Neuroactive steroid exposure impacts neurodevelopment: Comparison of human and rodent placental contribution

Abstract

The placenta is a fetal endocrine organ that secretes many neuroactive factors, including steroids, that play critical roles in brain development. The study of the placenta-brain axis and the links between placental function and brain development represents an emerging research area dubbed "neuroplacentology." The placenta drives many circulating fetal steroids to very high levels during gestation. Recent studies have highlighted the critical role of placental steroids in shaping specific brain structures and behaviors. This review uses a cross-species framework to discuss the genomic factors, in-utero environmental changes, and placental conditions that alter placental steroidogenesis, leading to changes in early developmental trajectories relevant for psychiatric conditions such as autism, in a sex-linked manner.

Keywords: autism; maternal‐fetal‐placental unit; neurodevelopment; placenta; sex steroids.

FIGURE 1

Overview of Steroidogenic Pathways in Human and Rodent Placenta: This figure illustrates the steroidogenic pathways discussed in this review. Color coding identifies the site of hormone production: placenta (red), ovaries (orange), adrenals (green), and hypothalamic‐pituitary axis (blue). Hormones shown in bold emphasize their placental production. Hormones with underlined names denote conserved pathways between rodents and humans, while non‐underlined hormones indicate pathways unique to primates. Straight arrows indicate enzymatic conversions (dotted arrows highlight multi‐step conversions), with labels identifying the principal enzyme isoforms catalyzing each reaction. Curved arrows depict hormonal transport, while faded arrows represent regulation pathways. ACTH, adrenocorticotropic hormone; CRH, corticotropin‐releasing hormone; CYP, cytochrome P450; DHEA, dehydroepiandrosterone; DHEA‐S, dehydroepiandrosterone sulfate; HSD, hydroxysteroid dehydrogenase; HP, hypothalamic‐pituitary.