Butyl paraben promotes apoptosis in human trophoblast cells through increased oxidative stress-induced endoplasmic reticulum stress

Butyl paraben (BP) has antimicrobial effects and is widely used as a preservative in cosmetics, foods, and pharmaceuticals. It is also absorbed into various tissues of the human body. It is known that BP is measurable in maternal and fetal tissues during pregnancy, but the effects of BP on placental development, essential for maintaining normal pregnancy, are unclear. Therefore, we investigated the effect of BP on the proliferation, apoptosis, and invasiveness of human trophoblast cells, using an HTR8/SVneo cell line. BP inhibited cell proliferation and induced both apoptosis and endoplasmic reticulum stress. In addition, BP promoted the production of intracellular reactive oxygen species, increased Ca2+ concentration in HTR8/SVneo cells, and induced mitochondrial membrane depolarization. BP also inhibited the activation of PI3K/AKT pathways including AKT, ribosomal protein S6, P70 S6 kinase, and glycogen synthase kinase 3. Furthermore, pretreatment of cells with LY294002 (an AKT inhibitor) and U0126 (ERK1/2 inhibitor) revealed that ERK1/2 activity is also involved in BP-mediated signal transduction in HTR8/SVneo cells. We therefore suggest that exposing human trophoblast cells to BP diminishes normal physiological activity, leading to apoptosis and problems with early placental development.