Pyrethroid insecticide cypermethrin modulates gonadotropin synthesis via calcium homeostasis and erk1/2 signaling in lbt2 mouse pituitary cells

Abstract

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 a [CGa], LHb and FSHb) in pituitary tissues. In this study, we further investigated the precisemechanismby which CP at concentrations of 1-100nM affected the synthesis of gonadotropins using amurine pituitary gonadotropic cell line LbT2.We found that calcium(Ca2 )-dependent extracellular signal-regulated kinase 1/2 (ERK1/2) activity was required for CP-regulated transcription of CGas, LHb and FSHb.We provided the novel evidence that CP caused both influx of extracellular Ca2 through L-type voltage-gated calciumchannels (VGCCs) and release of intracellular Ca2 fromendoplasmic 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 underlyingmechanisms of the disrupting effects of some pyrethroids (such as CP) on the synthesis of pituitary gonadotropins.