Activation of Mouse and Human Peroxisome Proliferator−Activated Receptor Alpha by Perfluoroalkyl Acids of Different Functional Groups and Chain Lengths

Abstract

Perfluoroalkyl acids (PFAAs) are surfactants used in consumer products and persist in the environment. Some PFAAs elicit adverse effects on rodent development and survival. PFAAs can activate peroxisome proliferator-activated receptor alpha (PPARalpha) and may act via PPARalpha to produce some of their effects. This study evaluated the ability of numerous PFAAs to induce mouse and human PPARalpha activity in a transiently transfected COS-1 cell assay. COS-1 cells were transfected with either a mouse or human PPARalpha receptor-luciferase reporter plasmid. After 24 h, cells were exposed to either negative controls (water or dimethyl sulfoxide, 0.1%); positive control (WY-14643, PPARalpha agonist); perfluorooctanoic acid or perfluorononanoic acid at 0.5-100 microM; perfluorobutanoic acid, perfluorohexanoic acid, perfluorohexane sulfonate, or perfluorodecanoic acid (PFDA) at 5-100 microM; or perfluorobutane sulfonate or perfluorooctane sulfonate at 1-250 microM. After 24 h of exposure, luciferase activity from the plasmid was measured. Each PFAA activated both mouse and human PPARalpha in a concentration-dependent fashion, except PFDA with human PPARalpha. Activation of PPARalpha by PFAA carboxylates was positively correlated with carbon chain length, up to C9. PPARalpha activity was higher in response to carboxylates compared to sulfonates. Activation of mouse PPARalpha was generally higher compared to that of human PPARalpha. We conclude that, in general, (1) PFAAs of increasing carbon backbone chain lengths induce increasing activity of the mouse and human PPARalpha with a few exceptions, (2) PFAA carboxylates are stronger activators of mouse and human PPARalpha than PFAA sulfonates, and (3) in most cases, the mouse PPARalpha appears to be more sensitive to PFAAs than the human PPARalpha in this model.

Tissue toxicokinetics of perfluoro compounds with single and chronic low doses in male rats

“…The human PPARα is more sensitive to C6A than C8S as reported by Wolf et al (2008), where concentrations predicted to produce 20% of the overall maximal responses for C6A and C8S are 16 and 262 μM, respectively. Nakamura et al (2016) reported that C6A as well as C8A induced DNA damage in an alkaline comet assay, using TK +/-heterozygote of the TK6 human lymphoblastoid cell line.…”

Immunotoxic and hepatotoxic effects of perfluoro-n-decanoic acid (PFDA) on female Harlan Sprague–Dawley rats and B6C3F1/N mice when administered by oral gavage for 28 days

“…6 carbon) PFAS have a longer half-life and are more potent activators of the peroxisome proliferator-activated receptor (PPAR)-a pathway (Buck et al 2011). There was also a positive correlation between carbon chain length and hepatomegaly (Kudo et al 2006), total and renal clearance (Kudo et al 2001;Ohmori et al 2003), hydrophobicity (Goecke-Flora and Reo 1996), and induction of PPARa (Wolf, Takacs, et al 2008), peroxisomal fatty acyl CoA-oxidase, hepatic phosphocholine (Goecke-Flora and Reo 1996), and peroxisomal b-oxidation (Kudo et al 2006). Following a systematic review of the literature on the immune effects of PFOA and PFOS, the National Toxicology Program Office of Health Assessment and Translation (OHAT) concluded that there was a moderate level of evidence that PFOA and PFOS suppress the anti-vaccine antibody response, and are presumed to be an immune hazard to humans (OHAT 2016).…”

Structure–activity relations in binding of perfluoroalkyl compounds to human thyroid hormone T3 receptor

“…Due to their structural similarity to fatty acids, previous mechanistic studies focused on PFCs' toxicity carried out through the peroxisome proliferator-activated receptor (PPAR) pathway (Wolf et al 2008). Direct binding and activation to PPARs have been demonstrated (Wolf et al 2012;Takacs and Abbott 2007).…”