Aniline Is Rapidly Converted Into Paracetamol Impairing Male Reproductive Development.
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.
['Holm|Jacob Bak|JB|', 'Chalmey|Clementine|C|', 'Modick|Hendrik|H|', 'Jensen|Lars Skovgaard|LS|', 'Dierkes|Georg|G|', 'Weiss|Tobias|T|', 'Jensen|Benjamin Anderschou Holbech|BA|', 'Nørregård|Mette Marie|MM|', 'Borkowski|Kamil|K|', 'Styrishave|Bjarne|B|', 'Martin Koch|Holger|H|', 'Mazaud-Guittot|Severine|S|', 'Jegou|Bernard|B|', 'Kristiansen|Karsten|K|', 'Kristensen|David Møbjerg|DM|']
D000082:Acetaminophen D000814:Aniline Compounds D000818:Animals D001711:Biotransformation D002274:Carcinogens, Environmental D045744:Cell Line, Tumor D004305:Dose-Response Relationship, Drug D052244:Endocrine Disruptors D005260:Female D047109:Fetal Development D006801:Humans D066298:In Vitro Techniques D007248:Infertility, Male D008099:Liver D008297:Male D008431:Maternal-Fetal Exchange D008810:Mice, Inbred C57BL D011247:Pregnancy D011374:Progesterone D046468:Sexual Development D013739:Testosterone D066007:Toxicokinetics
aniline paracetamol reproduction acetaminophen endocrine disruptors testosterone