Abstract
Perfluoroalkyl substances (PFAS), a family of environmental toxicants, are ubiquitous in the environment and the human population. PFAS are manmade chemicals that have been widely used in manufacturing since the 1940s. PFAS are extremely resistant to degradation leading to their accumulation within the environment and the general population. The most concentrated PFAS member present in the general population, perfluorooctanesulfonic acid (PFOS), has been linked to suppressed vaccine response, high serum cholesterol, low fetal birth weight, thyroid disease, increased markers of liver injury, and even certain types of cancers. PFOS was voluntarily phased out of manufacturing due to its bioaccumulutive and toxic properties by the year 2015. In 2016, the EPA dramatically lowered the federal health advisory level of PFOS in drinking water to 70ppt due to the emerging evidence of its toxicity. After the phase out of PFOS, replacement PFAS members perfluorononanoic acid (PFNA) and perfluorohexanesulfonic acid (PFHxS) took its place and began to rise in environmental and human serum concentrations. Currently, there is no federal health advisory level in place for PFNA or PFHxS. The relative toxicity of these replacement PFAS compounds is still being evaluated in the literature and by regulatory officials. PFAS, including PFOS, PFNA, and PFHxS, are known to augment hepatic lipid accumulation and steatosis in animal studies. However, there is a lack of knowledge concerning their potential role in the increasing incidence of nonalcoholic fatty liver disease (NAFLD) in the global population. It is difficult to study the potential link between PFAS exposure and NAFLD due to the lack of an accurate and widely accepted serum biomarker for the NAFLD. PFAS levels are typically measured through serum samples, however NAFLD is often diagnosed via liver biopsy. Obtaining human liver biopsy data that is matched to serum samples characterized for PFAS concentration has proven prohibitively difficult. The vast majority of studies that have evaluated PFAS exposure in the liver have utilized standard chow diets, high doses, and acute exposures. In the human population, NAFLD is most commonly induced by poor diet and lifestyle over time. The present work aimed to understand how environmentally relevant exposure to PFAS affect the onset and progression of NAFLD in the presence of a poor diet over a subchronic or chronic timeframe. Furthermore, this work sought to uncover the mechanistic drivers of these PFAS-diet interactions. In manuscript 1, male C57BL6 mice were fed with either a low fat diet (10% kcal
Highlights
Non-alcoholic fatty liver disease is described by the American Liver Foundation (ALF), as the excessive accumulation of fats in the liver in the absence of alcohol use
Using a diet-induced obesity rodent model, we sought to explore the potential role of diet in perfluorooctanesulfonic acid (PFOS) and perfluorononanoic acid (PFNA) induced fatty liver disease
Despite the lack of federal regulation, PFNA was significantly more potent than PFOS in altering hepatic molecular pathways and exhibited increased hepatic deposition. These findings suggest that PFNA may require stricter regulation than PFOS despite its structural similarity
Summary
Non-alcoholic fatty liver disease is described by the American Liver Foundation (ALF), as the excessive accumulation of fats in the liver in the absence of alcohol use. Dietary factors augment the onset and progression of the most common diseases burdening global health today: type II diabetes mellitus (T2DM), cardiovascular disease, non-alcoholic fatty liver disease (NAFLD), and numerous forms of neoplasias (1) Poor diet, such one rich in saturated fats and starches, has been linked to the generation of low grade inflammation systemically, exerting adverse effects on multiple organ systems within the body(2,3). The most common liver disease, NAFLD, and neurodegenerative diseases, such as Alzheimer’s, share obesity as a risk factor (4,5) Treatments for these diet-associated disorders include lipid/cholesterol reducers such as statins (atorvastatin, simvastatin), insulin sensitizers such as metformin and thiazolidinediones (e.g. rosiglitazone), alphaglucosidase inhibitors, fibrates, non-steroidal anti-inflammatory drugs (NSAIDs) and cholinesterase Inhibitors (6–12). The ability of PE to modulate the pro-inflammatory effects of a western style diet in the brains and livers of wild type C57BL/6 mice is explored
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