Endoplasmic reticulum rather than mitochondria plays a major role in the neuronal apoptosis induced by polybrominated diphenyl ether-153

Abstract

Polybrominated diphenyl ether-153 (BDE-153) has been demonstrated to induce neuronal apoptosis in rat cerebral cortex and primary neurons, however, the roles of mitochondria and endoplasmic reticulum (ER) remain unclear in the BDE-153-induced neuronal apoptosis. To this purpose, we observed the mitochondria and ER ultrastructure changes in the neuronal apoptosis in rats following BDE-153 treatment, detected the mitochondrial membrane potential (MMP), Ca2+-Mg2+-ATP enzyme activity, and the changes of mitochondria and ER apoptosis related molecules in rat cerebral cortex and in primary neurons following BDE-153 treatment. Results showed that compared to the control group, neuronal apoptosis was significantly increased in a dose-dependent manner in rat cerebral cortex and in primary neurons following BDE-153 treatment. In comparison with control, BDE-153 treatment induced remarkable ultrastructural changes in ER rather than in mitochondria, and the severity of ER damage was worse with the increasing BDE-153 dose. Meanwhile, ER apoptosis related molecules including caspase-12 (at mRNA level), cleaved caspase-12 (at protein level), and Tmem132a (at mRNA and protein levels) were significantly increased in the cerebral cortex in rats following BDE-153 treatment, while procaspase-12 protein was significantly decreased, comparing with control. In contrast, mitochondria apoptosis related molecules (MMP, Ca2+-Mg2+-ATP enzyme activity, cyt-C protein, caspase-3, 8, 9 mRNA, caspase-8, 9 enzyme activities) did not significantly changed in the cerebral cortex of rats or in primary neurons following BDE-153 treatment, except for the elevated caspase-3 mRNA and enzyme activity. Therefore, we conclude that BDE-153 induced neuronal apoptosis was dependent on p53, and mediated more by ER than mitochondria in the cerebral cortex of rats and in primary neurons. The findings suggest that ER is a potential sensitive target of BDE-153 neurotoxicity, providing a scientific evidence for the mechanism and intervention study on PBDE’s neurotoxicity.