title: TBBPA exposure during a sensitive developmental window produces neurobehavioral changes in larval zebrafish.
abstract: Tetrabromobisphenol A (TBBPA), one of the most widely used brominated flame retardants (BFRs), is a ubiquitous contaminant in the environment and in the human body. This study demonstrated that zebrafish embryos exposed to TBBPA during a sensitive window of 8-48 h post-fertilization (hpf) displayed morphological malformations and mortality. Zebrafish exposed exclusively between 48 and 96 hpf were phenotypically normal. TBBPA was efficiently absorbed and accumulated in zebrafish embryos, but was eliminated quickly when the exposure solution was removed. Larval behavior assays conducted at 120 hpf indicated that exposure to 5 μM TBBPA from 8 to 48 hpf produced larvae with significantly lower average activity and speed of movement in the normal condition than in those exposed from 48 to 96 hpf. Specifically, 8-48 hpf-exposed larvae spent significantly less time in both activity bursts and gross movements compared to control or 48-96 hpf exposed larvae. Consistent with the motor deficits, TBBPA induced apoptotic cell death, delayed cranial motor neuron development, inhibited primary motor neuron development and loosed muscle fiber during the early developmental stages. To further explore TBBPA-induced developmental and neurobehavioral toxicity, RNA-Seq analysis was used to identify early transcriptional changes following TBBPA exposure. In total, 1969 transcripts were significantly differentially expressed (P < 0.05, FDR < 0.05, 1.5-FC) upon TBBPA exposure. Functional and pathway analysis of the TBBPA transcriptional profile identified biological processes involved in nerve development, muscle filament sliding and contraction, and extracellular matrix disassembly and organization changed significantly. In addition, TBBPA also led to an elevation in the expression of genes encoding uridine diphosphate glucuronyl transferases (ugt), which could affect thyroxine (T4) metabolism and subsequently lead to neurobehavioral changes. In summary, TBBPA exposure during a narrow, sensitive developmental window perturbs various molecular pathways and results in neurobehavioral deficits in zebrafish.
authors.affiliation: State Environmental Protection Key Laboratory of Environmental Risk Assessment and Control on Chemical Process, School of Resources and Environmental Engineering, East China University of Science and Technology, No.130, Mei Long Road, Shanghai 200237, China; Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Jiangfei
authors.initials: J
authors.lastname: Chen
authors.affiliation: Environmental and Molecular Toxicology, The Sinnhuber Aquatic Research Laboratory and the Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97333, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Tanguay
authors.affiliation: Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Environmental and Molecular Toxicology, The Sinnhuber Aquatic Research Laboratory and the Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97333, USA.
authors.forename: Derik E
authors.initials: DE
authors.lastname: Haggard
authors.affiliation: Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Ge
authors.affiliation: Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Yinhang
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Qiaoxiang
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou 325035, China. Electronic address: cjhuang5711@163.com.
authors.forename: Changjiang
authors.initials: C
authors.lastname: Huang
authors.affiliation: State Environmental Protection Key Laboratory of Environmental Risk Assessment and Control on Chemical Process, School of Resources and Environmental Engineering, East China University of Science and Technology, No.130, Mei Long Road, Shanghai 200237, China. Electronic address: kflin@ecust.edu.cn.
authors.forename: Kuangfei
authors.initials: K
authors.lastname: Lin
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000502:physiology; D005411:Flame Retardants / Q000493:pharmacokinetics / Q000633:toxicity*; D007814:Larva / Q000187:drug effects / Q000502:physiology; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D011075:Polybrominated Biphenyls / Q000493:pharmacokinetics / Q000633:toxicity*; D015027:Zebrafish / Q000196:embryology / Q000502:physiology*
chemical_list: D005411:Flame Retardants; D011075:Polybrominated Biphenyls; C020806:tetrabromobisphenol A
keywords: Motor behavior; Neurotoxicity; Sensitive window; TBBPA; Zebrafish; ugt expression