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Molybdenum and cadmium co-induce hypothalamus toxicity in ducks via disturbing Nrf2-mediated defense response and
Ting Cui1, Wenjuan Jiang2, Fan Yang1
1Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China.
Abstract:
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.
Insights
Molybdenum and cadmium co-exposure in ducks inhibits the Nrf2 antioxidant response and activates PINK1/Parkin mitophagy in the hypothalamus, linked to metal accumulation.
Area of Science:
- Environmental Toxicology
- Cellular Biology
- Oxidative Stress
Background:
- Heavy metals like molybdenum (Mo) and cadmium (Cd) are known to induce toxicity.
- Nrf2-mediated antioxidant defense and mitophagy are implicated in heavy metal toxicity mechanisms.
- The specific effects of Mo and Cd co-exposure on these pathways in the duck hypothalamus remain unclear.
Purpose of the Study:
- To investigate the impact of Mo and/or Cd co-exposure on the Nrf2 antioxidant pathway and mitophagy in the duck hypothalamus.
- To elucidate the underlying toxicological mechanisms of combined Mo and Cd exposure.
Main Methods:
- 40 ducks were exposed to diets with varying doses of Mo and/or Cd for 16 weeks.
- Hypothalamic tissues were analyzed for metal content, oxidative stress markers (MDA, CAT, T-AOC, T-SOD, GSH-Px), Nrf2 pathway components (mRNA and protein), and mitophagy markers (mRNA, protein, and LC3/HSP60 colocalization).
Main Results:
- Mo and/or Cd exposure increased hypothalamic metal content and caused pathological damage and oxidative stress.
- Exposure significantly inhibited the Nrf2 antioxidant defense pathway by downregulating key genes and proteins.
- Co-exposure also disturbed mitochondrial dynamics and activated PINK1/Parkin-mediated mitophagy, indicated by altered expression of mitophagy-related genes and proteins.
Conclusions:
- Molybdenum and cadmium synergistically inhibit the Nrf2-mediated antioxidant defense response in the duck hypothalamus.
- Combined exposure activates the PINK1/Parkin pathway-dependent mitophagy.
- These effects are associated with the accumulation of Mo and Cd in the hypothalamus.
