Interaction of volatile organic compounds and underlying liver disease: a new paradigm for risk

Abstract

Occupational and environmental exposures to industrial chemicals are known to cause hepatotoxicity and liver injury, in humans and in animal models. Historically, research has focused on severe acute liver injury (e.g. fulminant liver failure) or endstage diseases (e.g. cirrhosis and HCC). However, it has become recently recognized that toxicants can cause more subtle changes to the liver. For example, toxicant-associated steatohepatitis, characterized by hepatic steatosis, and inflammation, was recently recognized in an occupational cohort exposed to vinyl chloride. At high occupational levels, toxicants are sufficient to cause liver damage and disease even in healthy subjects with no comorbidities for liver injury. However, it is still largely unknown how exposure to toxicants initiate and possibly more importantly exacerbate liver disease, when combined with other factors, such as underlying non-alcoholic fatty liver disease caused by poor diet and/or obesity. With better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of toxicant-induced liver disease, rational targeted therapy can be developed to better predict risk, as well as to treat or prevent this disease. The purpose of this review is to summarize established and proposed mechanisms of volatile organic compound-induced liver injury and to highlight key signaling events known or hypothesized to mediate these effects.

Keywords: environmental liver disease; hepatotoxicity; non-alcoholic fatty liver disease (NAFLD); organochlorines; toxicant; toxicant-associated steatohepatitis (TASH).

Figure 1

Risk factors of liver injury. There are well-known primary risk factors causing liver disease, such as obesity, alcohol or toxicants. However, it is less well understood how other mitigating factors such as host genetics or underlying comorbidities will impact or enhance liver injury caused by the primary risk factors. Importantly, although the effects of high-level occupational VOC exposures have been studied, it is becoming clear that low-level occupational and environmental exposure may interact with other risk-modifying factors, such as ‘secondary’ risk factors to cause liver injury at concentrations that are considered ‘safe.’

Figure 2

Potential mechanism(s) of liver injury by VOC exposure. Upon exposure to VC, reactive intermediates form though bio activation processes and diet-induced obesity decreases their elimination. Through carbonyl stress and the generation of reactive oxygen and nitrogen species (ROS/RNS), VC metabolites cause ER stress leading to mitochondrial damage, which impairs oxidative phosphorylation; the cell increases flux through glycolysis to compensate for this loss of ATP yield. The increased demand for glucose depletes glycogen stores. AcetylCoA is being shunted to lipid synthesis (causing steatosis) rather than β-oxidation, even under conditions of ATP depletion, resulting in an increase in lactate production. The combined metabolic stress of VC exposure and ATP depletion likely causes ‘liponecrosis’ associated with increased oxidative stress, ER stress, and inefficient mitochondrial respiration and energy production.