Pyrethroid Insecticide Cypermethrin Modulates Gonadotropin Synthesis via Calcium Homeostasis and ERK1/2 Signaling in LβT2 Mouse Pituitary Cells

Pyrethroids are a class of widely used insecticides. Cypermethrin (CP) is one of most commonly used pyrethroid insecticides and its residue has been frequently detected in environmental media. Our recent animal study reported that early postnatal exposure to CP induced an increase in serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) as well as the expression of gonadotropin subunit genes (chorionic gonadotropin α [CGα], LHβ and FSHβ) in pituitary tissues. In this study, we further investigated the precise mechanism by which CP at concentrations of 1-100 nM affected the synthesis of gonadotropins using a murine pituitary gonadotropic cell line LβT2. We found that calcium (Ca2+)-dependent extracellular signal-regulated kinase 1/2 (ERK1/2) activity was required for CP-regulated transcription of CGαs, LHβ and FSHβ. We provided the novel evidence that CP caused both influx of extracellular Ca2+ through L-type voltage-gated calcium channels (VGCCs) and release of intracellular Ca2+ from endoplasmic reticulum (ER) via inhibition of Ca2+-ATPase. Our results showed that CP disrupted Ca2+ homeostasis via these two separate and independent pathways, thus resulting in the activation of protein kinase C /c-Raf/ERK1/2/immediate-early genes pathways and subsequent increase in the transcription of gonadotropin subunit genes. Our findings would have important implications for understanding the underlying mechanisms of the disrupting effects of some pyrethroids (such as CP) on the synthesis of pituitary gonadotropins.