Perinatal exposure of rats to Bisphenol A affects the fertility of male offspring
Introduction
The increasing number of occurrences of impairment in the reproductive functions in humans and wildlife observed over the past few decades have raised concerns about certain chemicals in our environment known as endocrine disruptors (EDs) (Colborn et al., 1993, Toppari et al., 1996). EDs mimic hormone-like activities and have the potential to modulate or disrupt the endocrine system. One such estrogenic ED is Bisphenol A (BPA), a monomer used in the manufacturing of polycarbonate plastic and epoxy resins. Humans are ubiquitously exposed to BPA as it leaches from the inner lining of tin cans and microwave containers during heating, from dental sealant into saliva, and into beverages from the polycarbonate bottle due to repeated usage or contact with any acidic/alkaline content (Brotons et al., 1995, Olea et al., 1996).
The levels of BPA in biological fluids like maternal plasma, fetal plasma, placental tissue, amniotic fluid and umbilical cord blood indicate that BPA can easily transverse the placental barrier (Tsutsumi 2005). Developing fetuses would be more susceptible to BPA exposure as they have a decreased metabolism efficiency and a low concentration of serum binding proteins (Schonfelder et al., 2002, Takai et al., 2000). Earlier reports have documented that the in-utero and neonatal exposure of male rats to BPA leads to adverse effects on their reproductive functions, especially with regard to impairment in spermatogenesis and spermiogenesis (Aikawa et al., 2004, Toyama and Yuasa, 2004).
The perinatal period is considered to be one of the sensitive and vulnerable “windows” of development that encompasses a crucial period involving sexual differentiation wherein minor hormonal perturbations may have a long lasting impact on fertility (Saunders et al. 1997). Perinatal exposure of rats to BPA has also been demonstrated to cause problems in target organs like the brain and mammary gland in which BPA elicits its action by interacting with the SRs and their coregulators (Muñoz-de-Toro et al., 2005, Aloisi et al., 2001, Negishi et al., 2004, Xu et al., 2007). Similar to the brain and mammary gland, the developing male reproductive tract is an estrogen-responsive site containing a wide distribution of SRs. The majority of studies dealing with perinatal exposure to BPA have shown its effect on hormonal perturbations and depotentiation of sexual behavior in F1 male rats during adulthood (Akingbemi et al., 2004, Watanabe et al., 2003, Farabollini et al., 2002). However, no information is currently available on the effects on the fertility status of the male offspring of rats perinatally exposed to environmentally relevant doses of BPA. The present study was undertaken to answer this question; additionally our aim was to study whether these effects are transmitted through the germline to the next generation. The impairments in spermatogenesis observed in perinatally exposed F1 male offspring led us to further investigate the effects of perinatal exposure to BPA on SR expression in steroid-responsive organ like the testes. Since early life exposure to BPA is likely to predispose an individual to a wide range of disease states of fetal origin, the data generated will have a significant role in predicting human health risk assessment.
Section snippets
Chemicals and reagents
Bisphenol A (CAS # [80-05-7] (BPA; 99.8% purity)) and Diethylstilbestrol (DES; 99% purity) were purchased from Sigma Chemical Co., St. Louis, MO. Antibodies against testosterone and estradiol were obtained from the WHO and ICN, respectively, for performing radioimmunoassays. The standards for luteinizing hormone (LH; NIADDK-rat-LH-RP2) and follicle-stimulating hormone (FSH; NIADDK-rat-FSH-RP2) were obtained from the NIH. The standards for testosterone (T) and estradiol (E) were obtained from
Clinical observation and body weight changes in F0 females perinatally exposed to BPA
No adverse clinical signs and symptoms were observed in pregnant F0 females in any of the treated groups. The body weights recorded for treated F0 females throughout the dosing regime were comparable to the control.
