Sex, stress, and the heart: long-term cardiovascular effects of embryonic metabolic disruption

Adverse conditions within the embryonic environment can alter embryogenesis, programing systemic physiological changes that may manifest as disease states in adult life. The process of developmental programing represents an important factor underlying cardiometabolic diseases, many of which are leading causes of death globally. Importantly, there is evidence that males are less tolerant to certain environmental perturbations during embryogenesis, mirrored by sex differences in the incidence of certain cardiometabolic diseases. Understanding sex differences in programed responses in mammalian models is complicated by maternal compensation and placental factors. Avian models offer a valuable comparable system in which such effects are not present. Here, we investigate the influence of developmental hypoxia and hypothermia in programing cardiovascular structure and function in the domestic chicken (<i>Gallus gallus domesticus</i>). In agreement with mammalian studies, adult males but not females show pathological mitochondrial morphology and respiratory capacity, ventricular hypertrophy, and reduced body weight programed by embryonic hypothermia and hypoxia. Notably, adult males but not females incubated under combined hypoxia and hypothermia display reduced left ventricle size, more spherical mitochondria, and a reduction in mitochondrial complex IV activity in cardiomyocytes. Adult females incubated under hypothermic conditions show higher protein levels of mitochondrial complex V and do not display the same level of telomere shortening in comparison with males incubated under identical conditions. These data not only represent novel findings in birds but also demonstrate the utility of the avian model for understanding sex differences in developmental stress responses, revealing common responses among endothermic amniotes.<b>NEW & NOTEWORTHY</b> How does stress before birth shape lifelong heart health? We show that chickens exposed to low oxygen or cold during development grow into adults with long-lasting, sex-specific heart changes. Males developed smaller bodies, altered heart structure, mitochondrial dysfunction, and faster telomere shortening, whereas females showed enlarged hearts but preserved mitochondrial function. Our findings reveal how early environmental stress programs cardiovascular health differently in males and females, with broad relevance for understanding heart disease risk.