Neonatal exposure of male rats to Bisphenol A impairs fertility and expression of sertoli cell junctional proteins in the testis.
BACKGROUND
Sertoli cell junctional proteins (SCJP) (viz. adhesion, gap and tight junctions) are important for spermatogenesis and perturbations in expression of these proteins are associated with impairments in process of sperm production. Bisphenol A (BPA) is an endocrine disrupter that has been associated with impaired spermatogenesis. However the mechanistic basis of impaired spermatogenesis is unknown, whether BPA is a Sertoli cell toxicant has not yet been fully investigated.


OBJECTIVE
The present study was undertaken to decipher the effects of neonatal exposure of male rats to BPA on fertility and its effect on the testicular expression of SCJP during development.


METHODS
Neonatal male rats were s.c. injected with BPA at doses ranging from 0.6 to 10 microg/rat (100-1600 microg/kg bw of BPA) on post-natal days (PNDs) 1-5, and controls received vehicle. Diethylstilbestrol (DES) was used as a positive control. Male fertility was assessed during adulthood and the lowest dose of BPA that was most effective at impairing fertility was determined. Immunohistochemical localization for Connexin 43 (Cx-43, gap junctional), Zona Occludin-1 (ZO-1, tight junctions) and N-cadherin (adherens junction) was carried out on testicular tissue sections obtained from PNDs 15, 30, 45 and 90 of rats exposed to lowest dose of BPA that impaired fertility.


RESULTS
Females mated with male rats that were exposed neonatally to various concentrations of BPA showed a significant increase in post-implantation loss and a decrease in litter size. There were significant changes in sperm count along with hormonal imbalances in the rats exposed neonatally to BPA. The 2.4 microg dose (400 microg/kg bw) of BPA was determined as the lowest dose that was capable of impairing male fertility. A significant reduction in the expression of Cx-43 (PND 45 and 90) and increases in the expression of N-cadherin (PND 45 and 90) and ZO-1 (PND 90) were observed in the testes of rats exposed neonatally to effective dose of BPA. Interestingly, there was an altered expression pattern of Cx43 amongst the sloughed cells in the testes of the experimental rats as compared to controls.


CONCLUSIONS
Neonatal exposure of BPA to rats impairs their fertility and has the potential to induce perturbations in SCJP. These perturbations may be one of the contributing factors that lead to impairments in spermatogenesis in the exposed animals and can be used as potential biomarkers to study BPA-induced effects on testes.
National Center for Preclinical Reproductive and Genetic Toxicology, National Institute for Research in Reproductive Health (ICMR), JM Street, Parel, Mumbai 400 012, Maharashtra, India.
Smita
S
Salian
Tanvi
T
Doshi
Geeta
G
Vanage
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001559:Benzhydryl Compounds; D015820:Cadherins / Q000378:metabolism; D018031:Connexin 43 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors; D004822:Epididymis / Q000166:cytology; D005260:Female; D005298:Fertility / Q000187:drug effects*; D006728:Hormones / Q000097:blood; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism; D008098:Litter Size / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D010636:Phenols / Q000633:toxicity*; D010750:Phosphoproteins / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D012671:Seminiferous Tubules / Q000187:drug effects; D012708:Sertoli Cells / Q000187:drug effects* / Q000378:metabolism*; D013076:Sperm Count; D013081:Sperm Motility / Q000187:drug effects; D013737:Testis / Q000187:drug effects / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D015820:Cadherins; D018031:Connexin 43; D052244:Endocrine Disruptors; D006728:Hormones; D008565:Membrane Proteins; D010636:Phenols; D010750:Phosphoproteins; D062826:Zonula Occludens-1 Protein; C569044:Tjp1 protein, rat; C006780:bisphenol A; D000098826:Bisphenol A Compounds