title: Reproductive toxicity of low level bisphenol A exposures in a two-generation zebrafish assay: Evidence of male-specific effects.
abstract: Bisphenol A (BPA), a high-volume chemical used to make polycarbonate plastic and epoxy resins, is a ubiquitous contaminant in environment and human body. To investigate the reproductive effects of long-term exposure to low concentrations of BPA, a two-generation study was conducted using the aquatic model species of zebrafish. Our findings revealed that exposure to 1nM (0.228μg/L) BPA for continuous two generations resulted in female-biased sex ratio in both F1 and F2 adult population, decreased sperm density, and decreased sperm quality as measured by motility, velocity, ATP content and lipid peroxidation in F1 and F2 males. Females were less sensitive to BPA exposures than males as no adverse effects were found in female gonads or gametes. Delayed hatching at 48hpf and increased malformation and mortality were found in the offspring from BPA exposed F2, but not F1 parents. Most importantly, the adverse effect on larval development and survival from BPA exposed F2 parents was paternal-specific, resulting mainly from BPA exposed males. Subsequent transcription analysis of F2 male gonads revealed dysregulated mitochondrial biogenesis and significant activation of non-canonical Wnt/planar cell polarity and Wnt/Calcium signaling pathways. Gene expression analysis of larvae from BPA exposed F2 parents showed significant reduced expression of DNA methyltransferases such as dnmt1, dnmt3, and dnmt5. In conclusion, low level BPA exposures for continuous two generations not only affects sex ratio and sperm quantity/quality in F1 and F2 adults, reproductive success in offspring from F2 parents, but also perturbs various molecular pathways potentially contributing to these BPA induced male-specific reproductive defects.
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, 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: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Zengxin
authors.initials: Z
authors.lastname: Gai
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Zixu
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Chenglian
authors.initials: C
authors.lastname: Bai
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: Integrated Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Xu
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; 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: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou 325035, China. Electronic address: dqxdong@163.com.
authors.forename: Qiaoxiang
authors.initials: Q
authors.lastname: Dong
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006066:Gonads / Q000187:drug effects; D008297:Male; D008780:Methyltransferases / Q000235:genetics; D010636:Phenols / Q000633:toxicity*; D012098:Reproduction / Q000187:drug effects*; D012737:Sex Factors; D012744:Sex Ratio; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D015027:Zebrafish / Q000502:physiology*; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D008780:Methyltransferases; D010636:Phenols; D014874:Water Pollutants, Chemical; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: BPA; Chronic exposure; Mitochondrial biogenesis; Sperm; Wnt signaling; Zebrafish