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Perigestational exposure to low doses of PBDE-47 induces excessive ER stress, defective autophagy and the resultant apoptosis contributing to maternal thyroid toxicity
- Li, Pei, Liu, Luming, Zhou, Guoyu, Tian, Zhiyuan, Luo, Chen, Xia, Tao, Chen, Jingwen, Niu, Qiang, Dong, Lixin, Zhao, Qian, Wang, Aiguo, Zhang, Shun
- The Science of the total environment 2018 v.645 pp. 363-371
- DNA fragmentation, apoptosis, autophagy, blood serum, brain, caspase-12, caspase-3, endoplasmic reticulum, epithelial cells, females, fetus, flame retardants, gene expression regulation, infants, laboratory animals, mechanism of action, neurotoxicity, progeny, rats, triiodothyronine, unfolded protein response, weaning
- Brominated flame retardant 2,2′,4,4′‑tetrabromodiphenyl ether (PBDE-47) is known to induce developmental neurotoxicity by disturbing thyroid hormones (THs). Evidence shows that maternal THs are crucial for brain development and growth of fetuses and infants. However, little is known about the effects of PBDE-47 on maternal thyroid status and its mode of action. Here, using female Sprague-Dawley rats orally exposed to low doses of PBDE-47 (0.1, 1.0, 10 mg/kg/day) from pre-pregnancy until weaning of offspring to mimic human exposure, we show that perigestational exposure to PBDE-47 elevated serum triiodothyronine and thyroxine levels in mother rats. This is accompanied by disrupted thyroid follicle structure including expanded follicles, hyperplastic epithelial cells and shed cell remnants filled in the exhausted follicular lumen. Mechanistically, PBDE-47 enhanced apoptosis in thyroid tissue, as demonstrated by Caspase-3 activation, PARP cleavage and DNA fragmentation. Further study identified that PBDE-47 upregulated the levels of GRP78, ATF4, active Caspase-12 and CHOP, suggesting endoplasmic reticulum (ER) stress and unfolded protein response activation. Moreover, PBDE-47 reduced the levels of LC3-II, an autophagy marker protein essential for the autophagosomes formation, while increased the autophagy substrate p62 accumulation, indicating autophagy defect. Importantly, the colocalization of apoptotic cells with CHOP, a key mediator of ER stress-induced apoptosis, or p62, uncovered the contribution of excessive ER stress and defective autophagy to apoptosis. Collectively, our results suggest that excessive ER stress, defective autophagy and the resultant apoptosis are implicated in maternal thyroid injury following perigestational PBDE-47 exposure, which offers insight into a better understanding of PBDE-47-induced maternal thyroid toxicity.