Heat-Induced Pathophysiological and Metabolic Changes at the Feto-Maternal Interface Predisposing to Preterm Birth.

As global temperatures rise, the link between elevated temperature exposure and preterm birth (PTB) is a growing concern. Clinical interventions remain limited due to insufficient understanding of the underlying pathophysiological mechanisms. This study aims to examine heat-induced pathophysiological and metabolic changes at the feto-maternal interfaces (FMis) and explore their mechanistic implications in the pathophysiology of PTB. We employed a 2D in vitro heat exposure model using maternal decidual cells (DECs) and fetal amniotic epithelial cells (AECs), cultured at 39°C to induce heat stress. We assessed mitochondrial function (ATP levels and gene expression), oxidative stress by glutathione quantification, stress signaling (p38MAPK and NF-κB protein levels), cellular senescence (SA-β-Gal staining), and inflammatory activation (cytokine quantification). Targeted metabolomics was used to evaluate heat-induced metabolic shifts. Heat exposure induced mitochondrial dysfunction, indicated by reduced ATP production, and disrupted expression of Heat shock protein family D member 1 (HSPD1) and ATP Synthase F1 Subunit (ATP5F1) in both cell types and Voltage-dependent anion-selective channel 1 (VDAC1) in DECs. Heat-induced oxidative stress (reduced glutathione [GSH] levels in both cell types) caused DNA damage, stress signaler p38MAPK activation, senescence, and senescence-associated secretory phenotype (SASP; inflammatory cytokines [IL-6 and GM-CSF] increases). Heat-induced metabolic changes included energy, amino acids, epigenetics, and immune modulation-related metabolites and pathways. Although many heat-induced metabolite changes overlapped between AECs and DECs, cell-type-specific responses were also noted. Our findings highlight the sensitivity of both maternal and fetal cells to heat stress and provide insight into differential levels of heat-induced pathobiologic and metabolic disruptions as well as cell-specific responses. Future studies extending this work on the heat exposure model that integrates multiple cell types across the FMi could aid in identifying heat-associated biomarkers for PTB prediction.