Vinyl Chloride and High-Fat Diet as a Model of Environment and Obesity Interaction

Abstract

Vinyl chloride (VC), an abundant environmental contaminant, causes steatohepatitis at high levels, but is considered safe at lower levels.Although several studies have investigated the role of VC as a direct hepatotoxicant, the concept that VC modifies sensitivity of the liver to other factors, such as nonalcoholic fatty liver disease (NAFLD) caused by high-fat diet (HFD) is novel. This protocol describes an exposure paradigm to evaluate the effects of chronic, low-level exposure to VC. Mice are acclimated to low-fat or high-fat diet one week prior to the beginning of the inhalation exposure and remain on these diets throughout the experiment. Mice are exposed to VC (sub-OSHA level: <1 ppm) or room air in inhalation chambers for 6 hours/day, 5 days/week, for up to 12 weeks. Animals are monitored weekly for body weight gain and food consumption. This model of VC exposure causes no overt liver injury with VC inhalation alone. However, the combination of VC and HFD significantly enhances liver disease. A technical advantage of this co-exposure model is the whole-body exposure, without restraint. Moreover, the conditions more closely resemble a very common human situation of a combined exposure to VC with underlying nonalcoholic fatty liver disease and therefore support the novel hypothesis that VC is an environmental risk factor for the development of liver damage as a complication of obesity (i.e., NAFLD). This work challenges the paradigm that the current exposure limits of VC (occupational and environmental) are safe. The use of this model can shed new light and concern on the risks of VC exposure. This model of toxicant-induced liver injury can be used for other volatile organic compounds and to study other interactions that may impact the liver and other organ systems.

Environmental toxicant-induced maladaptive mitochondrial changes: A potential unifying mechanism in fatty liver disease?

“…External respiration is directly related to cellular respiration and largely driven by mitochondrial oxidative phosphorylation. We have also demonstrated both in vitro and in vivo that VC and its metabolites directly damage mitochondrial complexes, leading to decreased ATP production, oxygen consumption rate and an uncoupling of the electron transport chain 31 , 32 , 87 , 88 . This causes the cell to increase flux through anaerobic glycolysis to compensate for this loss of ATP yield 32 .…”

“…As outlined in Section 3.2 , a key mechanism of FLD is an increased production of ROS, leading to oxidative stress and the generation of aldehydes 47 , 48 , 49 , 50 . This is increased by VC in mice 31 , 32 , 86 ; and in human subjects, VC exposures were associated with antioxidant depletion consistent with oxidative stress, increased lipid peroxidation products, and decreased carnitine/carnitine esters, which were indicative of mitochondrial dysfunction 15 , 106 . Moreover, the VC-metabolite CAA selectively depletes glutathione (GSH) 88 , likely resulting in decreased GSH-linked antioxidant defenses.…”

“…Specifically, hepatocytes isolated from fatty livers are more sensitive to stress and to cytotoxic killing 27 , 28 , 29 , 30 . As a result, hepatocyte death is enhanced in experimental FLD 24 , 31 , 32 . A leitmotif in this review is to discuss potential unifying mechanisms in the interaction of environmental toxicants and underlying FLD.…”

“…Importantly, VOCs are directly hepatotoxic at high exposure concentrations, but can also enhance underlying liver injury and therefore contribute to the progression of FLD 16 , 81 , 82 . Recent studies by our laboratory indicate that vinyl chloride (VC), at concentrations that are not hepatotoxic per se , enhances liver disease via sensitization (see Section 2 ) 31 , 32 , 86 , 87 . We have shown that canonical mediators of inflammation in FLD are not enhanced by VC exposure in experimental NAFLD 32 .…”

Polystyrene nanoplastics potentiate the development of hepatic fibrosis in high fat diet fed mice

“…With respect to the small size, nanoplastics can easily infiltrate in tissue and biological barriers, which pose much more potentials to trigger toxicity 37,38 . The obesity prevalence has grown worldwide, which could cause lipid metabolism disorders, fatty liver development and ultimately related with the occurrence of NAFLD and enhance the susceptibility to other risk factor 39 . However, currently there are limited studies that examined the association between exposure to PS‐NPs and the development of chronic liver diseases in obese NAFLD patients.…”