Fig. 6: Proposed model of pro-inflammatory responses induced by low maternal T₄ levels during early pregnancy

Gestational HTX increases circulating levels of IL-6 and IL-17 A, similar to observations in MIA models. These cytokines are also elevated in placental tissues and embryonic brains. It is postulated that this pro-inflammatory environment at the maternal-fetal interface activates myeloid cells, including M1 macrophages, NK cells, and monocytes, thereby contributing to immune imbalance. This immune dysregulation may impair fetal neural progenitor cells (NPCs), particularly by affecting the proportion of intermediate progenitors, which could lead to an altered generation of deep-layer cortical neurons relevant for establishing early cortical circuitry and supporting higher-order cognitive functions. The increased expansion of microglial pool is also consistent with the pro-inflammatory environment at the embryonic developing brain that contribute to long-term neurostructural alterations, including reduced dendritic spine density and a decrease in mature-shaped spines in the hippocampus. These changes are associated with neurocognitive deficits in the offspring. Interestingly, T₄ supplementation during gestation prevents immune imbalance and mitigates these neurodevelopmental alterations, suggesting a critical role of maternal T₄ in modulating maternal-fetal immunity during early embryonic neurodevelopment during early. CP: cortical plate; IZ: intermediate zone; SVZ: subventricular zone; VZ: ventricular zone. Created with BioRender.