Fetal origin of adverse pregnancy outcome: The water disinfectant by-product chloroacetonitrile induces oxidative stress and apoptosis in mouse fetal brain

Texas A&M University - Galveston, Galveston, Texas, United States
NeuroToxicology (Impact Factor: 3.38). 09/2005; 26(4):633-40. DOI: 10.1016/j.neuro.2004.11.001
Source: PubMed


Developmental exposure to environmental chemicals may have detrimental effects on embryonic brains that could play a major role in the etio-pathology of fetal and adult neurological diseases. The exact mechanism by which prenatal exposures to environmental agents, such as drinking water disinfectant byproducts (DBP), cause neurological impairment in fetus is not known. Our objective is to examine the impact of prenatal exposure to DBP on fetal brain development. Pregnant CD-1 mice, at the sixth day of gestation (GD-6), received a daily (GD-6-GD-18) oral dose of chloroacetonitrile (CAN, 25 ppm), a member of DBP. To assess fetal brain uptake of CAN, several animals were injected with a tracer dose of 2-[(14)C]-CAN (333 microCi/kg, i.v.), at GD-12 and processed for quantitative in situ micro whole-body autoradiography (QIMWBA) at 1 and 24 h after treatment. The remaining animals continued receiving CAN until GD-18 when fetal brains were processed for biochemical determination of oxidative stress (OS) or prepared for histological examinations. The results indicate a rapid placental transfer and fetal brain uptake of 2-[(14)C]-CAN/metabolites in cortical areas and hippocampus. In treated animals 3-fold decrease in glutathione (GSH), 1.3-fold increase in lipid peroxidation and 1.4-fold increase in DNA oxidation were detected as compared to control. DeOlmos cupric silver staining of fetal brains indicated significant increase in cortical neurodegeneration in treated animals. Immunohistochemical labeling (TUNEL) of apoptotic nuclei in the cortices and choroid plexuses were also increased in treated animals as compared to control. In conclusion, CAN crosses the placental and fetal blood-brain barriers and induces OS that triggered apoptotic neurodegenration in fetal brain. Future studies will examine the molecular mechanisms of these events and its impact on neural development of offspring.

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