The glutathione redox system undergoes precise and dynamic changes during embryonic development, protecting against and mitigating oxidative insults. The antioxidant response is coordinately largely by the transcription factor Nuclear factor erythroid-2 (Nrf2), an endogenous sensor for cellular oxidative stress. We have previously demonstrated that impaired Nrf family signaling disrupts the glutathione redox system in the zebrafish embryo, and that impaired Nrf2 function increases embryonic sensitivity to environmental toxicants. Here, we investigated the persistent environmental toxicant and reported pro-oxidant perfluorooctanesulfonic acid (PFOS), and its impact on the embryonic glutathione-mediated redox environment. We further examined whether impaired Nrf2a function exacerbates PFOS-induced oxidative stress and embryotoxicity in the zebrafish, and the potential for Nrf2-PPAR crosstalk in the embryonic adaptive response. Wild-type and nrf2a^fh318−/− mutant embryos were exposed daily to 0 (0.01% v/v DMSO), 16, 32, or 64 μM PFOS beginning at 3 h post fertilization (hpf). Embryonic glutathione and cysteine redox environments were examined at 72 hpf. Gross embryonic toxicity, antioxidant gene expression, and apoptosis were examined at 96 hpf. Mortality, pericardial edema, and yolk sac utilization were increased in wild-type embryos exposed to PFOS. Embryonic glutathione and cysteine redox couples and gene expression of Nrf2 pathway targets were modulated by both exposure and genotype. Apoptosis was increased in PFOS-exposed wild-type embryos, though not in nrf2a mutants. In silico examination of putative transcription factor binding site suggested potential crosstalk between Nrf2 and PPAR signaling, since expression of PPARs and gene targets was modulated by both PFOS exposure and Nrf2a genotype. Overall, this work demonstrates that nrf2a modulates the embryonic response to PFOS, and that PPAR signaling may play a role in the embryonic adaptive response to PFOS.

谷胱甘肽氧化还原系统在胚胎发育过程中经历精确和动态的变化，防止和减轻氧化损伤。抗氧化反应主要由转录因子核因子 erythroid-2 (Nrf2) 协调，Nrf2 是细胞氧化应激的内源性传感器。我们之前已经证明，受损的 Nrf 家族信号传导会破坏斑马鱼胚胎中的谷胱甘肽氧化还原系统，受损的 Nrf2 功能会增加胚胎对环境毒物的敏感性。在这里，我们研究了持久性环境毒物并报道了促氧化剂全氟辛烷磺酸（PFOS），及其对胚胎谷胱甘肽介导的氧化还原环境的影响。我们进一步研究了 Nrf2a 功能受损是否会加剧 PFOS 诱导的斑马鱼氧化应激和胚胎毒性，以及 Nrf2-PPAR 串扰在胚胎适应性反应中的潜力。从受精后 3 小时 (hpf) 开始，将野生型和nrf2a ^fh318−/−突变体胚胎每天暴露于 0 (0.01% v/v DMSO)、16、32 或 64 μM PFOS。在 72 hpf 时检查胚胎谷胱甘肽和半胱氨酸氧化还原环境。 96 hpf 时检查总胚胎毒性、抗氧化基因表达和细胞凋亡。暴露于全氟辛烷磺酸的野生型胚胎的死亡率、心包水肿和卵黄囊利用率均增加。胚胎谷胱甘肽和半胱氨酸氧化还原对以及 Nrf2 途径靶标的基因表达受到暴露和基因型的调节。暴露于 PFOS 的野生型胚胎中细胞凋亡增加，但nrf2a突变体中则没有。 对推定转录因子结合位点的计算机检查表明，Nrf2 和 PPAR 信号传导之间存在潜在的串扰，因为 PPAR 和基因靶标的表达受到 PFOS 暴露和 Nrf2a 基因型的调节。总体而言，这项工作表明nrf2a调节胚胎对 PFOS 的反应，并且 PPAR 信号传导可能在胚胎对 PFOS 的适应性反应中发挥作用。