Effects of Endocrine Disruptors on Dehydroepiandrosterone Sulfotransferase and Enzymes Involved in PAPS Synthesis: Genomic and Nongenomic Pathways

Abstract

BackgroundSulfation plays an important role both in detoxification and in the control of steroid activity. Studies in rodents have shown that the conversion of dehydroepiandrosterone (DHEA) to DHEA-sulfate is involved in learning and the memory process.MethodsThe effects of a range of plasticizers and related compounds commonly encountered in the environment were evaluated kinetically against human DHEA sulfotransferase (SULT 2A1) and by reverse transcriptase-polymerase chain reaction (RT-PCR) against several enzymes involved in the synthesis of the sulfotransferase cofactor adenosine 3′-phosphate 5′-phosphosulfate (PAPS).ResultsWe found that several of the chemicals acted as competitive inhibitors of SULT 2A1 (Ki for 4-tert-octylphenol is 2.8 μM). Additionally, after treatment of TE 671 cells with 0.005–0.5 μM 4-n-octylphenol, bis(2-ethylhexyl)phthalate, and diisodecyl phthalate, real-time RT-PCR showed dose-dependent decreases in the steady-state mRNA levels of cysteine dioxygenase type I, sulfite oxidase, and 3′-phosphate 5′-phosphosulfate synthase I.ConclusionsThese data suggest that environmental contaminants may exert effects on neuronal function both by direct inhibition of sulfotransferase enzymes and by interrupting the supply of PAPS, which has wider implications for endocrine disruption and xenobiotic metabolism.