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DEHP Decreases Steroidogenesis through the cAMP and ERK1/2 Signaling Pathways in FSH-Stimulated Human Granulosa Cells

DEHP is an endocrine disruptor that interferes with the function of the female reproductive system. Several studies suggested that DEHP affects steroidogenesis in human and rodent granulosa cells (GC). Some studies have shown that DEHP can also affect the FSH-stimulated steroidogenesis in GC; however, the mechanism by which DEHP affects hormone-challenged steroidogenesis in human GC is not understood. Here, we analyzed the mechanism by which DEHP affects steroidogenesis in the primary culture of human cumulus granulosa cells (hCGC) stimulated with FSH. Cells were exposed to DEHP and FSH for 48 h, and steroidogenesis and the activation of cAMP and ERK1/2 were analyzed. The results show that DEHP decreases FSH-stimulated STAR and CYP19A1 expression, which is accompanied by a decrease in progesterone and estradiol production. DEHP lowers cAMP production and CREB phosphorylation in FSH but not cholera toxin- and forskolin-challenged hCGC. DEHP was not able to decrease steroidogenesis in cholera toxin- and forskolin-stimulated hCGC. Furthermore, DEHP decreases FSH-induced ERK1/2 phosphorylation. The addition of EGF rescued ERK1/2 phosphorylation in FSH- and DEHP-treated hCGC and prevented a decrease in steroidogenesis in the FSH- and DEHP-treated hCGC. These results suggest that DEHP inhibits the cAMP and ERK1/2 signaling pathways, leading to the inhibition of steroidogenesis in the FSH-stimulated hCGC.

 

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The study analyzed the mechanism by which DEHP affects steroidogenesis in human cumulus granulosa cells (hCGC) stimulated with FSH. The results indicate that DEHP reduces FSH-stimulated expression of STAR and CYP19A1, which results in decreased progesterone and estradiol production.

 

Moreover, DEHP decreases cAMP production and CREB phosphorylation in FSH-stimulated hCGC but not in cholera toxin- and forskolin-stimulated hCGC, indicating that DEHP inhibits the cAMP signaling pathway. Additionally, DEHP inhibits FSH-induced ERK1/2 phosphorylation, indicating that DEHP also inhibits the ERK1/2 signaling pathway.

Interestingly, the addition of EGF rescued ERK1/2 phosphorylation in FSH- and DEHP-treated hCGC, leading to the prevention of a decrease in steroidogenesis in the FSH- and DEHP-treated hCGC. These findings suggest that DEHP inhibits the cAMP and ERK1/2 signaling pathways, leading to the inhibition of steroidogenesis in FSH-stimulated hCGC.

Overall, these findings shed light on the potential mechanism by which DEHP affects hormone-challenged steroidogenesis in human GC and could have implications for understanding the impact of environmental toxins on female reproductive health.

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