Acetaminophen Modulates the Expression of Steroidogenesis-Associated Genes and Estradiol Levels in Human Placental JEG-3 Cells

Abstract

Acetaminophen is the only medication recommended for pain and fever management during pregnancy. However, studies have reported an association between in utero acetaminophen and neurocognitive disorders later in life. Additionally, acetaminophen has been shown to have endocrine disrupting properties altering hormones critical for normal fetal development. As the placenta is an endocrine organ that produces hormones for fetal development, any attempts to elucidate the mechanism underlying in utero acetaminophen and birth outcomes must also focus on the placenta. The present study set out to examine the effect of acetaminophen on mRNA expression, protein expression and hormone synthesis in placental JEG-3 cells. The analysis focused on genes involved in steroidogenesis and acetaminophen metabolism as well those with known roles as nuclear receptors and transporters. The results highlight that at high concentrations, acetaminophen reduced the gene expression of aromatase (CYP19A1) and type 1 3β-hydroxysteroid dehydrogenase (HSD3B1), and increased the expression of 17β-hydroxysteroid dehydrogenase (HSD17B1). Additionally, acetaminophen at high concentrations also reduced the protein expression of aromatase (CYP19A1). These effects were accompanied by a significant dose-dependent decrease in estradiol secretion. Estradiol plays an important role in the development of reproductive organs and the brain of the developing fetus. This study highlights the potential for acetaminophen to interfere with hormone regulation during pregnancy and underscores the need for additional studies aimed at understanding the endocrine disruption activity of acetaminophen during fetal development.

Developmental toxicity and programming alterations of multiple organs in offspring induced by medication during pregnancy

“…Using drugs during pregnancy may affect the endocrine function of the placenta. For example, estradiol is crucial for the development of fetal reproductive organs, and acetaminophen can inhibit estradiol secretion in human placental cells, which suggests that prenatal acetaminophen exposure may affect gonad development by inhibiting placental estradiol secretion 95 .…”

Paracetamol use during pregnancy — a call for precautionary action

“…In vivo, in vitro and ex vivo studies have shown that APAP directly perturbs hormone-dependent processes, including inhibition of androgen production and increased oestrogen production, disruption of steroidogenesis, depletion of sulfated sex hormones, perturbation of immune function, induction of oxidative stress and indirect activation of the endocannabinoid system 1,2,[61][62][63][64][65] . Independently of APAP, these processes have been implicated as mechanisms related to the development of neurodevelopmental [66][67][68][69][70][71][72][73][74][75][76] and reproductive disorders 2 .…”

“…Independently of APAP, these processes have been implicated as mechanisms related to the development of neurodevelopmental [66][67][68][69][70][71][72][73][74][75][76] and reproductive disorders 2 . In addition to potential effects on neuronal and reproductive development, a combination of clinical studies together with experimental work in animal models and cell lines has also suggested that APAP exposure during pregnancy might decrease fetal haematopoietic stem cell numbers alter steroidogenesis in the placenta and induce placental damage 65,[77][78][79][80] .…”

“…APAP effects on the cannabinoid and prostaglandin pathways alone or in combination might be the possible mechanisms 1,62,65,69,[152][153][154] . The antipyretic effect of APAP involves inhibition of prostaglandin-synthesizing cyclooxygenase enzymes in the brain 155 .…”

Using Experimental Models to Decipher the Effects of Acetaminophen and NSAIDs on Reproductive Development and Health

“…Conversely, APAP increased pregnenolone, but impaired its subsequent conversion to progesterone by CYP17A1 ( Holm et al, 2015 ). APAP also modulated the expression of steroidogenic genes, leading to a significant dose-dependent decrease in estradiol secretion in human placental JEG-3 cells ( Addo et al, 2021 ). Furthermore, the anti-androgenic and anti-estrogenic activities of anti-inflammatory drugs (APAP, IBU, DCF, naproxen) at doses between 10 −6 and 10 −5 M have been demonstrated using two in vitro reporter-gene assays based on a CXCL12-expressing human T47 breast carcinoma cell line and ERα and AR-expressing recombinant yeast assays ( Ezechias et al, 2016 ).…”