Differential Regulation of Dopamine Transporter Function and Location by Low Concentrations of Environmental Estrogens and 17β-Estradiol

BACKGROUND: The effects of 17β-estradiol (E(2)) and xenoestrogens (XEs) on dopamine transport may have important implications for the increased incidence of neurologic disorders, especially in women during life stages characterized by frequent hormonal fluctuations. OBJECTIVE: We examined low concentrations of XEs [dieldrin, endosulfan, o′, p′-dichlorodiphenyl-ethylene (DDE), nonylphenol (NP), and bisphenol A (BPA)] for nongenomic actions via action of membrane estrogen receptors (ERs). METHODS: We measured activity of the dopamine transporter (DAT) by the efflux of (3)H-dopamine in nontransfected nerve growth factor–differentiated PC12 rat pheochromocytoma cells expressing membrane DAT, ER-α, ER-β, and G-protein–coupled receptor 30. We used a plate immunoassay to monitor trafficking of these proteins. RESULTS: All compounds at 1 nM either caused efflux or inhibited efflux, or both; each compound evoked a distinct oscillatory pattern. At optimal times for each effect, we examined different concentrations of XEs. All XEs were active at some concentration < 10 nM, and dose responses were all nonmonotonic. For example, 10(−14) to 10(−11) M DDE caused significant efflux inhibition, whereas NP and BPA enhanced or inhibited efflux at several concentrations. We also measured the effects of E(2)/XE combinations; DDE potentiated E(2)-mediated dopamine efflux, whereas BPA inhibited it. In E(2)-induced efflux, 15% more ER-α trafficked to the membrane, whereas ER-β waned; during BPA-induced efflux, 20% more DAT was trafficked to the plasma membrane. CONCLUSIONS: Low levels of environmental estrogen contaminants acting as endocrine disruptors via membrane ERs can alter dopamine efflux temporal patterning and the trafficking of DAT and membrane ERs, providing a cellular mechanism that could explain the disruption of physiologic neurotransmitter function.