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 Km 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 Kic of 0.09±0.01 nM and Kiu of 5.2±2.9 nM. The IC50 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 Km 1.14±0.18 μM and Vmax 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.

Female exposure to phenols and phthalates and time to pregnancy: the Maternal-Infant Research on Environmental Chemicals (MIREC) Study

“…Animal studies with male rats (39,40) have shown that TCS decreases serum levels of testosterone and the activity of several important steroidogenic enzymes. In addition, TCS has been shown to be a powerful inhibitor of estrogen sulfonation in sheep placental tissue (41), which could impair the maintenance of pregnancy.…”

Estrogen Sulfotransferase/SULT1E1 Promotes Human Adipogenesis

“…Our results showed that pharmacological inhibition or genetic knockdown of EST attenuated the adipogenic process, suggesting that inhibition of EST may be an effective weight reduction strategy in the future. It is encouraging that major progress has been made in the identification and characterization of chemical EST inhibitors (27,40). Among limitations, it is noted that the age range of our human subjects was quite varied and that all samples were from abdominal subcutaneous fat.…”

Estrogen Sulfotransferase Is an Oxidative Stress-responsive Gene That Gender-specifically Affects Liver Ischemia/Reperfusion Injury

“…Pharmacological inhibition of EST, at least in females, might represent a novel therapeutic approach to manage hepatic I/R injury. It is encouraging that major progress has been made in the identification and characterization of chemical EST inhibitors (37).…”