Exposure to a PFOA, PFOS and PFHxS Mixture during Gestation and Lactation Alters the Liver Proteome in Offspring of CD-1 Mice.

Perfluroalkyl substances (PFASs) are persistent man-made chemicals considered to be emerging pollutants, with Perfluorooctanoic acid (PFOA), Perfluorooctanesulfonic acid (PFOS), and Perfluorohexanesulphonic acid (PFHxS) being linked to hepatotoxicity and steatosis. PFOA, PFOS, and PFHxS can undergo placental and lactational transfer, which results in PFOA, PFOS, and PFHxS distribution to the neonatal liver. Moreover, in pregnant dams, exposure to a PFAS mixture, in combination with a high fat diet, increased hepatic steatosis in offspring at postnatal day 21, but the mechanisms have not been elucidated. It was hypothesized that gestational/lactational PFAS exposure would alter the pup liver proteome and biochemical/signaling pathways. Timed-pregnant CD-1 dams were fed a standard chow or 60% kcal high-fat diet. From GD1 until PND20, dams were dosed via oral gavage with vehicle (0.5% Tween 20), individual doses of PFOA, PFOS, PFHxS at 1 mg/kg, or a mixture (1 mg/kg each, totaling 3 mg/kg). Livers were collected from PND21 offspring and SWATH-MS proteomics was performed. IPA analysis revealed PFAS exposure modified disease and biological function pathways involved in liver damage, xenobiotics, and lipid regulation in the PND21 liver. These pathways included lipid and fatty acid transport, storage, oxidation, and synthesis, as well as xenobiotic metabolism and transport, and liver damage and inflammation. This indicates the pup liver proteome is altered via maternal exposure and predisposes the pup to metabolic dysfunctions.

Species-Specific Unbound Fraction Differences in Highly Bound PFAS: A Comparative Study across Human, Rat, and Mouse Plasma and Albumin.

Per- and polyfluoroalkyl substances (PFAS) are a diverse group of fluorinated compounds which have yet to undergo comprehensive investigation regarding potential adverse health effects and bioaccumulative properties. With long half-lives and accumulative properties, PFAS have been linked to several toxic effects in both non-clinical species such as rat and mouse as well as human. Although biological impacts and specific protein binding of PFAS have been examined, there is no study focusing on the species-specific fraction unbound (fu) in plasma and related toxicokinetics. Herein, a presaturation equilibrium dialysis method was used to measure and validate the binding of 14 individual PFAS with carbon chains containing 4 to 12 perfluorinated carbon atoms and several functional head-groups to albumin and plasma of mouse (C57BL/6 and CD-1), rat, and human. Equivalence testing between each species-matrix combination showed positive correlation between rat and human when comparing fu in plasma and binding to albumin. Similar trends in binding were also observed for mouse plasma and albumin. Relatively high Spearman correlations for all combinations indicate high concordance of PFAS binding regardless of matrix. Physiochemical properties of PFAS such as molecular weight, chain length, and lipophilicity were found to have important roles in plasma protein binding of PFAS.