Mu Xueyan, LeBlanc Gerald A
Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695-7633, USA.
Environ Toxicol Chem. 2004 Apr;23(4):1085-91. doi: 10.1897/03-273.
Endocrine toxicants can interfere with hormone signaling through various mechanisms. Some of these mechanisms are interrelated in a manner that might result in synergistic interactions. Here we tested the hypothesis that combined exposure to chemicals that inhibit hormone synthesis and that function as hormone receptor antagonists would result in greater-than-additive toxicity. This hypothesis was tested by assessing the effects of the ecdysteroid-synthesis inhibitor fenarimol and the ecdysteroid receptor antagonist testosterone on ecdysteroid-regulated development in the crustacean Daphnia magna. Both compounds were individually characterized for effects on the development of isolated embryos. Fenarimol caused late developmental abnormalities, consistent with its effect on offspring-derived ecdysone in the maturing embryo. Testosterone interfered with both early and late development of embryos, consistent with its ability to inhibit ecdysone provided by maternal transfer (responsible for early developmental events) or de novo ecdysone synthesis (responsible for late developmental events). We predicted that, by decreasing endogenous levels of hormone, fenarimol would enhance the likelihood of testosterone binding to and inhibiting the ecdysone receptor. Indeed, fenarimol enhanced the toxicity of testosterone, while testosterone had no effect on the toxicity of fenarimol. Algorithms were developed to predict the toxicity of combinations of these two compounds based on independent joint action (IJA) alone as well as IJA with fenarimol-on-testosterone synergy (IJA+SYN). The IJA+SYN model was highly predictive of the experimentally determined combined effects of the two compounds. These results demonstrate that some endocrine toxicants can synergize, and this synergy can be accurately predicted.
内分泌毒物可通过多种机制干扰激素信号传导。其中一些机制以可能导致协同相互作用的方式相互关联。在此，我们检验了以下假设：联合暴露于抑制激素合成的化学物质和作为激素受体拮抗剂的化学物质会导致大于相加的毒性。通过评估蜕皮甾类合成抑制剂氯苯嘧啶醇和蜕皮甾类受体拮抗剂睾酮对甲壳类大型溞中蜕皮甾类调节发育的影响来检验这一假设。分别对这两种化合物对分离胚胎发育的影响进行了表征。氯苯嘧啶醇导致后期发育异常，这与其对成熟胚胎中后代来源蜕皮激素的影响一致。睾酮干扰胚胎的早期和后期发育，这与其抑制母体转移提供的蜕皮激素（负责早期发育事件）或从头合成蜕皮激素（负责后期发育事件）的能力一致。我们预测，通过降低激素的内源性水平，氯苯嘧啶醇会增加睾酮与蜕皮激素受体结合并抑制其活性的可能性。事实上，氯苯嘧啶醇增强了睾酮的毒性，而睾酮对氯苯嘧啶醇的毒性没有影响。开发了算法，以仅基于独立联合作用（IJA）以及具有氯苯嘧啶醇对睾酮协同作用的IJA（IJA+SYN）来预测这两种化合物组合的毒性。IJA+SYN模型对两种化合物的实验测定联合效应具有高度预测性。这些结果表明，一些内分泌毒物可产生协同作用，并且这种协同作用可以准确预测。
