Fluoxetine and its active metabolite norfluoxetine disrupt estrogen synthesis in a co-culture model of the feto-placental unit

Thibeault, Andrée-Anne Hudon; Laurent, Lætitia; Duy, Sung Vo; Sauvé, Sébastien; Caron, Patrick; Guillemette, Chantal; Sanderson, J. Thomas; Vaillancourt, Cathy

doi:10.1016/j.mce.2016.11.021

Cited by 31 publications

(15 citation statements)

References 50 publications

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“…Increasing the usage of SSRI by pregnant women plagued with depression is thus of major concern. While some studies have begun to examine how these drugs affect the placenta (Clabault, Cohen, Vaillancourt, & Sanderson, 2018; Clabault, Flipo, et al, 2018; Hudon Thibeault et al, 2017; Laurent et al, 2016), more experiments are needed to determine what concentrations of these drugs are achieved in the placenta and whether such drugs affect the placenta‐brain‐axis.…”

Section: Discussionmentioning

confidence: 99%

The placenta‐brain‐axis

Rosenfeld

2020

J of Neuroscience Research

140

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All mammalian species depend on the placenta, a transient organ, for exchange of gases, nutrients, and waste between the mother and conceptus. Besides serving as a conduit for such exchanges, the placenta produces hormones and other factors that influence maternal physiology and fetal development. To meet all of these adaptations, the placenta has evolved to become the most structurally diverse organ within all mammalian taxa. However, commonalities exist as to how placental responses promote survival against in utero threats and can alter the trajectory of fetal development, in particular the brain. Increasing evidence suggests that reactions of the placenta to various in utero stressors may lead to long‐standing health outcomes, otherwise considered developmental origin of health and disease effects. Besides transferring nutrients and gases, the placenta produces neurotransmitters, including serotonin, dopamine, norepinephrine/epinephrine, that may circulate and influence brain development. Neurobehavioral disorders, such as autism spectrum disorders, likely trace their origins back to placental disturbances. This intimate relationship between the placenta and brain has led to coinage of the term, the placenta‐brain‐axis. This axis will be the focus herein, including how conceptus sex might influence it, and technologies employed to parse out the effects of placental‐specific transcript expression changes on later neurobehavioral disorders. Ultimately, the placenta might provide a historical record of in utero threats the fetus confronted and a roadmap to understand how placenta responses to such encounters impacts the placental‐brain‐axis. Improved early diagnostic and preventative approaches may thereby be designed to mitigate such placental disruptions.

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Section: Discussionmentioning

confidence: 99%

The placenta‐brain‐axis

Rosenfeld

2020

J of Neuroscience Research

140

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“…Non-pregnant mice with deficient serotonin signaling have impaired lipid handling and excessive lipid accumulation in association with reduced adipose aromatase expression and circulating estrogen (Zha et al, 2017 ). Similarly, treating placental-derived trophoblast cells with norfluoxetine, a selective serotonin-reuptake inhibitor, inhibits aromatase activity and estrogen secretion in vitro (Hudon Thibeault et al, 2017 ). Supplementation of melatonin in non-pregnant humans reduces circulating triglycerides and cholesterol levels, but effects of lipid handling in pregnancy are unknown (Mohammadi-Sartang et al, 2017 ).…”

Section: Placental Hormones That Mediate Maternal Adaptations To Pregmentioning

confidence: 99%

The Role of Placental Hormones in Mediating Maternal Adaptations to Support Pregnancy and Lactation

et al. 2018

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During pregnancy, the mother must adapt her body systems to support nutrient and oxygen supply for growth of the baby in utero and during the subsequent lactation. These include changes in the cardiovascular, pulmonary, immune and metabolic systems of the mother. Failure to appropriately adjust maternal physiology to the pregnant state may result in pregnancy complications, including gestational diabetes and abnormal birth weight, which can further lead to a range of medically significant complications for the mother and baby. The placenta, which forms the functional interface separating the maternal and fetal circulations, is important for mediating adaptations in maternal physiology. It secretes a plethora of hormones into the maternal circulation which modulate her physiology and transfers the oxygen and nutrients available to the fetus for growth. Among these placental hormones, the prolactin-growth hormone family, steroids and neuropeptides play critical roles in driving maternal physiological adaptations during pregnancy. This review examines the changes that occur in maternal physiology in response to pregnancy and the significance of placental hormone production in mediating such changes.

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“…In this context the recently established co-culture models of choriocarcinoma cells (JEG-3 or BeWo) with H295R cells should be considered for future analysis. The H295R/BeWo co-culture model offers the opportunity to evaluate the effects of chemical exposures on androgen and estrogen biosynthesis, as well as on various other aspects of feto–placental communication ( Hudon Thibeault et al, 2017 ; Drwal et al, 2018 ; Thibeault et al, 2018 ).…”

Section: Steroid Hormonesmentioning

confidence: 99%

Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta

2018

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The steroid hormones progestagens, estrogens, androgens, and glucocorticoids as well as their precursor cholesterol are required for successful establishment and maintenance of pregnancy and proper development of the fetus. The human placenta forms at the interface of maternal and fetal circulation. It participates in biosynthesis and metabolism of steroids as well as their regulated exchange between maternal and fetal compartment. This review outlines the mechanisms of human placental handling of steroid compounds. Cholesterol is transported from mother to offspring involving lipoprotein receptors such as low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SRB1) as well as ATP-binding cassette (ABC)-transporters, ABCA1 and ABCG1. Additionally, cholesterol is also a precursor for placental progesterone and estrogen synthesis. Hormone synthesis is predominantly performed by members of the cytochrome P-450 (CYP) enzyme family including CYP11A1 or CYP19A1 and hydroxysteroid dehydrogenases (HSDs) such as 3β-HSD and 17β-HSD. Placental estrogen synthesis requires delivery of sulfate-conjugated precursor molecules from fetal and maternal serum. Placental uptake of these precursors is mediated by members of the solute carrier (SLC) family including sodium-dependent organic anion transporter (SOAT), organic anion transporter 4 (OAT4), and organic anion transporting polypeptide 2B1 (OATP2B1). Maternal–fetal glucocorticoid transport has to be tightly regulated in order to ensure healthy fetal growth and development. For that purpose, the placenta expresses the enzymes 11β-HSD 1 and 2 as well as the transporter ABCB1. This article also summarizes the impact of diverse compounds and diseases on the expression level and activity of the involved transporters, receptors, and metabolizing enzymes and concludes that the regulatory mechanisms changing the physiological to a pathophysiological state are barely explored. The structure and the cellular composition of the human placental barrier are introduced. While steroid production, metabolism and transport in the placental syncytiotrophoblast have been explored for decades, few information is available for the role of placental-fetal endothelial cells in these processes. With regard to placental structure and function, significant differences exist between species. To further decipher physiologic pathways and their pathologic alterations in placental steroid handling, proper model systems are mandatory.

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Fluoxetine and its active metabolite norfluoxetine disrupt estrogen synthesis in a co-culture model of the feto-placental unit

Cited by 31 publications

References 50 publications

The placenta‐brain‐axis

The placenta‐brain‐axis

The Role of Placental Hormones in Mediating Maternal Adaptations to Support Pregnancy and Lactation

Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta

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