Identification of lipidomic markers of chronic 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) exposure in the male rat liver

Abstract

Exposure to PCB 126, an environmentally relevant aryl hydrocarbon receptor agonist, is an environmental factor causing hepatic steatosis in rodent models; however, the lipidome of PCB 126-exposed rats has not been investigated in-depth. The objective of the present study was therefore to characterize dose-dependent changes in the lipid profile in the liver of male Sprague-Dawley rats exposed to PCB 126. Rats were exposed for three month to intraperitoneal injections of 0.01, 0.05 and 0.2 μmol/kg bw PCB 126 in corn oil. Control animals were exposed in parallel and received corn oil alone. Lipids were extracted from whole liver homogenate and levels of polar lipids and fatty acids incorporated into triglycerides (FATAGs) were determined with tandem mass spectrometry using electrospray ionization. PCB 126 exposure increased the hepatic content of polar lipids and FATAGs. Protein adjusted levels of several polar lipid classes, in particular phosphatidylserine levels, decreased, whereas FATAGs levels typically increased with increasing PCB 126 dose. Sensitive, dose-dependent endpoints of PCB 126 exposure included an increase in levels of adrenic acid incorporated into triglycerides and changes in levels of certain ether-linked phospholipid and 1-alkyl/1-alkenyldiacylglycerol species, as determined using partial least square discriminant analysis (PLS-DA) and ANOVA. These changes in the composition of polar lipids and fatty acid in the liver of PCB 126 exposed rats identified several novel markers of PCB 126-mediated fatty liver disease that need to be validated in further studies.

Inhibition of Aryl Hydrocarbon Receptor (AhR) Expression Disrupts Cell Proliferation and Alters Energy Metabolism and Fatty Acid Synthesis in Colon Cancer Cells

“…Previously, TCDD has been reported to regulate expression of the Scd1 gene in mouse liver [ 44 , 76 ], and numerous other toxic AhR agonists, including benzo[a]pyrene, 2,3,7,8-tetrachlorodibenzofuran or 3,3′,4′,4′,5-pentachlorobiphenyl, have been also shown to markedly alter lipid composition in the mouse liver [ 77 , 78 , 79 ]. Our present data indicate that both in colon cancer cells and in non-proliferating differentiated human liver HepaRG cells, the AhR deficiency leads to downregulation of SCD1 mRNA, suggesting that the AhR contributes to its transcriptional control in a manner that is independent of cell cycle deregulation.…”

Hepatic metabolomics reveals that liver injury increases PCB 126-induced oxidative stress and metabolic dysfunction

“…The results suggest that alterations of lipids and thiol metabolites were common metabolic features after PCB 126 exposure regardless of diet, and the metabolism disturbance effects due to PCB 126 exposure were more pronounced in MCD mice as more pathways were perturbed. It has been well established that lipid metabolism is changed after PCB exposure (Yadetie et al, 2014;Kania-Korwel et al, 2017), therefore, lipidomics was not explored further in the present study. Because metabolic pathways are interconnected and perturbation of certain central metabolites could have an impact on multiple metabolic pathways, we attempted to analyze effects of diet and PCB exposure on related metabolic pathways.…”

Thioesterase induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin results in a futile cycle that inhibits hepatic β-oxidation

“…11,12 Lipidomic analysis of hepatic steatosis induced by TCDD and related compounds reported marked increases in FAs, TAGs, phospholipids, and CEs. [13][14][15] Fat accumulation has been attributed to increased hepatic uptake of dietary and mobilized peripheral fats, inhibition of VLDL export, and repression of FA oxidation. 8,13,16,17 In humans, TCDD and related compounds are associated with altered lipid homeostasis, including steatosis with fibrosis and inflammation.…”