Wyrobek A J
Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, University of California 94550.
Reprod Toxicol. 1993;7 Suppl 1:3-16. doi: 10.1016/0890-6238(93)90064-e.
There is conclusive evidence that exposures of human males to ionizing radiation or certain chemicals can diminish sperm production and reduce fertility. Of approximately 100 chemical agents and mixtures that have been evaluated in men by semen analysis, about half (mostly drugs and a few occupational exposures) reduced sperm quantity and quality; several of these agents also affected the fertility of exposed men. It is now well recognized that the importance of the father in reproduction goes beyond fertilization. Abnormalities in paternal chromosomes (structural and numeric) have been found in various abnormal reproductive outcomes, including chromosomal abnormality syndromes among newborns. In rodent systems, exposure of males to mutagens before mating induces transmissible cytogenetic and genetic abnormalities as well as morphologic defects and cancer among offspring. Consistent with animal findings, there is growing epidemiologic evidence of associations between male exposures to exogenous agents and abnormal reproductive outcomes (fetal loss, birth defects, childhood cancer, etc.). However, no clear links have been established between exposure, mechanism of transmission, and abnormal reproductive outcomes. It is not known to what extent male-mediated birth defects and childhood cancer are due to genetic, epigenetic, or nongenetic causes. Viewed in a multigenerational context, the role of the father in abnormal reproductive outcomes is dependent on his exposure history and susceptibilities as well as those of his mate. Relevant exposures may occur any time between conception of the parents and production of their fertilizing gametes, including their development in utero, childhood, and adolescence. Efficient measurements (including biomarkers) of relevant exposure, early biologic effects, and susceptibility in human males are under development. An integrated approach is recommended for assessing male reproductive and genetic toxicity that utilizes biomarkers in (a) epidemiologic studies of exposed human populations, (b) risk characterization in sensitive laboratory species, and (c) in vivo and in vitro studies of the molecular mechanisms of action of toxicants. A special category of "bridging" biomarkers is needed for evaluating animal data for risk assessment and for discriminating among genetic, epigenetic, and nongenetic mechanisms of abnormal reproductive outcomes of paternal origin.
有确凿证据表明，男性接触电离辐射或某些化学物质会减少精子生成并降低生育能力。在通过精液分析对男性进行评估的约100种化学制剂和混合物中，约有一半（主要是药物和一些职业暴露）降低了精子数量和质量；其中几种制剂还影响了接触者的生育能力。现在人们已经充分认识到，父亲在生殖中的重要性不仅限于受精。在各种异常生殖结局中都发现了父本染色体（结构和数量）异常，包括新生儿中的染色体异常综合征。在啮齿动物系统中，雄性在交配前接触诱变剂会导致后代出现可传播的细胞遗传学和遗传异常以及形态缺陷和癌症。与动物研究结果一致，越来越多的流行病学证据表明男性接触外源性物质与异常生殖结局（胎儿丢失、出生缺陷、儿童癌症等）之间存在关联。然而，在接触、传播机制和异常生殖结局之间尚未建立明确的联系。尚不清楚男性介导的出生缺陷和儿童癌症在多大程度上是由遗传、表观遗传或非遗传原因引起的。从多代的角度来看，父亲在异常生殖结局中的作用取决于他的接触史和易感性以及他配偶的接触史和易感性。相关接触可能发生在父母受孕至其产生受精配子的任何时间，包括他们在子宫内的发育、童年和青春期。针对男性相关接触、早期生物学效应和易感性的有效测量方法（包括生物标志物）正在研发中。建议采用综合方法评估男性生殖和遗传毒性，该方法在以下方面利用生物标志物：(a) 对接触人群的流行病学研究，(b) 敏感实验物种的风险特征描述，以及 (c) 毒物作用分子机制的体内和体外研究。需要一类特殊的“桥梁”生物标志物来评估用于风险评估的动物数据，并区分父源异常生殖结局的遗传、表观遗传和非遗传机制。
