Chronic exposure to low dose of bisphenol A impacts on the first round of spermatogenesis via SIRT1 modulation

Abstract

Spermatogenesis depends on endocrine, autocrine and paracrine communications along the hypothalamus-pituitary-gonad axis. Bisphenol A (BPA), an estrogen-mimic endocrine disrupting chemical, is an environmental contaminant used to manufacture polycarbonate plastics and epoxy resins with toxic effects for male reproduction. Here we investigated whether the chronic exposure to low BPA doses affects spermatogenesis through the modulation of SIRT1, a NAD+-dependent deacetylase involved in the progression of spermatogenesis, with outcomes on apoptosis, oxidative stress, metabolism and energy homeostasis. BPA exposure via placenta first, and lactation and drinking water later, affected the body weight gain in male offspring at 45 postnatal days and the first round of spermatogenesis, with impairment of blood testis barrier, reactive oxygen species production, DNA damage and decreased expression of SIRT1. The analysis of SIRT1 downstream molecular pathways revealed the increase of acetyl-p53Lys370, γH2AX foci, the decrease of oxidative stress defenses and the higher apoptotic rate in the testis of treated animals, with partial rescue at sex maturation. In conclusion, SIRT1 pathways disruption after BPA exposure can have serious consequences on the first round of spermatogenesis.

Environmental Impact on Male (In)Fertility via Epigenetic Route

“…The rationale is simple: Sirt1 has an essential role in germ cells differentiation and fertility, thus an increase in the expression of this well-known class III-HDAC can possibly mediate the decreased acetylation levels of H3 and H4 histones observed in chronically BPA-treated rats [ 179 ]. Indeed, chronic exposure to a low BPA concentration can impact the first round of spermatogenesis through Sirt1 modulation [ 180 ]. First via placenta and then through lactation and drinking water, BPA is able to impair the blood-testis-barrier, induce the production of reactive oxygen species (ROS) and DNA damage and diminish Sirt1 expression.…”

“…Analysis of Sirt1 downstream molecular pathways shows increased acetyl-p53Lys370, γH2AX foci, decreased oxidative stress defenses and higher apoptotic rate in rat testis, with partial rescue at sex maturation. Importantly, the concentration used herein is lower or within the reference limit for humans and therefore, currently considered “safe” by the European Food Safety Agency (ESFA) and the U.S. Environmental Protection Agency (EPA) [ 180 ]. Nevertheless, it retrieves worrisome results.…”

BPA and Nutraceuticals, Simultaneous Effects on Endocrine Functions

“…Impairment of blood-testis barrier, apoptosis of Sertoli and germ cells, defective steroidogenesis, DNA breaking and reduced semen parameters (count, motility, viability) are the main outcomes on testis physiology and semen quality [ 40 ]. In rats exposed from gestational stage to BPA doses potentially considered safe for humans, impairment in both spermatogenesis and post-natal development of epididymis has been reported [ 41 , 42 ], thus suggesting that BPA may affect the microenvironment in which spermatozoa maturation occurs.…”

Quantitative proteomic analysis of mouse testis uncovers cellular pathways associated with bisphenol A (BPA)-induced male infertility

“…Bisphenol A (BPA), namely 2,2-bis (4-hydroxyphenyl) propane, is one of the highest volume of EDCs produced worldwide (Dohle et al 2003;Sweeney et al 2015;WHO and UNEP, 2013). It is frequently used to produce plas-tics that serves as line food or drink containers, goods of common use, thermal receipts, and medical devices such as dental sealants (Chianese et al 2018). It is well known that BPA can be detected in many human tissues, such as serum, urine, sweat, milk and placenta (Chianese et al 2018).…”

“…It is frequently used to produce plas-tics that serves as line food or drink containers, goods of common use, thermal receipts, and medical devices such as dental sealants (Chianese et al 2018). It is well known that BPA can be detected in many human tissues, such as serum, urine, sweat, milk and placenta (Chianese et al 2018). In general, the daily safe intake of BPA in human should be less than 1 μg/kg per day (Kang et al 2006).…”