Autophagy impairment contributes to PBDE-47-induced developmental neurotoxicity and its relationship with apoptosis.

Abstract

Apoptosis is involved in 2,2',4,4'- tetrabromodiphenyl ether (PBDE-47)-induced developmental neurotoxicity. However, little is known about the role of autophagy, especially its relationship with apoptosis underlying such neurotoxic process. Methods: Using female Sprague-Dawley rats exposed to low-dose PBDE-47 (0.1, 1.0 and 10 mg/kg/day) from pre-pregnancy until weaning of offspring to mimic human exposure, we investigated the effects of PBDE-47 on autophagy and apoptosis in relation to cognitive impairment of adult offspring rats. We also evaluated relationship between autophagy and apoptosis using neuroendocrine pheochromocytoma (PC12) cells, a widely used neuron-like cell line for neuronal development. Results: In vivo, perinatal exposure to PBDE-47 induced memory deficits in adult rats. This is accompanied by hippocampal neuronal loss partly as a result of apoptosis, as evidenced by caspase-3 activation and PARP cleavage. Further study identified that PBDE-47 triggered autophagic vesicles accumulation, increased levels of microtubule-associated protein 1 light chain 3 (LC3)-II, an essential protein for autophagosomes formation, and autophagy substrate sequestosome 1 (SQSTM1/p62), but reduced levels of autophagy-related protein (ATG) 7, a key protein for autophagosomes elongation, suggestive of autophagy impairment. These findings were further demonstrated by an in vitro model of PBDE-47-treated PC12 cells. Mechanistically, autophagy alteration is more sensitive to PBDE-47 treatment than apoptosis induction. Importantly, while stimulation of autophagy by the chemical inducer rapamycin and adenovirus-mediated Atg7 overexpression aggravated PBDE-47-induced apoptosis and cell death, inhibition of autophagy by the chemical inhibitor wortmannin and siRNA knockdown of Atg7 reversed PBDE-47-produced detrimental outcomes. Interestingly, blockage of apoptosis by caspase-3 inhibitor Ac-DEVD-CHO ameliorated PBDE-47-exerted autophagy impairment and cell death, though in combination with autophagy inhibitor did not further promote cell survival. Conclusion: Our data suggest that autophagy impairment facilitates apoptosis, which, in turn, disrupts autophagy, ultimately resulting in cell death, and that autophagy may act as a promising therapeutic target for PBDE-47-induced developmental neurotoxicity.

• Authors: Pei Li, Rulin Ma, Lixin Dong, Luming Liu, Guoyu Zhou, Zhiyuan Tian, Qian Zhao, Tao Xia, Shun Zhang, Aiguo Wang
• Journal: Theranostics (Theranostics) Vol. 9 Issue 15 Pg. 4375-4390 ( 2019) ISSN: 1838-7640 [Electronic] Australia
• PMID: 31285767 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Halogenated Diphenyl Ethers
• Neurotoxins
• 2,2',4,4'-tetrabromodiphenyl ether

Topics

• Animals
• Animals, Newborn
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Survival (drug effects)
• Growth and Development (drug effects)
• Halogenated Diphenyl Ethers (toxicity)
• Memory Disorders (pathology)
• Models, Biological
• Neurons (pathology)
• Neurotoxins (toxicity)
• PC12 Cells
• Rats
• Rats, Sprague-Dawley