Carvan Michael J, Kalluvila Thomas A, Klingler Rebekah H, Larson Jeremy K, Pickens Matthew, Mora-Zamorano Francisco X, Connaughton Victoria P, Sadler-Riggleman Ingrid, Beck Daniel, Skinner Michael K
School of Freshwater Sciences, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, United States of America.
Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, United States of America.
PLoS One. 2017 May 2;12(5):e0176155. doi: 10.1371/journal.pone.0176155. eCollection 2017.
Methylmercury (MeHg) is a ubiquitous environmental neurotoxicant, with human exposures predominantly resulting from fish consumption. Developmental exposure of zebrafish to MeHg is known to alter their neurobehavior. The current study investigated the direct exposure and transgenerational effects of MeHg, at tissue doses similar to those detected in exposed human populations, on sperm epimutations (i.e., differential DNA methylation regions [DMRs]) and neurobehavior (i.e., visual startle and spontaneous locomotion) in zebrafish, an established human health model. F0 generation embryos were exposed to MeHg (0, 1, 3, 10, 30, and 100 nM) for 24 hours ex vivo. F0 generation control and MeHg-exposed lineages were reared to adults and bred to yield the F1 generation, which was subsequently bred to the F2 generation. Direct exposure (F0 generation) and transgenerational actions (F2 generation) were then evaluated. Hyperactivity and visual deficit were observed in the unexposed descendants (F2 generation) of the MeHg-exposed lineage compared to control. An increase in F2 generation sperm epimutations was observed relative to the F0 generation. Investigation of the DMRs in the F2 generation MeHg-exposed lineage sperm revealed associated genes in the neuroactive ligand-receptor interaction and actin-cytoskeleton pathways being effected, which correlate to the observed neurobehavioral phenotypes. Developmental MeHg-induced epigenetic transgenerational inheritance of abnormal neurobehavior is correlated with sperm epimutations in F2 generation adult zebrafish. Therefore, mercury can promote the epigenetic transgenerational inheritance of disease in zebrafish, which significantly impacts its environmental health considerations in all species including humans.
甲基汞（MeHg）是一种普遍存在的环境神经毒素，人类接触主要源于食用鱼类。已知斑马鱼在发育过程中接触甲基汞会改变其神经行为。本研究调查了甲基汞在与暴露人群中检测到的剂量相似的组织剂量下，对斑马鱼精子表观突变（即差异DNA甲基化区域[DMRs]）和神经行为（即视觉惊吓和自发运动）的直接暴露和跨代影响，斑马鱼是一种成熟的人类健康模型。F0代胚胎在体外暴露于甲基汞（0、1、3、10、30和100 nM）24小时。F0代对照组和暴露于甲基汞的谱系饲养至成年并繁殖产生F1代，随后F1代繁殖产生F2代。然后评估直接暴露（F0代）和跨代作用（F2代）。与对照组相比，在暴露于甲基汞的谱系的未暴露后代（F2代）中观察到多动和视觉缺陷。相对于F0代，F2代精子表观突变增加。对F2代暴露于甲基汞的谱系精子中的DMRs进行研究发现，神经活性配体-受体相互作用和肌动蛋白细胞骨架途径中的相关基因受到影响，这与观察到的神经行为表型相关。发育过程中甲基汞诱导的异常神经行为的表观遗传跨代遗传与F2代成年斑马鱼精子表观突变相关。因此，汞可促进斑马鱼疾病的表观遗传跨代遗传，这对包括人类在内的所有物种的环境卫生考量具有重大影响。
