Abstract
Exposure to Per- and polyfluoroalkyl substances (PFAS) has been linked to multiple undesirable health outcomes across a full lifespan, both in animal models as well as in human epidemiological studies. Immunosuppressive effects of PFAS have been reported, including increased risk of infections and suppressed vaccination responses in early childhood, as well as association with immunotoxicity and diabetes. On a mechanistic level, PFAS exposure has been linked with metabolic disturbances, particularly in lipid metabolism, but the underlying mechanisms are poorly characterized. Herein we explore lipidomic signatures of prenatal and early-life exposure to perfluoroundecanoic acid (PFUnDA) in non-obese diabetic (NOD) mice; an experimental model of autoimmune diabetes. Female NOD mice were exposed to four levels of PFUnDA in drinking water at mating, during gestation and lactation, and during the first weeks of life of female offspring. At offspring age of 11–12 weeks, insulitis and immunological endpoints were assessed, and serum samples were collected for comprehensive lipidomic analyses. We investigated the associations between exposure, lipidomic profile, insulitis grade, number of macrophages and apoptotic, active-caspase-3-positive cells in pancreatic islets. Dose-dependent changes in lipidomic profiles in mice exposed to PFUnDA were observed, with most profound changes seen at the highest exposure levels. Overall, PFUnDA exposure caused downregulation of phospholipids and triacylglycerols containing polyunsaturated fatty acids. Our results show that PFUnDA exposure in NOD mice alters lipid metabolism and is associated with pancreatic insulitis grade. Moreover, the results are in line with those reported in human studies, thus suggesting NOD mice as a suitable model to study the impacts of environmental chemicals on T1D.
Highlights
Per- and polyfluoroalkyl substances (PFAS) are widespread in the environment as they are highly persistent and are used extensively in numerous consumer products and fire-fighting foams
In the present work we study the impact of exposure to perfluoroundecanoic acid (PFUnDA) on lipidomic profiles in non-obese diabetic (NOD) mice, and link this with previously-reported early markers for autoimmune diabetes (Bodin et al, 2016): 1) insulitis grade, 2) number of macrophages (MP) and 3) apoptotic, active caspase-3 positive cells (Aac3P) in pancreatic islets
The 32 female NOD mice were divided into four different exposure groups
Summary
Per- and polyfluoroalkyl substances (PFAS) are widespread in the environment as they are highly persistent and are used extensively in numerous consumer products and fire-fighting foams. PFAS interfere with mitochondrial fatty acid β-oxidation in the liver (Lu et al, 2019) and increase the expression of hepatic genes involved in fatty acid and triglyceride synthesis, possibly triggering steatosis through skewing of the balance between lipogenesis and lipolysis (Das et al, 2017). These results are supported by in vitro studies in primary human and rat hepatocytes, showing that PFAS exposure results in shift from carbohydrate metabolism to fatty acid accumulation and oxidation (Bjork et al, 2011). Immunotoxic effects of PFOA have been reported, both in vitro and in vivo (DeWitt et al, 2009; Corsini et al, 2014), purportedly due to alteration of PPARs, NF-κB regulated gene transactivation and/ or regulation of apoptosis (Chain et al, 2020), indicated by inhibition of the T-cell dependent antibody response in animal models
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