Fertility assessment of F1, F2 and F3 generation males
The fertility assessment data of adult male rats perinatally exposed to BPA and of the subsequent F2 and F3 generations sired by these males are summarized in Table 1. The time taken for copulation was found to be significantly higher in F1 male offspring of rats exposed to both
Discussion
In the present study, perinatal exposure of rats to BPA resulted in reduced sperm counts and motility in the male offspring; these males were found to be sub-fertile when mated with normal cycling females not exposed to BPA. The present study thus provides evidence that suggests impairment of fertility and spermatogenesis in F1 male offspring perinatally exposed to BPA. Importantly, these effects persisted in the subsequent F2 and F3 generations and were highly significant. These observations
Conclusion
The present study demonstrates for the first time that the exposure of rats to environmentally relevant doses of BPA during the perinatal period leads to impairments in fertility and perturbations in the testicular SR expression pattern in F1 male offspring and their subsequent generations. The transgenerational effects observed in the present study are mediated via germ line transmission.
Acknowledgements
The authors gratefully acknowledge Dr. P. Parte (Research Officer, National Institute for Research in Reproductive Health) for her valuable advice and critical reading of the manuscript. The authors would like to acknowledge the Department of Science and Technology (VII-PRDSF/101/05-06/TDT) and the Indian Council of Medical Research (44/3/99-BMS), India for providing the financial support and fellowship to Ms. S. Salian. The authors also thank Mr. H. Karekar, Mr. H.G. Pawar and Mr. P. Salunke
References (40)
- et al.
Bisphenol A differently affects estrogen receptors-alpha in estrous-cycling and lactating female rats
Neuroscience Letter
(2001) - et al.
Effect of high intratesticular estrogen on the seminiferous epithelium in adult male rats
Molecular and Cellular Endocrinology
(2005) - et al.
Rat two-generation reproductive toxicity study of Bisphenol A
Reproductive Toxicology
(2001) - et al.
Dietary diethylstilbestrol but not genistein adversely affects rat testicular development
Journal of Nutrition
(2003) - et al.
Effects of bisphenol A given neonatally on reproductive functions of male rats
Reproductive Toxicology
(2006) - et al.
Preimplantation exposure to Bisphenol A advances postnatal development
Reproductive Toxicology
(2000) - et al.
Effects of neonatal administration of 17beta-estradiol, beta estradiol 3-benzoate, or Bisphenol A on mouse and rat spermatogenesis
Reproductive Toxicology
(2004) Assessment of human contamination of estrogenic endocrine disrupting chemicals and their risk for human reproduction
Journal of Steroid Biochemistry and Molecular Biology
(2005)- et al.
Perinatal Bisphenol A affects the behavior and SRC-1 expression of male pups but does not influence on the thyroid hormone receptors and its responsive gene
Neuroscience Research
(2007) - et al.
Relief effect of vitamin A on the decreased motility of sperm and the increased incidence of malformed sperm in mice exposed neonatally to Bisphenol A
Cell Tissue Research
(2004)
Inhibition of testicular steroidogenesis by the xenoestrogen Bisphenol A is associated with reduced pituitary luteinizing hormone secretion and decreased steroidogenic enzyme gene expression in rat Leydig cells
Endocrinology
Effects of Bisphenol A on adult male mouse fertility
European Journal of Oral Sciences
Transgenerational effect of the endocrine disruptor vinclozolin on male spermatogenesis
Journal of Andrology
Immunohistochemical localization of androgen receptors in the rat testes: evidence for stage-dependent expression and regulation by androgens
Endocrinology
Xenoestrogens released from lacquer coatings in food cans
Environmental Health Perspectives
Transgenerational epigenetic imprinting of the male germline by endocrine disruptor exposure during gonadal sex determination
Endocrinology
Developmental effects of endocrine disrupting chemicals in wildlife and humans
Environmental Health Perspectives
Spermatogenesis
Human Reproduction
Effects of perinatal exposure to Bisphenol A on sociosexual behavior of female and male rats
Environmental Health Perspectives
Immunolocalisation of oestrogen receptor alpha within the testes and excurrent ducts of the rat and marmoset monkey from perinatal life to adulthood
Journal of Endocrinology
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