Sternberg Robin M, LeBlanc Gerald A
Department of Environmental and Molecular Toxicology, North Carolina State University, Campus Box 7633, Raleigh, NC 27695, United States.
Aquat Toxicol. 2006 Jun 30;78(3):233-42. doi: 10.1016/j.aquatox.2006.03.004. Epub 2006 Mar 24.
Exposure to tributyltin (TBT) has been causally associated with the global occurrence of a pseudohermaphroditic condition called imposex in neogastropod species. TBT elevates free testosterone levels in these organisms, and this upsurge in testosterone may be involved in the development of imposex. We investigated the ability of TBT to inhibit acyl coenzyme A:testosterone acyltransferase (ATAT) activity as well as microsomal acyl-coenzyme A:17beta-estradiol acyltransferase (AEAT) in a neogastropod, the eastern mud snail Ilyanassa obsoleta as a mechanism by which TBT elevates free testosterone. TBT significantly inhibited both ATAT and AEAT activities in vitro at toxicologically relevant in vivo concentrations. Kinetic analyses revealed that TBT is a competitive inhibitor of ATAT (K(i)= approximately 9microM) and is a weaker, noncompetitive inhibitor of AEAT (K(i)= approximately 31microM). ATAT and AEAT activities associated with different microsome preparations were significantly correlated, and 17beta-estradiol competitively inhibited the fatty acid esterification of testosterone suggesting that one enzyme is responsible for biotransforming both testosterone and 17beta-estradiol to their corresponding fatty acid esters. Overall, the results of this study supply the much-needed mechanistic support for the hypothesis that TBT elevates free testosterone in neogastropods by inhibiting their major regulatory process for maintaining free testosterone homeostasis-the fatty acid esterification of testosterone.
接触三丁基锡（TBT）与新腹足类物种中出现的一种名为性畸变的假两性畸形状况在全球范围内存在因果关系。TBT会提高这些生物体中的游离睾酮水平，而睾酮的这种激增可能与性畸变的发展有关。我们研究了TBT抑制新腹足类动物——东方泥螺（Ilyanassa obsoleta）中的酰基辅酶A：睾酮酰基转移酶（ATAT）活性以及微粒体酰基辅酶A：17β-雌二醇酰基转移酶（AEAT）的能力，以此作为TBT提高游离睾酮的一种机制。在毒理学相关的体内浓度下，TBT在体外显著抑制了ATAT和AEAT的活性。动力学分析表明，TBT是ATAT的竞争性抑制剂（K(i)约为9微摩尔），并且是AEAT的较弱的非竞争性抑制剂（K(i)约为31微摩尔）。与不同微粒体制剂相关的ATAT和AEAT活性显著相关，并且17β-雌二醇竞争性抑制睾酮的脂肪酸酯化，这表明一种酶负责将睾酮和17β-雌二醇都生物转化为它们相应的脂肪酸酯。总体而言，本研究结果为以下假设提供了急需的机制支持：TBT通过抑制新腹足类动物维持游离睾酮稳态的主要调节过程——睾酮的脂肪酸酯化，来提高游离睾酮水平。
