Intrauterine heat stress: molecular acclimation and epigenetic transmission in F1 and F2 male mice

Heat stress (HS) during gestation poses a major physiological challenge to the developing fetus, potentially inducing long-term adaptations that persist across generations. Understanding this process is crucial for reproductive biology, as climate change poses challenges to fertility. This study evaluated the effects of prenatal HS (41 °C, 65% relative humidity) during early, late, or full-term pregnancy on postnatal development and reproductive function of F1 male mice. Additionally, the potential transmission of heat acclimation was evaluated by analyzing gene expression in the testes of F1 males and in F2 blastocysts derived from matings between F1 males and control females (maintained at 25 °C, 45% relative humidity). Between the third and eighth postnatal weeks, F1 males exposed to HS showed accelerated weight gain (p < 0.05). Genes related to glucose transport (GLUT1, GLUT3, GLUT8) and lipid metabolism (FASN, ACACB) were upregulated (p < 0.05) in both generations. HS-response genes (HSP60, HSPA1A, HSPA1B) and autophagy-related ATG8 were also upregulated in early pregnancy and full-term pregnancy groups. Despite these molecular changes, sperm parameters (concentration, motility, morphology) and fertilization potential remained unaffected. These findings suggest that in utero HS induces metabolic and stress-response adaptations, promoting reproductive heat acclimation that persists in the next generation. Understanding these mechanisms may offer insights into fertility resilience under thermal stress.