Organophosphorus Flame Retardants Impair Intracellular Lipid Metabolic Function in Human Hepatocellular Cells.

Organophosphorus flame retardants (OPFRs), a replacement for brominated flame retardants, have gradually been accepted as endocrine disrupting chemicals (EDCs). Recently, evidence has shown that these EDCs could cause chronic health problems, such as obesity, and referred to as metabolic disruptors. However, the disturbance to lipid metabolism caused by OPFRs remains poorly understood, especially at biological molecular levels. Herein, we used the human hepatocellular cells (HepG2) to study the lipid metabolism disruption caused by nine OPFRs (halogenated-, aryl-, and alkyl-containing). All the tested OPFRs, excluding the long carbon chain alkyl-OPFRs, could cause intracellular triglyceride (TG) and/or total cholesterol (TC) accumulation. In detail, aryl-OPFRs (TPhP and TCP) induced both TC and TG deposition. Halogenated-OPFRs (TCEP, TBPP, TDCPP, and TCPP) induced intracellular TG accumulation, and only TDCPP also induced TC accumulation. Furthermore, TPhP induced lipid accumulation through regulation genes encoding proteins involved in fatty acid ß-oxidation, lipid, and fatty acid synthesis. All the halogenated-OPFRs cause TG accumulation only, enacted through ß-oxidation rather than lipid synthesis. TPhP and TDCPP induced TC accumulation through both PPARγ and srebp2 signaling. Mitochondrial dysfunction including decreased oxygen consumption rate and ATP content may also contribute to lipid metabolic disruption by the tested OPFRs. Our data indicated that halogenated- and aryl-OPFRs may not be safe candidates, and further information should be made available as potential for, as well as the mechanism of, metabolic disruption. And long carbon chain alkyl-OPFRs may be safer than the other two groups.

Pubertal exposure to the endocrine disruptor mono-2-ethylhexyl ester at body burden level caused cholesterol imbalance in mice.

Metabolic disturbance is the prerequisite to developing metabolic disease. An increasing number of reports have shown that exposure to environmental endocrine-disrupting chemicals (EDCs) can cause metabolic syndrome and may be related to metabolic disease. However, the potential mechanism of EDC-related lipid metabolism disruption in the endocrine organs (especially gut microbiome) during pubertal exposure remains elusive at the body burden level. We observed that male mice fed with 0.05 mg/kg b.w. MEHP under a high-fat diet caused enhancement in the fat mass, total cholesterol, high- and low-density lipoprotein cholesterol. MEHP intake induced a significant shift in microbiota composition, including the relative abundance of Firmicutes and reduction of Verrucomicrobia. Statistical analysis showed a positive correlation between several bacterial taxa and cholesterol body burden. Also, MEHP intake induced adipocyte hypertrophy and cholesterol overloading, which sense cholesterol synthesis genes such as Srebp2 and Hmgcr. That caused adipocyte dysfunction. Finally, cholesterol deposition and transportation was imbalance in the mice liver. Conclusively, by targeting the endocrine organs, EDCs would increase the risk of cholesterol burden even at a low concentration when coupled with a high-fat diet during pubertal period in male mice.

Suppression of progesterone synthesis in human trophoblast cells by fine particulate matter primarily derived from industry.

Epidemiological studies have exhibited a positive association between fine particulate matter (PM2.5) exposure and adverse pregnancy outcome (APO). However, source-related effect and the potential mechanism have not been thoroughly elucidated in toxicology. In this study, PM2.5 was collected during a severe winter haze episode in an energy-base city of China. We coupled this approach with the source appointment by applying the Lagrangian Integrated Trajectory and Concentration Weighted Trajectory model. We observed that the primary trajectory with high polluted air mass came from the northwest of the sampling site. Approximately 90% or more of PM2.5 was derived from the industry at this haze period. Next, the sampled PM2.5 was used to study the classical hormone synthesis pathway on trophoblast JEG-3 cells. PM2.5 induced the secretion of human chorionic gonadotrophin (HCG) and the proliferation of JEG-3 cells at a noncytotoxic concentration. However, the synthesis of progesterone was significantly suppressed, even if both hCG and cyclic adenosine monophosphate (cAMP) were increased, suggesting that PM2.5 may interfere the downstream of cAMP. As expected, the phosphorylated activity of protein kinase A (PKA) was attenuated. Subsequently, the downstream molecules of steroidogenesis, such as ferredoxin reductase (FDXR), CYP11A1 (encoded P450scc), and 3ß-Hydroxysteroid dehydrogenase type 1 (3ß-HSD1), were inhibited. Therefore, PM2.5, primarily derived from industry, may directly inhibit the phosphorylation status of PKA in JEG-3 which, in turn, inhibited the proteins expression in progesterone-synthesis to suppress progesterone levels. Considering the pivotal role of progesterone in pregnancy maintenance, the mechanism on hormone synthesis may provide a better understanding for PM2.5-caused APO. Industry-emanated PM2.5, though not specific, could threaten the placenta, which needs to be verified by further epidemiological studies.