Holm Jacob Bak, Chalmey Clementine, Modick Hendrik, Jensen Lars Skovgaard, Dierkes Georg, Weiss Tobias, Jensen Benjamin Anderschou Holbech, Nørregård Mette Marie, Borkowski Kamil, Styrishave Bjarne, Martin Koch Holger, Mazaud-Guittot Severine, Jegou Bernard, Kristiansen Karsten, Kristensen David Møbjerg
*Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, DK-2100 Copenhagen, Denmark;
Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Campus de Beaulieu, F-35042 Rennes, France;
Toxicol Sci. 2015 Nov;148(1):288-98. doi: 10.1093/toxsci/kfv179. Epub 2015 Aug 10.
Industrial use of aniline is increasing worldwide with production estimated to surpass 5.6 million metric tons in 2016. Exposure to aniline occurs via air, diet, and water augmenting the risk of exposing a large number of individuals. Early observations suggest that aniline is metabolized to paracetamol/acetaminophen, likely explaining the omnipresence of low concentrations of paracetamol in European populations. This is of concern as recent studies implicate paracetamol as a disrupter of reproduction. Here, we show through steroidogenic profiling that exposure to aniline led to increased levels of the Δ4 steroids, suggesting that the activity of CYP21 was decreased. By contrast, paracetamol decreased levels of androgens likely through inhibition of CYP17A1 activity. We confirm that aniline in vivo is rapidly converted to paracetamol by the liver. Intrauterine exposure to aniline and paracetamol in environmental and pharmaceutical relevant doses resulted in shortening of the anogenital distance in mice, a sensitive marker of fetal androgen levels that in humans is associated with reproductive malformations and later life reproductive disorders. In conclusion, our results provide evidence for a scenario where aniline, through its conversion into antiandrogenic paracetamol, impairs male reproductive development.
全球范围内，苯胺的工业用量正在增加，据估计2016年其产量将超过560万吨。通过空气、饮食和水接触苯胺会增加大量人群的接触风险。早期观察表明，苯胺会代谢为对乙酰氨基酚，这可能解释了欧洲人群中普遍存在低浓度对乙酰氨基酚的现象。这令人担忧，因为最近的研究表明对乙酰氨基酚是一种生殖干扰物。在这里，我们通过类固醇生成分析表明，接触苯胺会导致Δ4类固醇水平升高，这表明CYP21的活性降低。相比之下，对乙酰氨基酚可能通过抑制CYP17A1的活性而降低雄激素水平。我们证实，苯胺在体内会被肝脏迅速转化为对乙酰氨基酚。在环境和药物相关剂量下，子宫内接触苯胺和对乙酰氨基酚会导致小鼠肛门生殖器距离缩短，这是胎儿雄激素水平的一个敏感指标，在人类中与生殖畸形和后期生活中的生殖障碍有关。总之，我们的结果为这样一种情况提供了证据：苯胺通过转化为抗雄激素的对乙酰氨基酚，损害男性生殖发育。
