title: Intracellular redox imbalance and extracellular amino acid metabolic abnormality contribute to arsenic-induced developmental retardation in mouse preimplantation embryos.
abstract: Inorganic arsenic, an environmental contaminant, is known to cause cancer, developmental retardation, and many other serious diseases. Previous researches have shown that arsenic exerts its toxicity partially through generating reactive oxygen species (ROS). However, it is still not well understood how ROS links arsenic exposure to developmental retardation of preimplantation embryo. Here we demonstrate that high-level arsenite induces severe redox imbalance by decreasing the levels of glutathione and increasing the levels of ROS through the oxidative stress adaptor p66Shc, which induces apoptosis by activating the cytochrome c-caspase. In addition, low-level arsenite seriously perturbs the metabolism of extracellular amino acid, especially that of the cytotoxic and antioxidative amino acids in preimplantation embryos, may also be the reason for developmental delay. Furthermore, an antioxidant, N-acetyl-L-cysteine, improves the development of arsenite-exposed embryos by reducing intracellular ROS and adjusting amino acid metabolism, suggesting that increasing the intracellular antioxidant level may have preventive or therapeutic effects on arsenic-induced embryonic toxicity. In conclusion, we suggest that p66Shc-linked redox imbalance and abnormal extracellular amino acid metabolism mediate arsenite-induced embryonic retardation.
authors.affiliation: Graduate School of Peking Union Medical College, Beijing, China.
authors.forename: Chuanling
authors.initials: C
authors.lastname: Zhang
authors.forename: Chunmei
authors.initials: C
authors.lastname: Liu
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Nan
authors.initials: N
authors.lastname: Yao
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Yuan
authors.forename: Aiping
authors.initials: A
authors.lastname: Yu
authors.forename: Cailing
authors.initials: C
authors.lastname: Lu
authors.forename: Xu
authors.initials: X
authors.lastname: Ma
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D018053:Arsenites / Q000633:toxicity*; D001755:Blastocyst / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D046149:Embryo Culture Techniques; D047108:Embryonic Development / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D004789:Enzyme Activation; D005978:Glutathione / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013997:Time Factors
chemical_list: D000596:Amino Acids; D000975:Antioxidants; D018053:Arsenites; D004785:Environmental Pollutants; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D045304:Cytochromes c; D020169:Caspases; D005978:Glutathione; C015001:arsenite; D000111:Acetylcysteine