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 SN2 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.

Comparative toxicity of new halophenolic DBPs in chlorinated saline wastewater effluents against a marine alga: Halophenolic DBPs are generally more toxic than haloaliphatic ones

“…Besides, the toxicity rank orders of two additional groups of halo-DBPs (4-halophenols and 3,5-dihalo-4-hydroxybenzaldehydes) for the alga also followed this pattern, i.e., 4-iodophenol > 4-bromophenol > 4-chlorophenol; and 3,5-diiodo-4-hydroxybenzaldehyde > 3,5-dibromo-4-hydroxybenzaldehyde > 3,5-dichloro-4-hydroxybenzaldehyde. The same toxicity rank order of monohaloacetic acids has also been reported in the bioassays for different organisms Pals et al, 2013;Dad et al, 2013). Third, DBP isomers presented varying levels of toxicity.…”

“…Numerous studies have been conducted on the comparative toxicity of haloaliphatic DBPs in drinking water using different bioassay species, including bacteria, Chinese hamster ovary cells, and human cells. These studies have shown that iodo-DBPs were generally significantly more cytotoxic and genotoxic than their bromo-analogues, which in turn were more toxic than their chloro-analogues (Plewa et al, , 2008a(Plewa et al, , 2008bEchigo et al, 2004;Richardson et al, 2007;Richardson et al, 2008;Dad et al, 2013;Pals et al, 2013). Most recently, Yang and Zhang (2013) conducted toxicity tests for 24 halo-DBPs (most of which were newly identified in chlorinated saline wastewater effluents) using a marine polychaete Platynereis dumerilii, and found that this toxicity rank order (i.e., iodo-DBPs > bromoanalogues > chloro-analogues) applied also to the heterotrophic marine polychaete; moreover, the newly identified halophenolic DBPs were significantly more toxic than commonly known trihalomethanes and haloacetic acids, most of which have been regulated in the Disinfectants/DBPs rule by the U.S. EPA (2006).…”

“…With such a methodology, researchers and practitioners in wastewater treatment can prioritize which DBPs or which types of DBPs should be regulated and controlled. Such a methodology has been widely adopted in studies on comparative toxicity of haloaliphatic DBPs in drinking water (Pals et al, 2013;Dad et al, 2013;Richardson et al, 2008;Plewa et al, 2008aPlewa et al, , 2008b.…”

Charting a New Path To Resolve the Adverse Health Effects of DBPs

“…The primary cellular target molecule for the monohaloacetic acids (monoHAAs) is glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (57). Inhibition of GAPDH leads to pyruvate starvation and mitochondrial stress that generates ROS (58,59). New research demonstrated that the monohalonitriles, at non-cytotoxic concentrations, impact the M-phase of the cell cycle and induce hyperploidy in mammalian cells (35).…”

Design, Synthesis, and Biological Evaluation of Novel Tetramethylpyrazine Derivatives as Potential Neuroprotective Agents

“…Although the exact mechanism of IAA toxicity is unclear, 35) neural cells exposed to IAA present with an increased production of ROS, 36) leading to mitochondrial stress and DNA damage. 37,38) Since TMP can maintain mitochondrial function and suppresses ROS generation, 9) TMP was found to significantly prevent PC12 cells against IAA-induced neurotoxicity at 1-100 µM. However, TMP was less potent than 8a, b, 12a and 22a, b (Fig.…”