Acetaminophen (APAP, Paracetamol) Interferes With the First Trimester Human Fetal Ovary Development in an Ex Vivo Model

Abstract

Context Acetaminophen (APAP, paracetamol) is widely used by pregnant women. Although long considered safe, growing evidence indicates that APAP is an endocrine disruptor since in utero exposure may be associated with a higher risk of male genital tract abnormalities. In rodents, fetal exposure has long-term effects on the reproductive function of female offspring. Human studies have also suggested harmful APAP exposure effects. Objective Given that disruption of fetal ovarian development may impact women’s reproductive health, we investigated the effects of APAP on fetal human ovaries in culture. Design and setting Human ovarian fragments from 284 fetuses aged 7 to 12 developmental weeks (DW) were cultivated ex vivo for 7 days in the presence of human-relevant concentrations of APAP (10 -8 to 10 -3 M) or vehicle control. Main outcome measures Outcomes included examination of postculture tissue morphology, cell viability, apoptosis, and quantification of hormones, APAP and APAP metabolites in conditioned culture media. Results APAP reduced the total cell number specifically in 10-12 DW ovaries induced cell death and decreased KI67-positive cell density independently of fetal age. APAP targeted sub-populations of germ cells and disrupted human fetal ovarian steroidogenesis, without affecting prostaglandin or inhibin B production. Human fetal ovaries were able to metabolize APAP. Conclusions Our data indicate that APAP can impact first trimester human fetal ovarian development, especially during a 10-12 DW window of heightened sensitivity. Overall, APAP behaves as an endocrine disruptor in the fetal human ovary.

The profile of steroid hormones in human fetal and adult ovaries

“…Ovaries separated from mesonephroi were dissected, weighed, and immediately placed into ice-cold phosphate-buffered saline. Fetal ovaries were processed as previously described [ 10 ]. Briefly, each ovary was cut into 1 mm 3 size explants to ensure accessibility to nutrients and viability of the tissue.…”

“…This indicates an important role for steroid hormones in ovarian development and function. While the specific steroid hormones present at different life stages and their roles in ovarian development remain poorly understood [ 10 , 11 ], disruption of ovarian development by chemical exposure may lead to reproductive disorders later in life, known as ovarian dysgenesis syndrome [ 1 , 12 ]. In adulthood, recruited primordial follicles start forming primary, secondary, antral follicles and pre-ovulatory follicles, a maturation process known as folliculogenesis [ 13 ].…”

Potential adverse actions of prenatal exposure of acetaminophen to offspring

“…Human fetal ovarian steroidogenesis is affected (Lecante et al, 2022). A Danish National Birth Cohort study investigating 47,400 live-born singleton sons reports that maternal exposure of APAP over 4 weeks during pregnancy, especially within the first and second trimesters, may potentially elevate the presence of cryptorchidism in offspring (Henriksen and Olsen et al, 2010).…”

“…Another ex vivo study from isolating human ovarian fragments displays that 10 −3 –10 −8 mol/L APAP exposure for 7 days may decrease the total cell number ovaries and the KI67-positive cell density, induce cell death. Human fetal ovarian steroidogenesis is affected ( Lecante et al, 2022 ). A Danish National Birth Cohort study investigating 47,400 live-born singleton sons reports that maternal exposure of APAP over 4 weeks during pregnancy, especially within the first and second trimesters, may potentially elevate the presence of cryptorchidism in offspring ( Henriksen and Olsen et al, 2010 ).…”

Reproductive toxicity of combined effects of endocrine disruptors on human reproduction

“…The study investigated the association between prenatal exposure to persistent organic pollutants (POPs), including PCBs, and pubertal development in 13-to 15-year-old children. The findings suggest that higher prenatal PCB exposure could lead to more advanced pubertal development in both boys and girls, as indicated by higher levels of testosterone, pubic hair, breast development, and larger testicular volume Lecante et al (2022) Acetaminophen (APAP)…”