Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
壬基酚(NP),一种内分泌干扰化学物质，是一种环境污染物，在动物模型和野生型物种中已经报道了许多对雄性生育能力的臭名昭著的影响。这里,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)信号转导通路和脂质代谢中的作用.结果表明，急性（1小时）SC暴露于NP（10µM）增加了游离脂肪酸（FFA）的细胞内和细胞外浓度，主要是花生四烯酸(20:4n-6)。磷脂酰肌醇似乎是通过激活蛋白激酶A（PKA）/细胞质磷脂酶A2（cPLA2）途径而释放20：4n-6的主要磷脂来源。NP还增加了二酰基甘油（DAG）水平以及环氧合酶2（Cox2）和前列腺素E2（PGE2）的表达（mRNA）水平。值得注意的是,在24小时NP暴露后发生脂滴积累，两者都阻止了，PKA和PLA2抑制剂。像FSH,NP通过PKA/PLA2活化触发作为PGE2合成底物的20:4n-6的释放。此外,NP诱导DAG的形成，DAG可能是PKC介导的Cox2炎症途径激活的辅因子。我们的发现表明，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，这可能会引发睾丸生理学的不利影响。同时，SC增强中性脂质中多余游离脂肪酸(包括20:4n-6)的酰化,作为保护自身免受脂毒性和促炎信号的保护机制。
