Steroid Hormone Sulfation Catalyzed by Human Sulfotransferases SULT1E1 and SULT2A1 is Inhibited by Hydroxylated Metabolites of Commonly Observed Airborne Polychlorinated Biphenyls

Polychlorinated biphenyls (PCBs) are persistent, lipophilic molecules with significant human toxicities that include cancer, thyroid abnormalities, diabetes, and other diseases. The volatile PCB congeners with lower numbers of chlorine atoms are present in indoor and outdoor air. Their metabolic fate includes oxidation to hydroxylated PCBs (OH‐PCBs) and subsequent sulfation to form PCB‐sulfates. Endocrine disruption is a common theme in many forms of PCB toxicity, and one potential mechanism for the lower‐chlorinated OH‐PCBs to cause endocrine disruption is by inhibiting the sulfotransferases (SULTs) that convert active steroid hormones to inactive forms (i.e., the steroid sulfates). Therefore, we have explored the inhibition of human estrogen sulfotransferase (SULT1E1) and hydroxysteroid sulfotransferase (SULT2A1) by lower‐chlorinated OH‐PCBs and PCB‐sulfates using purified recombinant enzymes. Since SULT1E1 has been previously shown to be a key enzyme in the differentiation of human adipocytes, we have also studied the inhibition of SULT1E1 within cytosolic fractions derived from a human adipocyte cell culture model. We hypothesize that hydroxylated and sulfated metabolites of the lower chlorinated PCBs inhibit both SULT1E1 and SULT2A1, and, in the case of the adipocyte model, that these metabolites may inhibit adipogenesis through inhibition of SULT1E1. We have determined IC50 values for the SULT1E1‐catalyzed sulfation of 7.0 nanomolar estradiol and the SULT2A1‐catalyzed sulfation of 1 micromolar dehydroepiandrosterone using highly purified recombinant enzymes. Of those compounds examined, the OH‐PCBs were more potent inhibitors than the PCB‐sulfates. The most potent OH‐PCBs inhibited SULT1E1 and SULT2A1 at nanomolar and micromolar concentrations, respectively. The IC50 values that were observed suggest that some of these OH‐PCBs have inhibitory effects at concentrations near the concentration of endogenous hormone required for half‐maximal velocity of sulfation and, thus, might alter intracellular steroid hormone signaling. We isolated cytosolic fractions from both pre‐adipocytes and differentiated adipocytes and examined the di‐chlorinated 4‐OH‐PCB 11 as an inhibitor of SULT1E1‐catalyzed sulfation of 7.0 nM estradiol in these fractions. The resulting IC50 values were similar to those observed for assays with the purified recombinant SULT1E1. Our results indicate that OH‐PCB metabolites of these lower‐chlorinated airborne PCBs inhibit SULT1E1 and SULT2A1. Future studies will determine structure‐activity relationships for lower‐chlorinated OH‐PCBs and PCB‐sulfates as inhibitors of these SULTs as well as their potential for inhibition of adipogenesis through inhibition of SULT1E1 in this model for human adipocyte differentiation. Support or Funding Information Supported by NIH P42 ES013661 and R25 GM058939