Dichloroacetonitrile induces cytotoxicity through oxidative stress-mediated and p53-dependent apoptosis pathway in LO2 cells

Luo, Hao; Zhai, Ling; Yang, Hui; Xu, Leilei; Liu, Jiaxian; Liang, Heng; Tang, Huanwen

doi:10.1080/15376516.2017.1337257

Cited by 14 publications

(10 citation statements)

References 28 publications

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“…DCAN induced the lipid peroxidation, as indicated by an increase in MDA levels in rat livers. The observation is consistent with several studies, which found that DCAN-induced hepatic damage may be related to oxidative stress (Abdel-Naim et al, 2009; Luo et al, 2017). DCAN activates apoptotic signals through oxidative stress by increasing ROS, and MDA levels in LO2 cells (Luo et al, 2017).…”

Section: Discussionsupporting

confidence: 93%

“…An imbalance in ROS generation and antioxidant defense will trigger oxidative stress and damage normal liver and kidney functions. Luo et al (2017) demonstrated that DCAN induces cytotoxicity through oxidative stress-mediated apoptosis pathway in LO2 cells. DCAN is highly accumulated or metabolized in the liver, and mainly excreted through the kidney in various excretable forms (Lipscomb et al, 2009), which suggests that both the liver and kidney can be the target sites for its toxicity.…”

Section: Introductionmentioning

confidence: 99%

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

Dong

Shen

et al. 2017

Toxicol Ind Health

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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

Dong

Shen

et al. 2017

Toxicol Ind Health

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“…Apoptosis induced by factors causing oxidative stress is often accompanied by an increase in the level of another lipid peroxidation product-MDA [76][77][78]. However, there is currently no evidence that MDA is directly involved in the process of apoptosis, although it might be involved in the stimulation of lipid metabolic pathways that affect apoptosis.…”

Section: Ros-dependent Lipid Peroxidation Productsmentioning

confidence: 99%

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

et al. 2020

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Apoptosis is the physiological mechanism of cell death and can be modulated by endogenous and exogenous factors, including stress and metabolic alterations. Reactive oxygen species (ROS), as well as ROS-dependent lipid peroxidation products (including isoprostanes and reactive aldehydes including 4-hydroxynonenal) are proapoptotic factors. These mediators can activate apoptosis via mitochondrial-, receptor-, or ER stress-dependent pathways. Phospholipid metabolism is also an essential regulator of apoptosis, producing the proapoptotic prostaglandins of the PGD and PGJ series, as well as the antiapoptotic prostaglandins of the PGE series, but also 12-HETE and 20-HETE. The effect of endocannabinoids and phytocannabinoids on apoptosis depends on cell type-specific differences. Cells where cannabinoid receptor type 1 (CB1) is the dominant cannabinoid receptor, as well as cells with high cyclooxygenase (COX) activity, undergo apoptosis after the administration of cannabinoids. In contrast, in cells where CB2 receptors dominate, and cells with low COX activity, cannabinoids act in a cytoprotective manner. Therefore, cell type-specific differences in the pro- and antiapoptotic effects of lipids and their (oxidative) products might reveal new options for differential bioanalysis between normal, functional, and degenerating or malignant cells, and better integrative biomedical treatments of major stress-associated diseases.

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“…2016; Procházka et al. 2015; Luo et al. 2017), it is becoming clearer that the specific genes associated with oxidative stress involve additional layers of complexity (Pals et al.…”

Section: Discussionmentioning

confidence: 99%

Global Transcriptional Analysis of Nontransformed Human Intestinal Epithelial Cells (FHs 74 Int) after Exposure to Selected Drinking Water Disinfection By-Products

Prochazka

Melvin

Escher

et al. 2019

Environ Health Perspect

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Background:Drinking water disinfection inadvertently leads to the formation of numerous disinfection by-products (DBPs), some of which are cytotoxic, mutagenic, genotoxic, teratogenic, and potential carcinogens both in vitro and in vivo.Objectives:We investigated alterations to global gene expression (GE) in nontransformed human small intestine epithelial cells (FHs 74 Int) after exposure to six brominated and two chlorinated DBPs: bromoacetic acid (BAA), bromoacetonitrile (BAN), 2,6-dibromo-p-benzoquinone (DBBQ), bromoacetamide (BAM), tribromoacetaldehyde (TBAL), bromate (BrO3−), trichloroacetic acid (TCAA), and trichloroacetaldehyde (TCAL).Methods:Using whole-genome cDNA microarray technology (Illumina), we examined GE in nontransformed human cells after 4h exposure to DBPs at predetermined equipotent concentrations, identified significant changes in gene expression (p≤0.01), and investigated the relevance of these genes to specific toxicity pathways via gene and pathway enrichment analysis.Results:Genes related to activation of oxidative stress–responsive pathways exhibited fewer alterations than expected based on prior work, whereas all DBPs induced notable effects on transcription of genes related to immunity and inflammation.Discussion:Our results suggest that alterations to genes associated with immune and inflammatory pathways play an important role in the potential adverse health effects of exposure to DBPs. The interrelationship between these pathways and the production of reactive oxygen species (ROS) may explain the common occurrence of oxidative stress in other studies exploring DBP toxicity. Finally, transcriptional changes and shared induction of toxicity pathways observed for all DBPs caution of additive effects of mixtures and suggest further assessment of adverse health effects of mixtures is warranted. https://doi.org/10.1289/EHP4945

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Dichloroacetonitrile induces cytotoxicity through oxidative stress-mediated and p53-dependent apoptosis pathway in LO2 cells

Cited by 14 publications

References 28 publications

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

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

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

Global Transcriptional Analysis of Nontransformed Human Intestinal Epithelial Cells (FHs 74 Int) after Exposure to Selected Drinking Water Disinfection By-Products

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