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A protective role of autophagy in TDCIPP-induced developmental neurotoxicity in zebrafish larvae.
Aquat Toxicol 2018; 199:46-54AT

Abstract

Tris (1, 3-dichloro-2-propyl) phosphate (TDCIPP), an extensively used organophosphorus flame retardant, is frequently detected in various environmental media and biota, and has been demonstrated as neurotoxic. Autophagy has been proposed as a protective mechanism against toxicant-induced neurotoxicity. The purpose of the present study was to investigate the effect of TDCIPP exposure on autophagy, and its role in TDCIPP-induced developmental neurotoxicity. Zebrafish embryos (2-120 h post-fertilization [hpf]) were exposed to TDCIPP (0, 5, 50 and 500 μg/l) and a model neurotoxic chemical, chlorpyrifos (CPF, 100 μg/l). The developmental endpoints, locomotive behavior, cholinesterase activities, gene and protein expression related to neurodevelopment and autophagy were measured in the larvae. Our results demonstrate that exposure to TDCIPP (500 μg/l) and CPF causes developmental toxicity, including reduced hatching and survival rates and increased malformation rate (e.g., spinal curvature), as well as altered locomotor behavior. The expression of selected neurodevelopmental gene and protein markers (e.g., mbp, syn2a, and α1-tubulin) was significantly down-regulated in CPF and TDCIPP exposed zebrafish larvae. Treatment with CPF significantly inhibits AChE and BChE, while TDCIPP (0-500 μg/l) exerts no effects on these enzymes. Furthermore, the conversion of microtubule-associated protein I (LC3 I) to LC3 II was significantly increased in TDCIPP exposed zebrafish larvae. In addition, exposure to TDCIPP also activates transcription of several critical genes in autophagy (e.g. Becn1, atg3, atg5, map1lc3b and sqstm1). To further investigate the role of autophagy in TDCIPP induced developmental neurotoxicity, an autophagy inducer (rapamycin, Rapa, 1 nM) and inhibitor (chloroquine, CQ, 1 μM) were used. The results demonstrate that the hatching rate, survival rate, and the expression of mbp and а1-tubulin proteins were all significantly increased in larvae treated with TDCIPP (500 μg/l) and Rapa compared to TDCIPP alone. In contrast, co-treatment with the autophagy inhibitor CQ results in exacerbated neurodevelopmental toxicity. Taken together, our results confirm that exposure to TDCIPP induces autophagy, which plays a protective role in TDCIPP-induced developmental neurotoxicity in zebrafish embryos and larvae.

Authors+Show Affiliations

Department of Nutrition and Toxicology, School of Public Health, Wuhan University of Science and Technology, China; Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, China; State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.Department of Nutrition and Toxicology, School of Public Health, Wuhan University of Science and Technology, China; Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, China. Electronic address: zhangling@wust.edu.cn.State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.State Environmental Protection Key Laboratory of Environmental Risk Assessment and Control on Chemical Process, School of Resource and Environmental Engineering, East China University of Science and Technology, Shanghai 200237, China.State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China. Electronic address: bszhou@ihb.ac.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29605586

Citation

Li, Ruiwen, et al. "A Protective Role of Autophagy in TDCIPP-induced Developmental Neurotoxicity in Zebrafish Larvae." Aquatic Toxicology (Amsterdam, Netherlands), vol. 199, 2018, pp. 46-54.
Li R, Zhang L, Shi Q, et al. A protective role of autophagy in TDCIPP-induced developmental neurotoxicity in zebrafish larvae. Aquat Toxicol. 2018;199:46-54.
Li, R., Zhang, L., Shi, Q., Guo, Y., Zhang, W., & Zhou, B. (2018). A protective role of autophagy in TDCIPP-induced developmental neurotoxicity in zebrafish larvae. Aquatic Toxicology (Amsterdam, Netherlands), 199, pp. 46-54. doi:10.1016/j.aquatox.2018.03.016.
Li R, et al. A Protective Role of Autophagy in TDCIPP-induced Developmental Neurotoxicity in Zebrafish Larvae. Aquat Toxicol. 2018;199:46-54. PubMed PMID: 29605586.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A protective role of autophagy in TDCIPP-induced developmental neurotoxicity in zebrafish larvae. AU - Li,Ruiwen, AU - Zhang,Ling, AU - Shi,Qipeng, AU - Guo,Yongyong, AU - Zhang,Wei, AU - Zhou,Bingsheng, Y1 - 2018/03/15/ PY - 2018/02/01/received PY - 2018/03/13/revised PY - 2018/03/14/accepted PY - 2018/4/2/pubmed PY - 2018/6/7/medline PY - 2018/4/2/entrez KW - Autophagy KW - Developmental neurotoxicity KW - LC3 II KW - TDCIPP KW - Zebrafish larvae SP - 46 EP - 54 JF - Aquatic toxicology (Amsterdam, Netherlands) JO - Aquat. Toxicol. VL - 199 N2 - Tris (1, 3-dichloro-2-propyl) phosphate (TDCIPP), an extensively used organophosphorus flame retardant, is frequently detected in various environmental media and biota, and has been demonstrated as neurotoxic. Autophagy has been proposed as a protective mechanism against toxicant-induced neurotoxicity. The purpose of the present study was to investigate the effect of TDCIPP exposure on autophagy, and its role in TDCIPP-induced developmental neurotoxicity. Zebrafish embryos (2-120 h post-fertilization [hpf]) were exposed to TDCIPP (0, 5, 50 and 500 μg/l) and a model neurotoxic chemical, chlorpyrifos (CPF, 100 μg/l). The developmental endpoints, locomotive behavior, cholinesterase activities, gene and protein expression related to neurodevelopment and autophagy were measured in the larvae. Our results demonstrate that exposure to TDCIPP (500 μg/l) and CPF causes developmental toxicity, including reduced hatching and survival rates and increased malformation rate (e.g., spinal curvature), as well as altered locomotor behavior. The expression of selected neurodevelopmental gene and protein markers (e.g., mbp, syn2a, and α1-tubulin) was significantly down-regulated in CPF and TDCIPP exposed zebrafish larvae. Treatment with CPF significantly inhibits AChE and BChE, while TDCIPP (0-500 μg/l) exerts no effects on these enzymes. Furthermore, the conversion of microtubule-associated protein I (LC3 I) to LC3 II was significantly increased in TDCIPP exposed zebrafish larvae. In addition, exposure to TDCIPP also activates transcription of several critical genes in autophagy (e.g. Becn1, atg3, atg5, map1lc3b and sqstm1). To further investigate the role of autophagy in TDCIPP induced developmental neurotoxicity, an autophagy inducer (rapamycin, Rapa, 1 nM) and inhibitor (chloroquine, CQ, 1 μM) were used. The results demonstrate that the hatching rate, survival rate, and the expression of mbp and а1-tubulin proteins were all significantly increased in larvae treated with TDCIPP (500 μg/l) and Rapa compared to TDCIPP alone. In contrast, co-treatment with the autophagy inhibitor CQ results in exacerbated neurodevelopmental toxicity. Taken together, our results confirm that exposure to TDCIPP induces autophagy, which plays a protective role in TDCIPP-induced developmental neurotoxicity in zebrafish embryos and larvae. SN - 1879-1514 UR - https://www.unboundmedicine.com/medline/citation/29605586/A_protective_role_of_autophagy_in_TDCIPP_induced_developmental_neurotoxicity_in_zebrafish_larvae_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0166-445X(18)30078-X DB - PRIME DP - Unbound Medicine ER -