Paracetamol (N-acetyl-para-aminophenol) disrupts early human embryogenesis

Abstract It is estimated that 10–40% of all human conceptions fail around implantation¹⁻⁷. Genetics explain ≈ 50% of early embryonic loss, leaving a substantial part of early loss without a known cause⁸,⁹. Smoking and alcohol are known risk factors for spontaneous abortion, indicating the importance of the chemical environment during embryonic development¹⁰. Here we show that paracetamol (N-acetyl-para-aminophenol (APAP); otherwise known as acetaminophen), the recommended medication for pregnant people for treatment of mild to moderate pain and fever¹¹ and an environmental pollutant¹²⁻¹⁵, disrupts both mouse and human pre-implantation development. We found that APAP inhibited cell cycle progression, likely through ribonucleotide reductase, resulted in blockage of DNA synthesis across all model systems, and reduced pregnancy outcomes in mouse models. At concentrations found in the reproductive system of women after standard administration, APAP exposure decreased human cleavage stage embryo cell numbers or caused direct embryonic fatality. Similar exposure to human blastocyst stage embryos for 6 h resulted in decreased DNA synthesis as well as morphological changes. Our data demonstrate that a widely used mild analgesic and environmental pollutant might result in embryonic loss and provide a foundation for understanding environmentally caused cell cycle inhibition in other processes during development.