Crews D, Willingham E, Skipper J K
Institute of Reproductive Biology, University of Texas, Austin 78712, USA.
Q Rev Biol. 2000 Sep;75(3):243-60. doi: 10.1086/393498.
A variety of natural products and synthetic chemicals, known collectively as endocrine-disrupting compounds (EDCs), mimic or interfere with the mechanisms that govern vertebrate reproductive development and function. At present, research has focused on (i) the morphological and functional consequences of EDCs; (ii) identifying and determining the relative potencies of synthetic and steroidal compounds that have endocrine-disrupting effects; (iii) the mechanism of action of EDCs at the molecular level; and (iv) the recognition that in "real life," contamination usually reflects mixtures of EDCs. Future research must examine (i) the interactive nature of EDCs, particularly whether the threshold concept as developed in traditional toxicological research applies to these chemicals; (ii) when and how EDCs act at the physiological level, particularly how they may organize the neural substrates of reproductive physiology and behavior; (iii) the various effects these compounds have on different species, individuals, and even tissues; and (iv) how adaptations may evolve in natural populations with continued exposure to EDCs. Several predictions are offered that reflect these new perspectives. Specifically, (i) the threshold assumption will be found not to apply to EDCs because they mimic the actions of endogenous molecules (e.g., estrogen) critical to development; hence, the threshold is automatically exceeded with exposure. (ii) Behavior can compound and magnify the effects of EDCs over successive generations; that is, bioaccumulated EDCs inherited from the mother not only influence the morphological and physiological development of the offspring but also the offsprings' reproductive behavior as adults. This adult behavior, in turn, can have further consequences on the sexual development of their own young. (iii) The sensitivity of a species or an individual to a compound is related to species (individual)-typical concentrations of circulating gonadal steroid hormones. Related to this is the recent finding that alternate forms of the putative receptors are differentially distributed, thereby contributing to the different effects that have been observed. (iv) Except in extraordinary situations, populations often continue to exist in contaminated sites. One possible explanation for this observation that needs to be considered is that animals can rapidly adapt to the nature and level of contamination in their environment. It is unlikely that successive generations coincidentally become insensitive to gonadal steroid hormones fundamentally important as biological regulators of development and reproduction. Rather, adaptive alterations in the genes that encode steroid receptors may occur with chronic exposure to EDCs, allowing the sex hormone receptor to discriminate natural steroids from EDCs.
多种天然产物和合成化学品，统称为内分泌干扰化合物（EDC），它们模拟或干扰控制脊椎动物生殖发育和功能的机制。目前，研究集中在：（i）EDC的形态学和功能后果；（ii）识别和确定具有内分泌干扰作用的合成化合物和甾体化合物的相对效力；（iii）EDC在分子水平的作用机制；（iv）认识到在“现实生活”中，污染通常反映了EDC的混合物。未来的研究必须考察：（i）EDC的相互作用性质，特别是传统毒理学研究中提出的阈值概念是否适用于这些化学品；（ii）EDC在生理水平上何时以及如何起作用，特别是它们如何组织生殖生理和行为的神经基础；（iii）这些化合物对不同物种、个体甚至组织的各种影响；（iv）在持续接触EDC的情况下，自然种群中适应性如何进化。文中提出了一些反映这些新观点的预测。具体而言：（i）将发现阈值假设不适用于EDC，因为它们模拟了对发育至关重要的内源性分子（如雌激素）的作用；因此，接触后阈值会自动被超过。（ii）行为可以在连续几代中加剧并放大EDC的影响；也就是说，从母亲那里遗传的生物累积EDC不仅会影响后代的形态和生理发育，还会影响其成年后的生殖行为。反过来，这种成年行为又会对其自身幼崽的性发育产生进一步影响。（iii）一个物种或个体对一种化合物的敏感性与循环性腺甾体激素的物种（个体）典型浓度有关。与此相关的是最近的发现，即假定受体的不同形式分布不同，从而导致观察到的不同效应。（iv）除了在特殊情况下，种群通常会继续存在于受污染的地点。对于这一观察结果，一个需要考虑的可能解释是，动物可以迅速适应其环境中的污染性质和水平。连续几代人不太可能偶然对作为发育和繁殖的重要生物调节因子的性腺甾体激素变得不敏感。相反，长期接触EDC可能会导致编码甾体受体的基因发生适应性改变，使性激素受体能够区分天然甾体和EDC。
