Hexafluoropropylene Oxide Dimer Acid (Hfpo-Da) Induced Developmental Cardiotoxicity And Hepatotoxicity In Hatchling Chickens: Roles Of Peroxisome Proliferator Activated Receptor Alpha*

Hexafluoropropylene oxide dimer acid (HFPO-DA) is a perfluorooctanoic acid (PFOA) substitute. In the current study, potential developmental cardiotoxicity and hepatotoxicity following HFPO-DA exposure in chicken embryo has been investigated, focusing on the roles of peroxisome proliferator activated receptor alpha (PPAR alpha), the major molecular target in PFOA-induced toxicities. HFPO-DA was exposed to fertile chicken eggs via air cell injection, morphology and function of the target organs (heart and liver) in hatchlings were investigated with histopathology and electrocardiography, and the serum levels of HFPO-DA had been measured with quadrupoletime of flight liquid chromatograph-mass spectrometer (Q-TOF LC/MS). Additionally, lentivirus-mediated in ovo PPAR alpha silencing was used to assess the roles of PPAR alpha in HFPO-DA induced developmental toxicities. The results indicated that developmental exposure to HFPO-DA induced developmental cardiotoxicity, including thinned right ventricular wall and elevated heart rates, similar to those observed with PFOA exposure, as well as developmental hepatotoxicity in the form of steatosis. Silencing of PPAR alpha alleviated such effects, suggesting participation of PPAR alpha in HFPO-DA induced developmental toxicities in chicken embryo. Moreover, enhanced expression of PPAR alpha downstream genes, cluster of differentiation 36 (CD36) and enoyl-CoA hydratase and 3hydroxyacyl CoA dehydrogenase (EHHADH), were observed in HFPO-DA exposed animal heart tissues, which can be abolished by PPAR alpha silencing. On the other hand, liver-type fatty acid binding protein (L-FABP) and CD36 expression were effectively enhanced in exposed liver tissues, but not EHHADH, suggesting differential mechanism of toxicity in heart and liver tissues. In summary, developmental exposure to HFPO-DA induced developmental cardiotoxicity and hepatotoxicity in hatchling chickens similar to PFOA, and PPAR alpha still participates in such toxicities, with some differential downstream gene regulations in different organs. Further investigation on HFPO-DA-induced developmental toxicities is guaranteed.