Intracellular redox imbalance and extracellular amino acid metabolic abnormality contribute to arsenic-induced developmental retardation in mouse preimplantation embryos.

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. (c) 2009 Wiley-Liss, Inc.