Nickel (Ni) is a significant environmental pollutant that poses a risk to human health due to its carcinogenic nature which involves DNA damage, oxidative stress, and disruption of cellular signaling pathways. These effects contribute to the development of lung, nasal, and sinonasal cancers, as well as damage to various tissues and organs. Nickel chloride (NiCl2), an inorganic divalent Ni compound, has been reported to induce oxidative stress in cellular systems by disrupting redox homeostasis. This study aimed to  investigate the effect of a single acute oral dose of NiCl2 on the rat small intestine, especially on the antioxidant defence system and DNA integrity. Male Wistar rats were divided into five groups: one control (untreated) and four NiCl2-treated groups, each receiving single oral dose of NiCl2 at 45, 90, 135, and 180 mg/kg body weight. NiCl2 treatment diminished the content of reduced glutathione and total sulfhydryl groups but increased lipid and protein oxidation and also hydrogen peroxide levels. The antioxidant power of the intestine was compromised due to inhibition of key antioxidant enzymes and decreased reduced glutathione levels which led to impaired free radical quenching and metal-reducing ability. Oral administration of NiCl2 inhibited the marker enzymes of intestinal brush border membrane. Enzymes of pathways of carbohydrate metabolism like glycolysis, gluconeogenesis, citric acid cycle, and hexose monophosphate shunt were also inhibited. The diphenylamine and comet assays showed significantly increased DNA fragmentation, while DNA–protein cross-linking in intestinal mucosa of NiCl2-administered animals was also elevated, when compared to the control group. Histopathology showed abnormal morphology of intestinal villi with marked lymphocytic infiltration in NiCl2-treated rats. This is likely due to increased ROS production and oxidative damage of cell components. All changes were seen in a NiCl2 dose-dependent manner. The observed intestinal damage could be due to significant impairment in the antioxidant defence system elicited by oxidative stress produced upon exposure to NiCl2 with more prominent changes at higher doses of the metal ion. Graphical Abstract Schematic representation of the effects of oral administration of NiCl2 on rat intestine. Ni2+ enters the cells and generates reactive oxygen species and free radicals. This causes oxidation of membrane proteins and lipids, leading to membrane damage and greater Ni2+ influx. The activities of BBM enzymes were inhibited. Ni2+ disrupts the AO status of cells and lowers glutathione levels and AO enzyme activities. Carbohydrate metabolism pathways were inhibited by Ni2+. Additionally, Ni2+ induces genotoxic effects, promoting DNA–protein cross-linking, DNA fragmentation, and strand scission. The cumulative effect of these changes is altered intestinal histology and tissue damage. NiCl2, nickel chloride; AO, antioxidant; BBM, brush border membrane; GSH, reduced glutathione; DPC, DNA–protein cross-linking.

Nickel chloride-induced ROS cause cyto- and geno-toxicity in rat intestine: a biochemical and histological study

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发表日期：

2025年8月1日

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Monika Sharma,
Neha Qasim,
Aijaz Ahmed Khan,
Fahim Halim Khan,
Riaz Mahmood

摘要

Nickel (Ni) is a significant environmental pollutant that poses a risk to human health due to its carcinogenic nature which involves DNA damage, oxidative stress, and disruption of cellular signaling pathways. These effects contribute to the development of lung, nasal, and sinonasal cancers, as well as damage to various tissues and organs. Nickel chloride (NiCl₂), an inorganic divalent Ni compound, has been reported to induce oxidative stress in cellular systems by disrupting redox homeostasis. This study aimed to investigate the effect of a single acute oral dose of NiCl₂ on the rat small intestine, especially on the antioxidant defence system and DNA integrity. Male Wistar rats were divided into five groups: one control (untreated) and four NiCl₂-treated groups, each receiving single oral dose of NiCl₂ at 45, 90, 135, and 180 mg/kg body weight. NiCl₂ treatment diminished the content of reduced glutathione and total sulfhydryl groups but increased lipid and protein oxidation and also hydrogen peroxide levels. The antioxidant power of the intestine was compromised due to inhibition of key antioxidant enzymes and decreased reduced glutathione levels which led to impaired free radical quenching and metal-reducing ability. Oral administration of NiCl₂ inhibited the marker enzymes of intestinal brush border membrane. Enzymes of pathways of carbohydrate metabolism like glycolysis, gluconeogenesis, citric acid cycle, and hexose monophosphate shunt were also inhibited. The diphenylamine and comet assays showed significantly increased DNA fragmentation, while DNA–protein cross-linking in intestinal mucosa of NiCl₂-administered animals was also elevated, when compared to the control group. Histopathology showed abnormal morphology of intestinal villi with marked lymphocytic infiltration in NiCl₂-treated rats. This is likely due to increased ROS production and oxidative damage of cell components. All changes were seen in a NiCl₂ dose-dependent manner. The observed intestinal damage could be due to significant impairment in the antioxidant defence system elicited by oxidative stress produced upon exposure to NiCl₂ with more prominent changes at higher doses of the metal ion.

Graphical Abstract

Schematic representation of the effects of oral administration of NiCl₂ on rat intestine. Ni²⁺ enters the cells and generates reactive oxygen species and free radicals. This causes oxidation of membrane proteins and lipids, leading to membrane damage and greater Ni²⁺ influx. The activities of BBM enzymes were inhibited. Ni²⁺ disrupts the AO status of cells and lowers glutathione levels and AO enzyme activities. Carbohydrate metabolism pathways were inhibited by Ni²⁺. Additionally, Ni²⁺ induces genotoxic effects, promoting DNA–protein cross-linking, DNA fragmentation, and strand scission. The cumulative effect of these changes is altered intestinal histology and tissue damage. NiCl₂, nickel chloride; AO, antioxidant; BBM, brush border membrane; GSH, reduced glutathione; DPC, DNA–protein cross-linking.