MRC Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, UK.
Royal Hospital for Sick Children, Edinburgh, UK.
Hum Reprod Update. 2019 Jul 1;25(4):397-421. doi: 10.1093/humupd/dmz004.
Overall, the incidence of male reproductive disorders has increased in recent decades. Testicular development during fetal life is crucial for subsequent male reproductive function. Non-genomic factors such as environmental chemicals, pharmaceuticals and lifestyle have been proposed to impact on human fetal testicular development resulting in subsequent effects on male reproductive health. Whilst experimental studies using animal models have provided support for this hypothesis, more recently a number of experimental studies using human tissues and cells have begun to translate these findings to determine direct human relevance.
The objective of this systematic review was to provide a comprehensive description of the evidence for effects of prenatal exposure(s) on human fetal testis development and function. We present the effects of environmental, pharmaceutical and lifestyle factors in experimental systems involving exposure of human fetal testis tissues and cells. Comparison is made with existing epidemiological data primarily derived from a recent meta-analysis.
For identification of experimental studies, PubMed and EMBASE were searched for articles published in English between 01/01/1966 and 13/07/2018 using search terms including 'endocrine disruptor', 'human', 'fetal', 'testis', 'germ cells', 'testosterone' and related search terms. Abstracts were screened for selection of full-text articles for further interrogation. Epidemiological studies involving exposure to the same agents were extracted from a recent systematic review and meta-analysis. Additional studies were identified through screening of bibliographies of full-texts of articles identified through the initial searches.
A total of 25 experimental studies and 44 epidemiological studies were included. Consistent effects of analgesic and phthalate exposure on human fetal germ cell development are demonstrated in experimental models, correlating with evidence from epidemiological studies and animal models. Furthermore, analgesic-induced reduction in fetal testosterone production, which predisposes to the development of male reproductive disorders, has been reported in studies involving human tissues, which also supports data from animal and epidemiological studies. However, whilst reduced testosterone production has been demonstrated in animal studies following exposure(s) to a variety of environmental chemicals including phthalates and bisphenol A, these effects are not reproduced in experimental approaches using human fetal testis tissues.
Direct experimental evidence for effects of prenatal exposure(s) on human fetal testis development and function exists. However, for many exposures the data is limited. The increasing use of human-relevant models systems in which to determine the effects of environmental exposure(s) (including mixed exposures) on development and function of human tissues should form an important part of the process for assessment of such exposures by regulatory bodies to take account of animal-human differences in susceptibility.
近年来，男性生殖系统疾病的发病率总体呈上升趋势。胎儿期的睾丸发育对于男性生殖功能至关重要。环境化学物质、药物和生活方式等非基因组因素被认为会影响人类胎儿睾丸发育，从而对男性生殖健康产生后续影响。虽然使用动物模型的实验研究为此假说提供了支持，但最近使用人类组织和细胞的一些实验研究已开始将这些发现转化为确定直接人类相关性。
本系统综述的目的是全面描述产前暴露对人类胎儿睾丸发育和功能的影响的证据。我们介绍了环境、药物和生活方式因素在涉及人类胎儿睾丸组织和细胞暴露的实验系统中的影响。并将其与主要来自最近荟萃分析的现有流行病学数据进行了比较。
为了确定实验研究，我们在 PubMed 和 EMBASE 中使用了包括“内分泌干扰物”、“人类”、“胎儿”、“睾丸”、“生殖细胞”、“睾酮”和相关搜索词在内的搜索词，搜索了自 1966 年 1 月 1 日至 2018 年 7 月 13 日期间发表的英文文章。筛选摘要以选择全文文章进行进一步查询。从最近的系统评价和荟萃分析中提取了涉及相同试剂暴露的流行病学研究。通过对通过初步搜索确定的文章的全文参考文献进行筛选，确定了其他研究。
共纳入 25 项实验研究和 44 项流行病学研究。在实验模型中，证明了镇痛药和邻苯二甲酸酯暴露对人类胎儿生殖细胞发育的一致影响，与流行病学研究和动物模型的证据相吻合。此外，在涉及人类组织的研究中，已报道镇痛药诱导的胎儿睾酮产生减少会导致男性生殖系统疾病的发展，这也支持了来自动物和流行病学研究的数据。然而，尽管在动物研究中已经证明了暴露于邻苯二甲酸酯和双酚 A 等多种环境化学物质后睾酮产生减少，但在使用人类胎儿睾丸组织的实验方法中并未重现这些影响。
存在关于产前暴露对人类胎儿睾丸发育和功能的影响的直接实验证据。然而，对于许多暴露，数据是有限的。越来越多的使用人类相关模型系统来确定环境暴露（包括混合暴露）对人类组织发育和功能的影响，应成为评估此类暴露的监管机构的重要组成部分，以考虑动物-人类之间易感性的差异。
