The Industrial Chemical Bisphenol A (BPA) Interferes with Proliferative Activity and Development of Steroidogenic Capacity in Rat Leydig Cells
The Industrial Chemical Bisphenol A (BPA) Interferes with Proliferative Activity and Development of Steroidogenic Capacity in Rat Leydig Cells
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DOI：
10.1095/biolreprod.111.095349
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发表时间：
2012-05-01
影响因子：
3.6
通讯作者：
Akingbemi, Benson T.
中科院分区：
文献类型：
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作者：
Nanjappa, Manjunatha K.;Simon, Liz;Akingbemi, Benson T.
消费品中双酚 A (BPA) 的存在引发了人们对生殖健康潜在不利影响的担忧。睾丸间质细胞是男性性类固醇激素睾酮的主要来源，睾酮支持男性表型。本报告描述了雄性大鼠在妊娠第 12 天至产后第 21 天期间以 2.5 和 25 μg/kg 体重强饲给怀孕和哺乳期的 Long-Evans 母鼠对 BPA 发育的影响。这种暴露模式刺激了青春期前的间质细胞分裂，并在 90 天时增加了成年雄性大鼠睾丸中的间质细胞数量。体外实验观察结果证实，BPA 直接充当间质细胞中有丝分裂原。然而，BPA 诱导的体内增殖活性可能由多种因素介导，例如 1) 蛋白激酶（例如，丝裂原激活蛋白激酶或 MAPK），2) 生长因子受体（例如，胰岛素样生长因子 1 受体-β 和表皮生长因子受体），以及 3) 支持细胞分泌的抗苗勒管激素（也称为苗勒管抑制物质）。另一方面，BPA 抑制黄体生成激素受体 (LHCGR) 和 17β-羟基类固醇脱氢酶 (HSD17B3) 的蛋白表达，从而减少 Leydig 细胞的雄激素分泌。我们将这些发现解释为，在发育过程中接触 BPA 后，雄激素分泌不足对血清雄激素水平可能产生的影响会因间质细胞数量的增加而减轻。然而，目前的结果强化了这样的观点，即双酚 A 在与环境相关的暴露水平下会产生生物效应，并且其在消费品中的存在可能对公众健康产生影响。
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 mu g/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.