Apoptosis-inducing activity of endocrine-disrupting chemicals in cultured PC12 cells

Abstract

Endocrine-disrupting chemicals (EDCs) are known to exert estrogen-like effects that are similar to those made by naturally produced hormones or by inhibition of the receptors in the cell receiving the hormones. Recently, several reports have indicated that EDCs can affect the developing central nervous system. In our current study, we report that some EDCs induce apoptosis in cultured PC12 cells and can be classified into three groups. Bisphenol A (BPA), pnonylphenol (NP) and tributyltin chloride (TBT) were found to induce endoplasmic reticulum (ER) stress-associated apoptosis and activate the unfolded protein response (UPR) system, whereas benomyl (beno) induced non-ER stress-associated apoptosis. The half-maximal apoptosis-inducing concentrations (IC 50 ) of these EDCs were 160 µM for BPA, 25.6 µM for NP, 640 nM for TBT and 48 µM for beno. Although these concentrations are higher than those found in the environment, some EDCs may have apoptotic effects on various cells in the body, including neurons, through their accumulation in the body over time or condensation through the food chain. On the other hand, benzopyrene, fenvalerate, styrene monomer and bis(2-ethylhexyl)phthalate did not induce apoptosis in PC12 cells. We analyzed also whether apoptosis-inducing EDCs had an estrogen-like effect on cultured PC12 cells transfected with a luciferase reporter plasmid, the activity of which is dependent on estrogen receptor α. We found that BPA had an estrogen-like effect (EC 50 = 5.9 µM) but that NP, TBT and beno did not in transfected PC12 cells. These results suggest that BPA may predominantly exert estrogenic effects, but others may predominantly have apoptosis-inducing effects on cells in the body exposed to a polluted environment.

Ultraspiracle-independent anti-apoptotic function of ecdysone receptors is required for the survival of larval peptidergic neurons via suppression of grim expression in Drosophila melanogaster

“…A growing body of evidence shows that steroid hormones play important roles in neuroprotection following brain injuries via various mechanisms including suppression of cell death [48]. Hence, such neuroprotective roles can be compromised by EDCs, as demonstrated by in vitro and in vivo studies [49][50][51].…”

Endocrine-Disrupting Chemicals and Their Adverse Effects on the Endoplasmic Reticulum

“…Regarding the influence of 4NP, studies detected CHOP upregulation in rat primary cortical neurons [71], human liver HepG2 cells [72], and PC12 cells [73]. Moreover, GRP78 is upregulated in every reference [70][71][72][73][74][75]. Several disease models have been reported.…”

Ameliorative Effects of the Sesquiterpenoid Valerenic Acid on Oxidative Stress Induced in HepG2 Cells after Exposure to the Fungicide Benomyl

“…In addition, benomyl stimulates oxidative stress also in cell lines by enhancing lipid peroxidation and by decreasing the reduced form of glutathione (GSH) [ 16 ]. Concerning the mechanisms by which benomyl could induce oxidative stress in the endoplasmic reticulum (ER), there are conflicting findings, a fact that confirms the largely unknown method of action of this fungicide at the molecular level [ 17 , 18 , 19 , 20 , 21 ] .…”