title: Pyruvate remediation of cell stress and genotoxicity induced by haloacetic acid drinking water disinfection by-products.
abstract: Monohaloacetic acids (monoHAAs) are a major class of drinking water disinfection by-products (DBPs) and are cytotoxic, genotoxic, mutagenic, and teratogenic. We propose a model of toxic action based on monoHAA-mediated inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a target cytosolic enzyme. This model predicts that GAPDH inhibition by the monoHAAs will lead to a severe reduction of cellular ATP levels and repress the generation of pyruvate. A loss of pyruvate will lead to mitochondrial stress and genomic DNA damage. We found a concentration-dependent reduction of ATP in Chinese hamster ovary cells after monoHAA treatment. ATP reduction per pmol monoHAA followed the pattern of iodoacetic acid (IAA) > bromoacetic acid (BAA) >> chloroacetic acid (CAA), which is the pattern of potency observed with many toxicological endpoints. Exogenous supplementation with pyruvate enhanced ATP levels and attenuated monoHAA-induced genomic DNA damage as measured with single cell gel electrophoresis. These data were highly correlated with the SN 2 alkylating potentials of the monoHAAs and with the induction of toxicity. The results from this study strongly support the hypothesis that GAPDH inhibition and the possible subsequent generation of reactive oxygen species is linked with the cytotoxicity, genotoxicity, teratogenicity, and neurotoxicity of these DBPs.
authors.affiliation: Department of Crop Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois; Comsats Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Azra
authors.initials: A
authors.lastname: Dad
authors.forename: Clara H
authors.initials: CH
authors.lastname: Jeong
authors.forename: Justin A
authors.initials: JA
authors.lastname: Pals
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Wagner
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Plewa
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000633:toxicity*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage / Q000187:drug effects*; D004203:Disinfection; D060766:Drinking Water / Q000737:chemistry; D011506:Proteins / Q000378:metabolism; D019289:Pyruvic Acid / Q000494:pharmacology*; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D018508:Water Purification
chemical_list: D000085:Acetates; D060766:Drinking Water; D011506:Proteins; D014874:Water Pollutants, Chemical; C016274:bromoacetate; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate
keywords: DBP; GAPDH; SCGE; monohaloacetic acids; reactive oxygen species
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