Article

Neurological impairment in fetal mouse brain by drinking water disinfectant byproducts.

Molecular Toxicology Laboratory of the Department of Pathology, 06-09, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.
NeuroToxicology (Impact Factor: 2.65). 09/2005; 26(4):633-40. DOI: 10.1016/j.neuro.2004.11.001
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
41 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This study used the extensive monitoring datasets of the Korea Ministry of Environment to examine trends in dissolved organic carbon (DOC) in Han River raw water. To estimate the organic contents of water, we adopted allied parameters such as biochemical oxygen demand (BOD) and chemical oxygen demand (COD) as substitutes for DOC. Spatial and temporal analyses were performed on monthly BOD and COD data from 36 monitoring stations (14 for Main Han River, 7 for North Han River and 15 for South Han River) measured from 1989 to 2007. The results of trend analysis indicated that, on the whole, water quality according to BOD showed a downward trend at more than 67% of monitoring stations (9 for Main Han River, 6 for North Han River and 9 for South Han River). However, the water quality of COD showed an upward trend at more than 78% of monitoring stations (8 for Main Han River, 7 for North Han River and 13 for South Han River). The upward trend of COD contrary to the BOD trend indicates that there has been an increase in recalcitrant organic matter in Han River water that is not detectable by means of BOD.
    Eng. Res. 01/2010; 414:256-260.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chloroacetonitrile (CAN) is a disinfection by-product of chlorination of drinking water. The present study was designed to investigate the potential adverse effects of maternal exposure to CAN on fetal liver in mice. Based on an initial dose-response experiment, CAN (25mg/(kgday)) was given orally to pregnant mice at gestation day (GD) 6, till GD 18. Fetuses were collected and fetal livers were used for assessing oxidative status, apoptosis and histopathological changes. Maternal exposure to CAN resulted in observed oxidative stress and redox imbalance in fetal liver tissues as marked by significant decrease in reduced glutathione (GSH) and elevation of oxidized glutathione (GSSG), malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in genomic DNA. Further, CAN induced apoptosis as indicated by a significant increase in binding of Hoechst reagent to damaged DNA fragments of fetal liver and enhancement of the activity of caspase-3 in cytosolic fractions of fetal livers. Histopathological examination of fetal livers of CAN-treated mice showed hepatocytes with vacuolated cytoplasm, karyolysis and karyorrhexis as well as depletion of their glycogen content. In conclusion, maternal exposure to CAN adversely affects mouse fetal livers as evidenced by the induction of oxidative stress, apoptosis and histopathological changes.
    Toxicology Letters 08/2009; 190(2):123-7. · 3.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The brain develops and grows within a well-controlled internal environment that is provided by cellular exchange mechanisms in the interfaces between blood, cerebrospinal fluid and brain. These are generally referred to by the term "brain barriers": blood-brain barrier across the cerebral endothelial cells and blood-CSF barrier across the choroid plexus epithelial cells. An essential component of barrier mechanisms is the presence of tight junctions between the endothelial and epithelial cells of these interfaces. This review outlines historical evidence for the presence of effective barrier mechanisms in the embryo and newborn and provides an up to date description of recent morphological, biochemical and molecular data for the functional effectiveness of these barriers. Intercellular tight junctions between cerebral endothelial cells and between choroid plexus epithelial cells are functionally effective as soon as they differentiate. Many of the influx and efflux mechanisms are not only present from early in development, but the genes for some are expressed at much higher levels in the embryo than in the adult and there is physiological evidence that these transport systems are functionally more active in the developing brain. This substantial body of evidence supporting the concept of well developed barrier mechanisms in the developing brain is contrasted with the widespread belief amongst neurotoxicologists that "the" blood-brain barrier is immature or even absent in the embryo and newborn. A proper understanding of the functional capacity of the barrier mechanisms to restrict the entry of harmful substances or administered therapeutics into the developing brain is critical. This knowledge would assist the clinical management of pregnant mothers and newborn infants and development of protocols for evaluation of risks of drugs used in pregnancy and the neonatal period prior to their introduction into clinical practice.
    NeuroToxicology 12/2011; 33(3):586-604. · 2.65 Impact Factor