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Atrazine activates multiple signaling pathways enhancing the rapid hCG-induced androgenesis in rat Leydig cells
- Pogrmic-Majkic, Kristina, Fa, Svetlana, Samardzija, Dragana, Hrubik, Jelena, Kaisarevic, Sonja, Andric, Nebojsa
- Toxicology 2016 v.368-369 pp. 37-45
- Leydig cells, acetylcysteine, androgenesis, androgens, atrazine, biosynthesis, cAMP-dependent protein kinase, calcium, cyclic AMP, endocrine-disrupting chemicals, females, gene expression, human chorionic gonadotropin, males, messenger RNA, protein kinase C, rats, signal transduction, steroidogenic acute regulatory protein
- Atrazine (ATR) is an endocrine disruptor that affects steroidogenic process, resulting in disruption of reproductive function of the male and female gonads. In this study, we used the primary culture of peripubertal Leydig cells to investigate the effect of ATR on the rapid androgen production stimulated by human chorionic gonadotropin (hCG). We demonstrated that ATR activated multiple signaling pathways enhancing the rapid hCG-stimulated androgen biosynthesis in Leydig cells. Low hCG concentration (0.25ng/mL) caused cAMP-independent, but ERK1/2-dependent increase in androgen production after 60min of incubation. Co-treatment with ATR for 60min enhanced the cAMP production in hCG-stimulated cells. Accumulation of androgens was prevented by addition of U0126, N-acetyl-l-cysteine and AG1478. Co-treatment with hCG and ATR for 60min did not alter steroidogenic acute regulatory protein (Star) mRNA level in Leydig cells. After 120min, hCG further increased androgenesis in Leydig cells that was sensitive to inhibition of the cAMP/PKA, ERK1/2 and ROS signaling pathways. Co-treatment with ATR for 120min further enhanced the hCG-induced androgen production, which was prevented by inhibition of the calcium, PKC and EGFR signaling cascades. After 120min, ATR enhanced the expression of Star mRNA in hCG-stimulated Leydig cells through activation of the PKA and PKC pathway. Collectively, these data suggest that exposure to ATR caused perturbations in multiple signaling pathways, thus enhancing the rapid hCG-dependent androgen biosynthesis in peripubertal Leydig cells.