Evaluation of the water disinfection by-product dichloroacetonitrile-induced biochemical, oxidative, histopathological, and mitochondrial functional alterations: Subacute oral toxicity in rats

Abstract

Dichloroacetonitrile (DCAN), an emerging nitrogenous disinfection by-product, is more genotoxic and cytotoxic than the currently regulated carbonaceous disinfection by-products such as haloacetic acids. Few mechanistic studies have been conducted on the hepatic and renal toxicities of DCAN. This study examined the clinical biochemical, hematological, histopathological, oxidative, and mitochondrial functional alterations to evaluate the systematic toxicity after subacute oral exposure of 11 or 44 mg/kg/day in rats for 28 days. Body and spleen weights were lower, and organ-to-body weight ratios of the liver and kidney were higher in rats administered 44-mg/kg DCAN than in controls. The activities of serum alanine aminotransferase and alkaline phosphatase, and concentrations of blood serum urea nitrogen and retinol-binding protein were increased in rats administered 44-mg/kg DCAN compared with those of controls, thereby indicating hepatic and renal damage in this group. This was confirmed by histopathological alterations, including hepatic sinus dilation, extensive hemorrhage, vacuolar degeneration in the liver and glomerulus hemorrhage, and renal tubular swelling, in DCAN-exposed rats. Exposure to 44-mg/kg DCAN induced hepatic oxidative damage shown by the significant increase in malonaldehyde levels, a poisonous product of lipid peroxidation. Exposure to 44-mg/kg DCAN significantly increased hepatic glutathione content and mitochondrial bioenergy as noted by the elevation of mitochondrial membrane potential and cytochrome c oxidase activity, which might be attributed to compensatory pathophysiologic responses to DCAN-induced hepatic mitochondrial damage.

Comparative Quantitative Toxicology and QSAR Modeling of the Haloacetonitriles: Forcing Agents of Water Disinfection Byproduct Toxicity

“…44 Oxidative stress was a significant mechanism of DCAN-induced hepatic mitochondrial injury in rats. 45 Toxicity pathway-based studies uncovered a potential to damage or inhibit proteins and enzymes. A soft electrophilic mechanism of action was suggested.…”

“…A metabolomics study in mice found that HANs increased toxicity with increasing numbers of bromine substituents; these bromo-HANs induced oxidative stress-associated disruptions in amino acid, energy and lipid metabolic processes . Oxidative stress was a significant mechanism of DCAN-induced hepatic mitochondrial injury in rats . Toxicity pathway-based studies uncovered a potential to damage or inhibit proteins and enzymes.…”

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“…Nitrogenous and iodinated DBPs such as haloacetamide (HAcAms) are usually in low levels in drinking water and have not been regulated (Krasner et al, 2006;Ding et al, 2013;Dong et al, 2019), yet it has attracted much attention due to its extremely high cytotoxicity and genotoxicity (Richardson et al, 2007;Wagner and Plewa 2017;Hong et al, 2023). Many studies have been carried out on the toxicity of haloacetonitriles since the 1980s (Lin et al, 1986;Ahmed et al, 1989;Ahmed et al, 1991;Lipscomb et al, 2009;Komaki et al, 2014;Dong et al, 2018b), but the toxicology research on HAcAms, especially on iodinated haloacetamides (I-HAcAms), remained sparse. This may be because commercial standards for I-HAcAms have not been available until recently.…”