The Industrial Chemical Bisphenol A (BPA) Interferes with Proliferative Activity and Development of Steroidogenic Capacity in Rat Leydig Cells1

Abstract

The presence of bisphenol A (BPA) in consumer products has raised concerns about potential adverse effects on reproductive health. Testicular Leydig cells are the predominant source of the male sex steroid hormone testosterone, which supports the male phenotype. The present report describes the effects of developmental exposure of male rats to BPA by gavage of pregnant and lactating Long-Evans dams at 2.5 and 25 μg/kg body weight from Gestational Day 12 to Day 21 postpartum. This exposure paradigm stimulated Leydig cell division in the prepubertal period and increased Leydig cell numbers in the testes of adult male rats at 90 days. Observations from in vitro experiments confirmed that BPA acts directly as a mitogen in Leydig cells. However, BPA-induced proliferative activity in vivo is possibly mediated by several factors, such as 1) protein kinases (e.g., mitogen-activated protein kinases or MAPK), 2) growth factor receptors (e.g., insulin-like growth factor 1 receptor-beta and epidermal growth factor receptors), and 3) the Sertoli cell-secreted anti-Mullerian hormone (also called Mullerian inhibiting substance). On the other hand, BPA suppressed protein expression of the luteinizing hormone receptor (LHCGR) and the 17beta-hydroxysteroid dehydrogenase enzyme (HSD17B3), thereby decreasing androgen secretion by Leydig cells. We interpret these findings to mean that the likely impact of deficits in androgen secretion on serum androgen levels following developmental exposure to BPA is alleviated by increased Leydig cell numbers. Nevertheless, the present results reinforce the view that BPA causes biological effects at environmentally relevant exposure levels and its presence in consumer products potentially has implication for public health.

Brief maternal exposure of rats to the xenobiotics dibutyl phthalate or diethylstilbestrol alters adult-type Leydig cell development in male offspring

“…These results are similar to those recently reported for maternal bisphenol A exposure, which appears to have comparable estrogenic effects on adult-type Leydig cell differentiation. 33 There is also a good correlation between the findings reported here and our recent study on the influence of DBP and DES upon adult-type Leydig cell regeneration following ethane dimethane sulfonate ablation, 4 where also the kinetics of Leydig cell differentiation was modulated by these xenobiotics.…”

Low‐Dose Bisphenol A Exposure: A Seemingly Instigating Carcinogenic Effect on Breast Cancer

“…Thus, these preliminary studies suggest that low‐dose BPA has the potential to pose health hazards. Recent studies have also aimed to evaluate the role of BPA in carcinogenesis,7, 22, 23 and have indicated that exposure to BPA may account, at least partially, for the increased incidence of multiple cancers, including breast cancer,24, 25, 26, 27 ovarian cancer,28, 29 uterine cancer,30 prostate cancer,31, 32 testicular cancer,33 and liver cancer 34. The carcinogenic effects of BPA are summarized in Table 1 .…”

Bisphenol A and Male Reproductive System

“…Estrogen receptors (ERs) are highly expressed as well as androgen receptors at male reproductive tract including Leydig cells (60,61). It is reported that estrogens are as important as androgens in male reproductive tract biology (62).…”

“…A number of researchers have reported that BPA has the ability to bind the estrogen receptor and bring about defects in the reproductive tract at studies in vitro rodent models (64)(65)(66). It is assumed that BPA has a higher affinity for ER-β but BPA can active ER-α and ER-β-mediated transcription process with comparable effectiveness in some tissues (61,67,68). Previous investigations have reported that BPA acts as an AR (Androgen Receptor) antagonist and can interact with ER-α and ER-β (69).…”

“…Moreover, BPA has the ability to exhibit antiandrogenic activity (73,74) and rise bioavailability of sex steroid hormones via interrupting metabolic breakdown (61,75). In addition, due to suppressing expression of LH receptors (LHCGR) and the enzyme HSD17B3, BPA reduces releasing of androgen (61).…”