Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bahía Blanca, Argentina.
Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS), Bahía Blanca, Argentina.
Reproduction. 2024 Jun 13;168(1). doi: 10.1530/REP-23-0292. Print 2024 Jul 1.
The endocrine disruptor, nonylphenol (NP) increases 20:4n-6 release in Sertoli cells via PKA/cPLA2 activation. Our data show that lipid metabolism could be a target of NP-induced abnormal reproductive outcomes.
Nonylphenol (NP), an endocrine-disrupting chemical, is an environmental contaminant, and many notorious effects on male fertility have been reported in animal models and wild-type species. Here, we evaluated the effects of NP in follicle-stimulating hormone (FSH) signal transduction pathways and lipid metabolism using an in vitro model of rat Sertoli cell (SC) primary culture. Results show that an acute (1 h) SC exposure to NP (10 µM) increased the intra- and extra-cellular concentrations of free fatty acids (FFAs), mainly arachidonic acid (20:4n-6). Phosphatidylinositol seemed to be the major phospholipid source of this 20:4n-6 release by activation of the protein kinase A (PKA)/cytoplasmic phospholipase A2 (cPLA2) pathway. NP also increased diacylglycerols (DAG) levels and the expression (mRNA) of cyclooxygenase 2 (Cox2) and prostaglandin E2 (PGE2) levels. It is noteworthy that accumulation of lipid droplets took place after 24 h NP exposition, which was prevented by both a PKA inhibitor and a PLA2 inhibitor. Like FSH, NP triggers the release of 20:4n-6, which is a substrate for PGE2 synthesis via PKA/PLA2 activation. In addition, NP induces the formation of DAG, which could be required as a cofactor of the PKC-mediated activation of the COX2 inflammatory pathway. Our findings suggest that NP alters lipid homeostasis in SCs by inducing the activation of pro-inflammatory pathways that may trigger adverse effects in testis physiology over time. Concomitantly, the SC enhances the acylation of surplus FFAs (including 20:4n-6) in neutral lipids as a protective mechanism to shield itself from lipotoxicity and pro-inflammatory signals.
壬基酚（NP）是一种内分泌干扰化学物质，也是一种环境污染物，在动物模型和野生型物种中已报道其对男性生育力有许多不良影响。在此，我们使用大鼠支持细胞（SC）原代培养的体外模型评估了 NP 在卵泡刺激素（FSH）信号转导途径和脂质代谢中的作用。结果表明，急性（1 h）NP（10 µM）暴露于 SC 会增加细胞内外游离脂肪酸（FFA）的浓度，主要是花生四烯酸（20:4n-6）。通过蛋白激酶 A（PKA）/细胞质型 PLA2（cPLA2）途径的激活，似乎磷酸肌醇是这种 20:4n-6 释放的主要磷脂来源。NP 还增加了二酰基甘油（DAG）的水平和环氧化酶 2（Cox2）和前列腺素 E2（PGE2）的表达（mRNA）。值得注意的是，在 24 h NP 暴露后会发生脂滴的积累，这可以通过 PKA 抑制剂和 PLA2 抑制剂来预防。与 FSH 一样，NP 触发 20:4n-6 的释放，这是通过 PKA/PLA2 激活合成 PGE2 的底物。此外，NP 诱导 DAG 的形成，这可能作为 PKC 介导的 COX2 炎症途径激活的辅助因子。我们的研究结果表明，NP 通过诱导促炎途径的激活来改变 SC 中的脂质稳态，随着时间的推移，这些途径可能会对睾丸生理学产生不良影响。同时，SC 通过将多余的 FFA（包括 20:4n-6）酰化为中性脂质来增强自身的保护机制，以防止脂质毒性和促炎信号。
