Concentration-dependent effects of chlorpyrifos oxon on peroxisome proliferator-activated receptor signaling in MCF-7 cells. (February 2022)

• Record Type: Journal Article
• Authors: Herriage, Stacey; Chen, Guangping; Pope, Carey
• Is Part Of: Toxicology in vitro. Volume 78(2022)
• Publication Date: 2022-02
• Subjects: Fatty acid amide hydrolase -- Endocannabinoids -- Lipid metabolism -- Acetylcholinesterase -- Gene expression; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2021.105268
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: Chlorpyrifos oxon (CPO) is the active metabolite of the organophosphorus pesticide, chlorpyrifos. CPO is a potent inhibitor of acetylcholinesterase (AChE) and other serine hydrolases including fatty acid amide hydrolase (FAAH). AChE is critical in regulating cholinergic signaling while FAAH catalyzes the inactivation of fatty acid signaling lipids including the endocannabinoid (eCB) N-arachidonylethanolamine (anandamide, AEA) and eCB-like metabolites ( e.g., oleoylethanolamide, OEA). AEA and OEA are both peroxisome proliferator-activated receptor (PPAR) agonists that regulate numerous genes involved in lipid metabolism and energy homeostasis. We used the MCF-7 human breast cancer cell line, which expresses AChE, FAAH and PPAR alpha and gamma subtypes, to evaluate the potential effects of CPO on PPAR-related gene expression in an in vitro human cell system. CPO elicited relatively similar concentration-dependent inhibition of both AChE and FAAH. Marked concentration- and time-dependent changes in the expression of four selected PPAR-related genes, LXRα, ACOX1, ABCG2 and AGPAT2, were noted. These findings suggest chlorpyrifos may influence lipid metabolism through blocking the degradation of eCBs or eCB-like metabolites and in turn affecting PPAR receptor activation. The results highlight the potential for non-cholinesterase actions of this common insecticide metabolite through disruption of PPAR signaling including effects on lipid metabolism, immune function and inflammation. Highlights: AChE and FAAH activity in MCF-7 cells were inhibited by CPO in a concentration- and time-dependent manner. The expression of selected target genes showed concentration- and time-dependent changes with CPO exposure. The PPAR antagonist GW9662 markedly reversed AGPAT2 and ABCG2 expression increases elicited by CPO. The data suggest a potential link between chlorpyrifos exposure and altered lipid metabolism, inflammation and immune function mediated by PPARs.