title: Triclosan is a potent inhibitor of estradiol and estrone sulfonation in sheep placenta.
abstract: The personal care product Triclosan, 5-chloro-2(2,4-dichlorophenoxy)-phenol, is widely used in consumer products as an antibacterial agent and is increasingly found in the environment as a contaminant of sewage sludge and wastewater. This compound has been identified in plasma and urine of people in the United States, Sweden and Australia. Triclosan is known to inhibit sulfonation of phenolic xenobiotics and is structurally related to inhibitors of estrogen sulfotransferase, such as polychlorobiphenylols. In pregnancy, the placenta is an important source of estrogen, which is needed for normal fetal development and successful parturition, and estrogen sulfotransferase is thought to play an important role in regulation of estrogen availability. In this study, we examined the effect of Triclosan on sheep placental cytosolic sulfotransferase activity with 17-beta-estradiol and estrone as substrates. For comparison, we studied the effects of 4-hydroxy-3,3',4',5-tetrachlorobiphenyl and 2'-hydroxytriclocarban on estradiol sulfonation. The apparent K(m) for placental cytosolic sulfotransferase activity with estradiol as substrate was 0.27 ± 0.06 nM (mean ± S.D., n = 3 individuals) and with estrone as substrate was 1.86 ± 0.22 nM. Partial substrate inhibition was observed with estradiol at concentrations higher than 10-20 nM, as is typical of estrogen sulfotransferases (SULT1E1) in other species. Studies of the effect of Triclosan on estrogen sulfotransferase activity were conducted with several concentrations (0.1-6 nM) of estradiol and with 2 nM estrone. Triclosan was a very potent inhibitor of both estradiol and estrone sulfonation. For estradiol the inhibition was shown to be mixed competitive/uncompetitive, with K(ic) of 0.09 ± 0.01 nM and K(iu) of 5.2 ± 2.9 nM. The IC(50) for inhibition of estrone sulfonation was 0.60 ± 0.06 nM. At an environmentally relevant concentration of 1 µM, Triclosan was not a substrate for glucuronidation in sheep placental microsomes. Triclosan could be sulfonated in placental cytosol with K(m) 1.14 ± 0.18 µM and V(max) 160 ± 26 pmol/min/mg protein, however the calculated rates of Triclosan sulfonation were negligible at the low nM concentrations that potently inhibit estrogen sulfonation. The high potency of Triclosan as an inhibitor of estrogen sulfotransferase activity raises concern about its possible effects on the ability of the placenta to supply estrogen to the fetus, and in turn on fetal growth and development.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610-0485, USA. mojames@ufl.edu
authors.forename: Margaret O
authors.initials: MO
authors.lastname: James
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.forename: David P
authors.initials: DP
authors.lastname: Summerlot
authors.forename: Laura
authors.initials: L
authors.lastname: Rowland-Faux
authors.forename: Charles E
authors.initials: CE
authors.lastname: Wood
mesh_terms: D000818:Animals; D004785:Environmental Pollutants / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000633:toxicity*; D004958:Estradiol / Q000378:metabolism*; D004970:Estrone / Q000378:metabolism*; D005260:Female; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010920:Placenta / Q000187:drug effects / Q000201:enzymology*; D011247:Pregnancy; D012756:Sheep; D013451:Sulfonic Acids / Q000378:metabolism; D015238:Sulfotransferases / Q000037:antagonists & inhibitors*; D014260:Triclosan / Q000633:toxicity*
chemical_list: D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D013451:Sulfonic Acids; D004970:Estrone; D014260:Triclosan; D004958:Estradiol; D015238:Sulfotransferases; C020122:estrone sulfotransferase