Molybdenum and cadmium co-induce hypothalamus toxicity in ducks via disturbing Nrf2-mediated defense response and triggering mitophagy.
Molybdenum and cadmium co-induce hypothalamus toxicity in ducks via disturbing Nrf2-mediated defense response and triggering mitophagy.
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DOI：
10.1016/j.ecoenv.2021.113022
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发表时间：
2021-11
影响因子：
6.8
通讯作者：
Ting Cui;Wenjuan Jiang;Fan Yang;Junrong Luo;Ruiming Hu;H. Cao;G. Hu;Caiying Zhang
中科院分区：
文献类型：
--
作者：
Ting Cui;Wenjuan Jiang;Fan Yang;Junrong Luo;Ruiming Hu;H. Cao;G. Hu;Caiying Zhang
越来越多的证据表明，Nrf 2介导的抗氧化防御反应和线粒体自噬参与了重金属的毒性机制，但钼（Mo）和镉（Cd）联合暴露对鸭下丘脑Nrf 2介导的抗氧化防御反应和线粒体自噬的影响尚未阐明。选用健康7日龄肉鸭40只，随机分为4组，分别饲喂含不同剂量钼和镉的日粮16周。结果表明，Mo和Cd显著升高下丘脑中Cu、Fe、Zn、Se含量，降低Cu、Fe、Zn、Se含量，引起病理损伤和氧化应激，并伴有MDA含量升高和CAT、T-AOC、T-SOD、GSH-Px活性降低。此外，Mo和/或Cd不仅通过降低Nrf 2、HO-1、NQO 1、GST、CAT、SOD 1、GCLM mRNA表达水平和Nrf 2蛋白表达水平抑制Nrf 2通路，而且通过提高MFF、PINK 1、Parkin、Bnip 3、LC 3A、LC 3B mRNA表达水平和PINK 1、Parkin、LC 3B-II/LC 3B-I蛋白表达水平，干扰线粒体动力学，触发PINK 1/Parkin介导的线粒体自噬，抑制Mfn 1、Mfn 2、OPA 1、P62 mRNA表达水平和P62蛋白表达水平，促进LC 3与HSP 60的共定位。Mo和Cd共同处理下，上述因子的变化最为显著。结果表明，Mo和Cd可协同抑制鸭下丘脑Nrf 2介导的抗氧化防御反应，激活PINK 1/Parkin通路依赖的线粒体自噬，其机制可能与Mo和Cd的积累有关。
Growing evidences reveal that Nrf2-mediated antioxidant defense response and mitophagy are involved in the toxic mechanism of heavy metals, but the effects of molybdenum (Mo) and cadmium (Cd) co-exposure on Nrf2-mediated antioxidant defense response and mitophagy in duck hypothalamus have yet to be elucidated. Herein, 40 healthy 7-day-old ducks were randomly assigned to 4 groups and fed diets containing different doses of Mo or/and Cd for 16 weeks, respectively. The data demonstrated that Mo or/and Cd notably elevated their contents in hypothalamus, decreased Cu, Fe, Zn and Se contents, caused pathological damage and oxidative stress accompanied by elevating MDA content and reducing CAT, T-AOC, T-SOD, GSH-Px activities. Moreover, Mo or/and Cd not only restrained Nrf2 pathway by decreasing Nrf2, HO-1, NQO1, GST, CAT, SOD1, GCLM mRNA expression levels and Nrf2 protein expression level, but also disturbed mitochondrial dynamics and triggered PINK1/Parkin-mediated mitophagy by enhancing MFF, PINK1, Parkin, Bnip3, LC3A, LC3B mRNA expression levels and PINK1, Parkin, LC3B-II/LC3B-I protein expression levels, inhibiting Mfn1, Mfn2, OPA1, P62 mRNA expression levels and P62 protein expression level, and facilitating the colocalization between LC3 and HSP60. The changes of above factors were most remarkable under Mo and Cd co-treatment. Overall, the results elucidate that Mo and Cd can synergistically inhibit Nrf2-mediated antioxidant defense response and activate PINK1/Parkin pathway-dependent mitophagy in duck hypothalamus, whose mechanism is somehow related to Mo and Cd accumulation.