No abstract

Endocrine disruption, metabolic syndrome, diabetes, cancer, and other diseases have been associated with exposure to polychlorinated biphenyls. There is a growing interest in the lower chlorinated PCBs due to their presence in the indoor air of older buildings, their susceptibility to metabolism catalyzed by cytochrome P450 to form hydroxylated PCBs (OH‐PCBs), and their potential to disrupt endocrine function. OH‐PCBs are further metabolized in reactions catalyzed by cytosolic sulfotransferases (SULTs) to form PCB‐sulfates. Estrogen sulfotransferase (SULT1E1) is important in the regulation of cellular levels of active and inactive estrogens, with estradiol being a primary physiological substrate. Recent literature has suggested that decreased activity of SULT1E1 can impact adipocyte differentiation. We hypothesize that some lower‐chlorinated OH‐PCBs potently inhibit SULT1E1 causing increased cellular levels of estradiol and a decrease in human adipocyte differentiation. Our studies using purified recombinant human SULT1E1 (at 7.0 nM estradiol) found 4‐OH‐PCB 11 and 4′‐OH‐PCB 25 to be potent inhibitors, with IC50 values of 7.2 and 7.3 nM, respectively. 4′‐OH‐PCB 8 and 4‐OH PCB 52 inhibited SULT1E1 with IC50 values of 17.6 and 18.6 nM, respectively, and the least potent inhibitor, 4′‐OH‐PCB 3, had an IC50 of 1300 nM. We have exposed immortalized human adipocytes to these five OH‐PCBs and another known inhibitor of SULT1E1, triclosan, at concentrations of 1 uM and 10 uM for 72 hours followed by differentiation for 11 days. The cells were stained with AdipoRed to quantitate lipid accumulation. Exposure to 4′‐OH‐PCB 3 resulted in no significant reduction in lipid accumulation, while the remaining OH‐PCBs and triclosan showed significant reductions in adipocyte differentiation. This congener‐selective ability to inhibit SULT1E1 and adipocyte differentiation is consistent with the hypothesis that OH‐PCB‐mediated inhibition of SULT1E1 can inhibit human adipogenesis. Future studies will explore the role of this inhibition of SULT1E1 in adipogenesis by measuring mRNA expression of SULT1E1 and prominent adipogenic markers in these cells as well as cellular levels of estradiol and estradiol‐sulfate.Support or Funding InformationSupported by NIH grants P42 ES013661 and R25 GM058939, and a William Townsend Porter Fellowship from the American Physiological Society.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.