Models of Endocrine-Disrupting Effects: Human Placental Steroidogenesis

Abstract

Endocrine disruption during pregnancy has gained increasing interest as epidemiological studies report associations of exposures and adverse effects on fetal growth, followed by effects on the growing child and ultimately in the adult. When studying endocrine disruption during pregnancy, the placental steroidogenesis is difficult to model, as the human placenta is unique in the pathway of cellular uptake of cholesterol, the high levels of progesterone production and the expression of aromatase. Models to test for endocrine disruption should respect species differences, with preference to human models for human risk assessment. Here, we present existing research of placental steroidogenesis and other placental hormones using human placental models: placental perfusion, placental explants, fragments, microsomes and vesicles, primary cell culture, stem cells, placenta on a chip and choriocarcinoma cell cultures: BeWo, HTR-8/SVneo, Jar, JEG-3 and ACH-3P. We conclude that there is a lack of research focused on placental steroidogenesis and the effects of endocrine-disrupting compounds. Advantages and limitations of existing models are discussed, and future directions suggested.

Keywords: cell culture; endocrine disruption; fetal exposure; model of human placenta; placenta on a chip; placental barrier.

FIGURE 1

Hormone levels in the human menstrual cycle, pregnancy and postpartum. Folliculogenesis and ovulation are regulated by the hypothalamic–pituitary–gonadal (HPG) axis secreting the luteinizing hormone (LH) and follicle‐stimulating hormone (FSH). After ovulation, the corpus luteum produces progesterone (PROG) and oestrogens. If implantation occurs, the corpus luteum continues the release of PROG and oestrogens until around 10–12 weeks of gestation, when the developing placenta takes over and the corpus luteum degenerates. The placental production of PROG inhibits smooth muscle contractility, and the production of oestradiol is important for fetal organ development. The placenta secretes human chorionic gonadotropin (hCG) to maintain the structure of the corpus luteum and cortisol (COR), which suppresses the maternal immune response and is essential for fetal lung development. At term gestation, the placenta secretes corticotropin‐releasing hormone, stimulating a maternal increased production of COR, crucial for parturition, by competing with PROG for placental corticosteroid receptors. Oestradiol promotes the synthesis of prostaglandins, stimulating myometrial contractility and ripening of the cervix. Lines measured on the left axis in ng/mL: light pink: follicular stimulating hormone, pink: LH, green: cortisol, brown: prolactin, purple: human chorionic gonadotropin. Lines measured on the right axis in pg/mL: red: oestrogen, orange: progesterone, blue: oxytocin.

FIGURE 2

Disruption of maternal and placental steroid profile by endocrine‐disrupting chemical (EDCs). EDC can affect the placental steroid profile in two ways: 1^st EDC impact: The EDC affects the steroid profile of the mother and thereby the steroids available in maternal blood for substrates and signals for placental steroidogenesis. 2^nd EDC impact: The EDC disrupt the placental steroidogenesis directly.