Resmethrin disrupts mitochondria-associated membranes and activates endoplasmic reticulum stress, leading to proliferation inhibition in cultured mouse Leydig and Sertoli cells

Abstract

Resmethrin, a pyrethroid pesticide used to control insects, is toxic to non-target organisms and other mammals. However, little is known about the reproductive toxicity of resmethrin in the testes, or its mechanism of toxicity. In this study, we investigated the testicular toxicity of resmethrin on mouse Leydig (TM3) and Sertoli (TM4) cells, focusing on the mitochondria and endoplasmic reticulum (ER). We found that resmethrin inhibited proliferation and cell cycle progression and disrupted mitochondrial membrane potential (MMP; ΔΨ) in TM3 and TM4 cells. In particular, resmethrin exposure significantly reduced the expression of mitochondria-associated membranes (MAMs) proteins, such as Vapb, Vdac, and Grp75, in both cell lines. Resmethrin also disrupts calcium homeostasis in the mitochondrial matrix and cytoplasm. In addition, resmethrin activates oxidative stress-mediated ER stress signals. Finally, we confirmed that 4-PBA, an ER stress inhibitor, restored the growth of TM3 and TM4 cells, which was decreased by resmethrin. Therefore, we confirmed that resmethrin hampered MAMs and activated ER stress, thus suppressing TM3 and TM4 cell proliferation.