MOE Key Lab of Environmental Remediation and Ecosystem Health, Research Center for Air Pollution and Health, Institute of Environmental Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.
Zhejiang Key Laboratory of Organ Development and Regeneration, Institute of Developmental and Regenerative Biology, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China.
Environ Pollut. 2024 Apr 15;347:123716. doi: 10.1016/j.envpol.2024.123716. Epub 2024 Mar 6.
Parabens are widely used as antibacterial preservatives in foods and personal care products. The knowledge about the modes of toxic action of parabens on development and reproduction remain very limited. The present study attempted to establish a development and reproduction-associated adverse outcome pathway (AOP) by evaluating the effects of methylparaben (MP), ethylparaben (EP), propylparaben (PP) and butylparaben (BP) on the biosynthesis of gonadotropins, which are key hormones for development and reproduction. MP and BP significantly upregulated the mRNA and protein levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) in pituitary gonadotropic cells in a concentration-dependent manner. Activation of gonadotropin-releasing hormone receptor (GnRHR) was required for gonadotropin biosynthesis induced by BP, but not MP. Molecular docking data further demonstrated the higher binding efficiency of BP to human GnRHR than that of MP, suggesting GnRHR as a potential molecular initiative event (MIE) for BP-induced gonadotropin production. L-type voltage-gated calcium channels (VGCCs) were found to be another candidate for MIE in gonadotropic cells response to both MP and BP exposure. The calcium-dependent activation of extracellular signal-regulated kinase 1 (ERK1) and ERK2 was subsequently required for MP- and BP-induced activation of GnRHR and L-type VGCCs pathways. In summary, MP and BP promoted gonadotropin biosynthesis through their interactions with cellular macromolecules GnRHR, L-type VGCCs, and subsequent key event ERK1/2. This is the first study to report the direct interference of parabens with gonadotropin biosynthesis and establish a potential AOP based on pathway-specific mechanism, which contributes to the effective screening of environmental chemicals with developmental and reproductive health risks.
对羟基苯甲酸酯作为食品和个人护理产品中的抗菌防腐剂被广泛使用。然而，对其影响发育和生殖的毒性作用模式的了解非常有限。本研究通过评估对羟基苯甲酸甲酯（MP）、对羟基苯甲酸乙酯（EP）、对羟基苯甲酸丙酯（PP）和对羟基苯甲酸丁酯（BP）对促性腺激素生物合成的影响，试图建立一个与发育和生殖相关的不良结局途径（AOP）。MP 和 BP 以浓度依赖的方式显著上调了垂体促性腺细胞中促卵泡激素（FSH）和促黄体生成素（LH）的 mRNA 和蛋白水平。BP 诱导促性腺激素生物合成需要激活促性腺激素释放激素受体（GnRHR），而 MP 则不需要。分子对接数据进一步表明，BP 与人类 GnRHR 的结合效率高于 MP，提示 GnRHR 可能是 BP 诱导促性腺激素产生的潜在分子起始事件（MIE）。L 型电压门控钙通道（VGCCs）也被发现是促性腺细胞对 MP 和 BP 暴露反应的另一个 MIE 候选者。随后，钙依赖性细胞外信号调节激酶 1（ERK1）和 ERK2 的激活对于 MP 和 BP 诱导的 GnRHR 和 L 型 VGCCs 途径的激活是必需的。综上所述，MP 和 BP 通过与细胞大分子 GnRHR、L 型 VGCCs 相互作用，并随后激活关键事件 ERK1/2，促进促性腺激素的生物合成。这是首次报道对羟基苯甲酸酯直接干扰促性腺激素生物合成并基于特定途径的机制建立潜在 AOP 的研究，有助于有效筛选具有发育和生殖健康风险的环境化学物质。
