomarker for evaluation of sperm quality.…”

“…Bisphenol A exposure raised the 5hmc levels in the promoter regions of acetylcholinesterase (AChE) and homeobox C4 (HoxC4) genes in human spermatozoa (Zheng et al., ). AChE is the primary acetylcholine‐hydrolysing enzyme in the body.…”

Potential Health Risks Linked to Emerging Contaminants in Major Rivers and Treated Waters

“…BPA exposure can also lead to disruptions in DNA methylation and histone acetylation patterns [144]. Also, as was shown with atrazine exposure, a potential epigenetic transgenerational effect (on insulin production in this case) has been reported in F1 and F2 mouse offspring after maternal BPA exposure [145].…”