Date of Award
Master of Science (MS)
William S Baldwin
Perfluorooctanesulfonic acid (PFOS) is a persistent, toxic fluorosurfactant foam used in firefighting foams, textiles, and other industrial products. Human CYP2B6 is predominantly expressed in the liver and responsible for metabolizing xeno- and endobiotics. CYP2B is induced by PFOS and high-fat diets in rodents and therefore it was hypothesized that CYP2B contributed to PFOS-induced steatosis. Cyp2b-9/10/13-null (Cyp2b-null) and humanized CYP2B6-Tg (hCYP2B6-Tg) mice were treated with PFOS (0, 1, or 10 mg/kg/day) by oral gavage in mice fed either a typical chow diet (ND) or a high-fat diet (HFD). Our studies show human CYP2B6 is also inducible in vivo by PFOS. In addition, three ND-fed hCYP2B6-Tg female mice treated with 10 mg/kg/day PFOS died during the exposure period. Similarly treated HFD-fed mice did not die. Interestingly, hCYP2B6-Tg mice retained significantly more PFOS in the serum and liver than Cyp2b-null mice presumably leading to the observed toxicity. Serum PFOS retention was significantly reduced in the HFD-fed hCYP2B6-Tg mice, which is the opposite trend observed in HFD-fed Cyp2b-null mice. Hepatotoxicity biomarkers, ALT and ALP, were higher in PFOS-treated mice and lowered by a HFD. However, PFOS combined with a HFD exacerbated hepatic lipid accumulation in all mice, especially in the hCYP2B6-Tg mice with significant disruption of key lipid metabolism genes such as Srebp1, Pparg, and Cpt1a. In conclusion, CYP2B6 is induced by PFOS and protects from PFOS-mediated steatosis in ND-fed mice; however, it’s presence increases hepatic triglyceride content in HFD-PFOS co-treated mice and increases toxicity in ND-fed mice.
Hamilton, Matthew C., "Role of CYP2B6 in Perfluorooctanesulfonic Acid (PFOS)-Induced Toxicity and Non Alcoholic Fatty Liver Disease (NAFLD)" (2020). All Theses. 3385.