Subhepatotoxic exposure to arsenic enhances lipopolysaccharide-induced liver injury in mice

Abstract

Exposure to arsenic via drinking water is a serious health concern in the US. Whereas studies have identified arsenic alone as an independent risk factor for liver disease, concentrations of arsenic required to damage this organ are generally higher than found in the US water supply. The purpose of the current study was to test the hypothesis that arsenic (at subhepatotoxic doses) may also sensitize the liver to a second hepatotoxin. To test this hypothesis, the effect of chronic exposure to arsenic on liver damage caused by acute lipopolysaccharide (LPS) was determined in mice. Male C57Bl/6J mice (4-6 weeks) were exposed to arsenic (49 ppm as sodium arsenite in drinking water). After 7 months of exposure, animals were injected with LPS (10 mg/kg i.p.) and sacrificed 24 h later. Arsenic alone caused no overt hepatotoxicity, as determined by plasma enzymes and histology. In contrast, arsenic exposure dramatically enhanced liver damage caused by LPS, increasing the number and size of necroinflammatory foci. This effect of arsenic was coupled with increases in indices of oxidative stress (4-HNE adducts, depletion of GSH and methionine pools). The number of apoptotic (TUNEL) hepatocytes was similar in the LPS and arsenic/LPS groups. In contrast, arsenic pre-exposure blunted the increase in proliferating (PCNA) hepatocytes caused by LPS; this change in the balance between cell death and proliferation was coupled with a robust loss of liver weight in the arsenic/LPS compared to the LPS alone group. The impairment of proliferation after LPS caused by arsenic was also coupled with alterations in the expression of key mediators of cell cycle progression (p27, p21, CDK6 and Cyclin D1). Taken together, these results suggest that arsenic, at doses that are not overtly hepatotoxic per se, significantly enhances LPS-induced liver injury. These results further suggest that arsenic levels in the drinking water may be a risk modifier for the development of chronic liver diseases.

Extracellular matrix proteins and the liver-lung axis in disease.

“…Therefore, OFC may also be protecting against damage in this model by preventing hepatic sensitization caused by HFD-induced endotoxemia. Such a mechanism is supported by previous studies that arsenic-exposed livers are more sensitive to exogenous LPS (47) and that liver injury here in OFC-fed mice was insensitive to arsenic administration.…”

“…For instance, Pinyayev et al showed that bacteria from the mouse cecum can metabolize arsenic (141) and others have shown that the human gut flora can metabolize arsenic into toxic metabolites (142,143). Whereas this is distinctly possible, it should be noted that concentrations that are 10-fold higher than used here were not directly hepatotoxic (47). Alternatively, the effects of arsenic on the microbiome may mediate the observed hepatotoxicity.…”

“…Moreover, low levels of arsenic have also been shown to sensitize the liver to inflammatory insult (47). A previous study from our group has implicated an interaction between HFD and subhepatotoxic arsenic exposure, the combination of which caused enhanced liver injury.…”

“…Indeed, chronic arsenic exposure causes hepatomegaly, non-cirrhotic portal fibrosis and portal hypertension (113)(114)(115). The concentrations of arsenic found in the US water supply are generally considered lower than those necessary to cause overt liver damage, however lower levels of arsenic can cause more subtle changes in the liver (46) and can sensitize the liver to injury by another insult (47). Therefore, while arsenic levels in the US may not be high enough to directly injure the liver, there is evidence that low levels of arsenic may interact with other risk-modifying factors to cause hepatic injury.…”

Arsenic in drinking water causes gene expression changes in the liver related to inflammation and metabolic dysfunction and accelerates atherosclerosis in ApoE-/-mice

“…A high fat diet enchanced arsenic-induced liver fibrosis in this study and caused an array of related aberrant gene expression changes [36]. Arteel et al demonstrated similar results using four to 6 week-old C57BLl6J mice were exposed to 49 ppm arsenic as sodium arsenite in drinking water for seven months [37]. They showed AL T and AST levels were significantly increased 2 and 3 fold, respectively in response to lipopolysaccharide (LPS) challenge.…”