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.
Highlights
Spermatogenesis is a complex biological process that requires the self-renewal and the commitment of diploid spermatogonia for proliferation, the meiosis of spermatocytes and the post-meiotic differentiation of haploid spermatids into mature spermatozoa
We investigated whether the chronic exposure of rats to low BPA doses affects the first round of spermatogenesis modulating SIRT1 expression and its downstream molecular pathways
In order to assess the integrity of seminiferous epithelium that can affect the correct progression of spermatogenesis, we evaluated the expression and the localization of connexin 43 (Cx43) and zonula occludens 1 (ZO-1), well-known markers of the BTB27
Summary
Spermatogenesis is a complex biological process that requires the self-renewal and the commitment of diploid spermatogonia for proliferation, the meiosis of spermatocytes and the post-meiotic differentiation of haploid spermatids into mature spermatozoa This process strongly depends on endocrine control through the hypothalamus-pituitary-gonad (HPG) axis and requires intratesticular autocrine and paracrine communications between germ and somatic cells[1,2,3,4,5]. Sirt[1] knockout male mice are infertile due to the down-regulation of the HPG axis[24] In this model, spermatogenesis arrests before the completion of meiosis, apoptosis of pachytene spermatocytes occurs, somatic Leydig and Sertoli cells share abnormal maturation and testis produces low testosterone levels. We investigated whether the chronic exposure of rats (from foetal period until the completion of the first round of spermatogenesis) to low BPA doses affects the first round of spermatogenesis modulating SIRT1 expression and its downstream molecular pathways
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