| Effects of Endocrine Disruptors on Dehydroepiandrosterone Sulfotransferase and Enzymes Involved in PAPS Synthesis: Genomic and Nongenomic Pathways Robert Harris,1 Nahid Turan,2 Christopher Kirk,1 David Ramsden,2 and Rosemary Waring1 1School of Biosciences, The University of Birmingham, Edgbaston, Birmingham, United Kingdom; 2Department of Medicine, Division of Medical Sciences, The University of Birmingham, Queen Elizabeth Hospital, Birmingham, United Kingdom Abstract
Background: Sulfation 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. Methods: The 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) . Results: We found that several of the chemicals acted as competitive inhibitors of SULT 2A1 (Kifor 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. Conclusions: These 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. Key words: DHEA, endocrine disruptor, nongenomic, PAPS, plasticizers, sulfotransferase. Environ Health Perspect 115(suppl 1) :51–54 (2007) . doi:10.1289/ehp.9365 available via http://dx.doi.org/ [Online 8 June 2007]
Address correspondence to R. Harris, School of Biosciences, The University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. Telephone: 44 (0) 121 414 3393. Fax: 44 (0) 121 414 5925. E-mail: R.M.Harris@bham.ac.uk This article is part of the monograph "Endocrine Disruptors—Exposure Assessment, Novel End Points, and Low-Dose and Mixture Effects." We thank members of the Queen Elizabeth Hospital Clinical Transplant Unit and The Liver Research Laboratories for assistance with collection of liver tissue. This study was supported by the European Commission's Quality of Life Programme, Key Action Environment and Health, contract QLK4-CT-2002-02637. The authors declare they have no competing financial interests. Received 22 May 2006 ; accepted 23 October 2006.
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