EDC IMPACT: Is exposure during pregnancy to acetaminophen/paracetamol disrupting female reproductive development?

Frederic Schrøder Arendrup, Severine Mazaud-Guittot, Bernard Jégou, David Møbjerg Kristensen, Frederic Schrøder Arendrup, Severine Mazaud-Guittot, Bernard Jégou, David Møbjerg Kristensen

Abstract

Concern has been raised over chemical-induced disruption of ovary development during fetal life resulting in long-lasting consequences only manifesting themselves much later during adulthood. A growing body of evidence suggests that prenatal exposure to the mild analgesic acetaminophen/paracetamol can cause such a scenario. Therefore, in this review, we discuss three recent reports that collectively indicate that prenatal exposure in a period of 13.5 days post coitum in both rats and mouse can result in reduced female reproductive health. The combined data show that the exposure results in the reduction of primordial follicles, irregular menstrual cycle, premature absence of corpus luteum, as well as reduced fertility, resembling premature ovarian insufficiency syndrome in humans that is linked to premature menopause. This could especially affect the Western parts of the world, where the age for childbirth is continuously being increased and acetaminophen is recommended during pregnancy for pain and fever. We therefore highlight an urgent need for more studies to verify these data including both experimental and epidemiological approaches.

Keywords: acetaminophen/paracetamol; development; fertility; follicles; primordial germ cells; tylenol.

© 2018 The authors.

Figures

Figure 1
Figure 1
Overview of APAP exposure window and highlight of the ovary development in mouse and rat. Top; overview of ovary development in mouse with the start of mitosis of the germ cells around 10.5 dpc and extends until 12.5 dpc, followed by a period dominated by meiosis from 13.5 dpc. Prior to birth, on 19.5 dpc, follicle assembly is initiated on 18.5 and dominates the neonatal period. Holm and coworkers (16) exposed C57BL/6J mice to APAP (50 mg/kg/day) from 7 to 13.5 dpc (spanning mitosis and early meiosis) and APAP (50 or 150 mg/kg/day) from 7 dpc until birth (spanning mitosis, meiosis and early follicle assembly). Bottom; overview of ovary development in rats with the start of mitosis of the germ cells around 12.5 dpc and lasting until around 16 dpc. Meiosis in the rat initiates on 16.5 dpc and continues throughout gestation. Just prior to birth, on 21.5 dpc, follicle assembly is initiated and dominates the neonatal life of the rat. Dean and coworkers (17) exposed Wistar rats to APAP (350 mg/kg/day) from 13.5 to 21.5 dpc (spanning mitosis and meiosis). Johansson and coworkers (18) exposed Wistar rats to APAP (360 mg/kg/day) in two windows; 13.5–19.5 dpc and again from 14 to 22 pnd (spanning mitosis, meiosis and follicle growth in the neonatal period).

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