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

ABSTRACT 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.