The Variable Regulatory Effect of Arsenic on Nrf2 Signaling Pathway in Mouse: a Systematic Review and Meta-analysis
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Arsenic is known to cause oxidative damage. Nuclear factor E2-relate factor-2 (Nrf2) can resist this toxicity. Scholars demonstrated that Nrf2 pathway was activated by arsenic. In contrast, other articles established arsenic-induced inhibition of Nrf2 pathway. To resolve the contradiction and elucidate the mechanism of Nrf2 induced by arsenic, 39 publications involving mouse models were identified through exhaustive database retrieval and were analyzed. The pooled results suggested that arsenic obviously elevated transcription and translation levels of Nrf2 and its downstream genes, NAD(P)H dehydrogenase 1 (NQO1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and GST-glutathione-S-transferase1/2 (GSTO1/2). Arsenic increased the level of reactive oxygen species (ROS), but reduced the level of glutathione (GSH). Subgroup analysis between arsenic and control groups showed that the levels of Nrf2 and its downstream genes are greater in high dose than that in the low dose, higher in short-term exposure than long term, female subjects tolerated better than males, higher in mice than the rats, and greater in other organs than the liver. However, the contents of genes of Nrf2 pathway between the arsenic and control groups were lower in rats than in mice and were less for long-term exposure than the short term (P < 0.05). Conclusively, a variable regulation of arsenic on Nrf2 pathway is noted. Higher dose and short-term exposure of female mice organs except for liver promoted Nrf2 pathway. On the other hand, arsenic inhibited Nrf2 pathway for long-term exposure on rats.
KeywordsArsenic Nrf2 signaling pathway Meta-analysis Systematic review
The authors would like to thank the Department of Public Health, Shihezi University School of Medicine for the assistance with this work as well as the funding from the National Natural Science Foundation of China (No. 81560517, 81760584), the Key Areas of Science and Technology Research Project of Xinjiang Production and Construction Corps (No. 2014BA039, No. 2015AG014), the High-tech Intellectual Project of Shihezi University (No. RCZX201112), and the International Cooperative Project of Shihezi University (No. GJHZ201602).
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Conflict of Interest
The authors declare that they have no conflict of interests.
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