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

Abstract

A growing number of couples experience fertility issues with almost half being due to malefactors. The exposure to toxic environmental contaminants, such as endocrine disruptors (EDs), has been shown to negatively affect male fertility. EDs are present in the environment, and exposure to these toxins results in the failure of spermatogenesis. The deleterious effects of EDs on spermatogenesis have been well documented, whereas improvement of infertility associated with spermatogenesis defects remains a great challenge. Herein, we report that in vitro exposure of prepuberal mouse testes to two well-known endocrine disruptors (EDs), bisphenol A (BPA) or diethylhexyl phthalate (DEHP), impairs spermatogenesis with perturbing self-renewal, spermatogonia activity, and meiosis. Evidence indicates that such effects are likely due, at least in part, to decreased G9a-dependent H3K9 di-methylation. Of note, we found that melatonin (MLT) protected the testis from the negative ED impacts with preserving spermatogonia stem and meiotic cells, along with maintaining normal H3K9 di-methylation in these cells. Taken together, this work documents that BPA and EDHP adversely affect prepuberal spermatogenesis and perturb crucial epigenetic activities in male germ cells and highlight the protective ability of MLT.

Bisphenol A-Induced Epigenetic Changes and Its Effects on the Male Reproductive System

“…Consequently, the ability to interfere with the hormonal axis has been observed, thereby influencing steroid signaling (12). BPA affects testis competence, varying the gene expression of steroid hormone receptors and influencing the enzymes that catalyze DNA methylation, as demonstrated by in vivo and in vitro animal studies (13)(14)(15)(16)(17)(18)(19)(20)(21).…”

“…Another mechanism by which epigenetic changes are induced may be the increase in oxidative stress caused by BPA exposure (18,19); in this sense, an in vitro study from Zhang et al (20) showed that after exposing mouse testicular cells to BPA, the mRNA levels of proteins involved in sexual hormone steroidogenesis as StAR, P450scc, Cyp17a1, and 3β-HSD were reduced but were also normalized after exposure to melatonin. Finally, the exposure to BPA in mouse preimplantation embryo produces a disruption of testicular synthesis of testosterone and reduction of StAR promoter histone acetylation, thereby inducing a retard of testis development (21).…”

Advances in Characterizing Recently-Identified Molecular Actions of Melatonin: Clinical Implications

“…Melatonin appears to be particularly suitable in serving as an environmental sensor [106], given that its secretion is affected by different wavelengths of light [192], temperature [160], altitude [116] and seasonal cycles [85]. Recent literature indicates that melatonin protects spermatogonial stem cells from endocrine disruptors such as bisphenol A or diethylhexyl phthalate by maintaining histone H3K9 dimethylation and promotes their recovery [284]. Similarly, melatonin also protects spermatogonial stem cells in mice from hexavalent chromium, another environmental carcinogen, by preventing trimethylation of histone H3K9 or H3K27, thereby preventing germ cell apoptosis and maintaining fertility [148,287].…”

DNA oxidation induced by fetal exposure to BPA agonists impairs female meiosis

“…Wang et al, 2016;. Lastly, some studies have shown that post-natal exposure to BPA increases the amount of reactive oxygen species (ROS) compromising oocyte maturation and chromosome segregation and inducing DNA damages such as 8-hydroxydeoxyguanosine (8OdG) (Ganesan & Keating, 2016;T. Zhang et al, 2018).…”