Increased toxicity and retention of perflourooctane sulfonate (PFOS) in humanized CYP2B6-Transgenic mice compared to Cyp2b-null mice is relieved by a high-fat diet (HFD). (June 2021)

• Record Type: Journal Article
• Authors: Hamilton, Matthew C.; Heintz, Melissa M.; Pfohl, Marisa; Marques, Emily; Ford, Lucie; Slitt, Angela L.; Baldwin, William S.
• Is Part Of: Food and chemical toxicology. Volume 152(2021)
• Publication Date: 2021-06
• Subjects: Perflourooctane sulfonate (PFOS) -- Non-alcoholic fatty liver disease (NAFLD) -- Cytochrome P450 -- CYP2B6 -- Hepatotoxicity -- Polyunsaturated fatty acids (PUFAs); Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2021.112175
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: PFOS is a persistent, fluorosurfactant used in multiple products. Murine Cyp2b's are induced by PFOS and high-fat diets (HFD) and therefore we hypothesized that human CYP2B6 may alleviate PFOS-induced steatosis. Cyp2b-null and hCYP2B6-Tg mice were treated with 0, 1, or 10 mg/kg/day PFOS by oral gavage for 21-days while provided a chow diet (ND) or HFD. Similar to murine Cyp2b10, CYP2B6 is inducible by PFOS. Furthermore, three ND-fed hCYP2B6-Tg females treated with 10 mg/kg/day PFOS died during the exposure period; neither Cyp2b-null nor HFD-fed mice died. hCYP2B6-Tg mice retained more PFOS in serum and liver than Cyp2b-null mice presumably causing the observed toxicity. In contrast, serum PFOS retention was reduced in the HFD-fed hCYP2B6-Tg mice; the opposite trend observed in HFD-fed Cyp2b-null mice. Hepatotoxicity biomarkers, ALT and ALP, were higher in PFOS-treated mice and repressed by a HFD. However, PFOS combined with a HFD exacerbated steatosis in all mice, especially in the hCYP2B6-Tg mice with significant disruption of key lipid metabolism genes such as Srebp1, Pparg, and Hmgcr . In conclusion, CYP2B6 is induced by PFOS but does not alleviate PFOS toxicity presumably due to increased retention. CYP2B6 protects from PFOS-mediated steatosis in ND-fed mice, but increases steatosis when co-treated with a HFD. Graphical abstract: Image 1 Highlights: Human CYP2B6 is inducible by PFOS in an in vivo model. hCYP2B6-Tg mice retain more PFOS than Cyp2b-nulls and in turn show greater toxicity. A high-fat diet (HFD) reduced PFOS-mediated hepatotoxicity, but increased steatosis. HFD has opposing effects on PFOS retention in Cyp2b-null and hCYP2B6 mice. CYP2B6 is protective from PFOS-mediated steatosis but not HFD-mediated steatosis.