Impairment in HPT Axis of Male Rat Offspring (F1) Perinatally Exposed to Environmentally Relevant Dose of Bisphenol A.

Abstract

BPA is a monomer that is used in the manufacture of polycarbonate plastics, epoxy resins and a multitude of consumer products. It easily leaches from the inner lining of tin cans and microwave containers into food during heating, from dental sealant into saliva and into beverages from repeated usage or contact with any acidic/alkaline content in polycarbonate bottles. The detection of BPA in biological fluids like maternal plasma, fetal plasma, placental tissue, amniotic fluid and umbilical cord blood have indicated that it can easily transverse the placental barrier. Perinatal period (gestation day (GD) 12-post natal day (PND) 21) encompasses the critical period of gestation and lactation wherein development of the hypothalamus-pituitary-testicular (HPT) axis occurs, especially development of testes that occurs on GD12. Studies on perinatal exposure of BPA have documented its effect on expression of steroid receptors (SRs) in target organs like the mammary gland and brain respectively, resulting in changes in morphogenesis and disturbances in sexual and mating behavior. However, no information is currently available on the effects of BPA in the male offspring of rats exposed to environmentally relevant doses during the critical perinatal period of development and growth of the reproductive tract. The present study aimed at investigating the effects of BPA exposure during this critical window of development (GD12-PND21) on fertility of F1 offspring and understanding its mechanism. Pregnant Holtzman rats (F0) were gavaged with BPA (1.2 and 2.4 μg/Kg /day ) from GD 12-PND 22. Pregnant female treated similarly with DES served as positive control. ON PND 75, fertility assessment of F1 males was performed by cohabitating them with normal cycling adult females. Copulated females were distributed in two sets, one was allowed to deliver the pups and the other was sacrificed on GD 20. The copulated females were examined for various fertility parameters. After fertility assessment male rats (F1) were sacrificed and serum hormonal profile, epididymal sperm count and motility was determined. Histological examination of testis and staging of seminiferous tubules Immuno histochemistry for steroid receptors and their co regulators was performed in testis and quantitative image analysis was performed to assess their levels of expression. A significant increase in the number of copulated females exhibiting resorption was observed at both dose groups of BPA. The adult F1 male offspring showed significant decrease in LH, FSH T and E2. A significant reduction in epididymal sperm count and motility was observed. At the testicular level majority of the seminiferous tubules exhibited sloughing of germ cells. Immunohistchemical localization studies demonstrated significant increase in ER with no effect on AR where as a significant reduction in the expression of SRC-1 and NCoR with a parallel increase in the expression of p/CIP and GRIP -1 was observed. Perinatal exposure to environmentally relevant dose of BPA affects the male gem line leading to impairment in the fertility of F1 male offspring. (platform)