Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that are associated with varied adverse health effects. Lower chlorinated PCBs are prevalent in indoor and outdoor air and can be metabolized to their hydroxylated derivatives (OH-PCBs) followed by sulfation to form PCB sulfates. Sulfation is also a means of signal termination for steroid hormones. The human estrogen sulfotransferase (SULT1E1) and alcohol/hydroxysteroid sulfotransferase (SULT2A1) catalyze the formation of steroid sulfates that are inactive at steroid hormone receptors. We investigated the inhibition of SULT1E1 (IC50s ranging from 7.2 nM to greater than 10 μM) and SULT2A1 (IC50s from 1.3 μM to over 100 μM) by five lower-chlorinated OH-PCBs and their corresponding PCB sulfates relevant to airborne PCB-exposure. Several congeners of lower chlorinated OH-PCBs relevant to airborne PCB exposures were potent inhibitors of SULT1E1 and SULT2A1 and thus have the potential to disrupt regulation of intracellular concentrations of the receptor-active steroid substrates for these enzymes.

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.

The potential disruption of estrogen and androgen homeostasis The potential disruption of estrogen and androgen homeostasis and adipocyte differentiation by metabolites of common airborne and adipocyte differentiation by metabolites of common airborne polychlorinated biphenyls polychlorinated biphenylsii To my family iii I can do all things through Christ which strengtheneth me.Philippians 4:13 King James Version iv ACKNOWLEDGEMENTS First and foremost, I would like to thank God for seeing me through this process.He has surrounded me with so many genuine, supportive and caring people that have helped me along this journey. I would also like to express my gratitude to several other individuals that have helped me to achieve various milestones and dreams.I would like to thank Dr. Duffel for accepting me into his lab and for his mentorship and advisement throughout my graduate education. I appreciate the many letters of recommendation that he has written on my behalf and his guidance on my research. With his support and advocacy, I was awarded many fellowships, completed an internship at SC Johnson and Sons, and presented at over 20 conferences that took place in Japan, California, Puerto Rico, and other fascinating places. I appreciate his patience and support during my time in his lab and for the many lessons that I was grateful to learn there. Two important lessons that I learned was to always believe in myself especially when facing adversity and that I can accomplish anything that I set my mind to. My experiences and training during my time in your lab elevated my networking skills, professional network, mentoring style, helped me discover many scientific opportunities and I received many incredible job opportunities spanning from industry and academia upon graduation. I look forward to seeing the new heights that our careers will reach and staying in contact! Thank you again for all that you've done! I would also like to thank my thesis committee members: Dr. Michael Duffel, Dr.