Embryo-fetal and early-life protein restriction programs pulmonary structure and molecular parameters in both dams and female offspring

The Developmental Origins of Health and Disease (DOHaD) theory proposes that adverse conditions during critical developmental windows can increase disease susceptibility throughout life. Maternal protein restriction (MPR) is a well-established experimental model that impairs offspring lung development, affecting pulmonary structure, metabolism, and molecular pathways from early life to aging. However, little is known about its effects on maternal pulmonary health and female offspring, representing an important gap in the literature. Therefore, this study investigated the effects of MPR on lung structure and metabolism in dams at the end of lactation and in female offspring at weaning. Sprague Dawley rats were fed either a control diet (17% protein) or a low-protein diet (6% protein) throughout gestation and lactation. Dams and female offspring were euthanized at weaning, and pulmonary alterations were assessed through histological, biochemical, molecular, zymographic, and in silico analyses. MPR increased collagen deposition, mast cell density, and Acta expression, while reducing reticular fibers in maternal lungs, accompanied by a trend toward increased lipid peroxidation. In female offspring, MPR reduced alveolar diameter, mast cell density, and reticular fibers, while increasing collagen deposition, MMP-2 activity, PI3K and MyoD expression, and decreasing mTOR expression as well as Nduf transcript levels. No significant alterations in antioxidant parameters were observed in either dams or offspring. Integrative analyses indicate that MPR promotes structural remodeling in maternal lungs, potentially compromising ventilatory function. In female offspring, MPR induces delayed pulmonary development, extracellular matrix remodeling, alterations in smooth muscle-related pathways, and disturbances in energy metabolism. Together, these findings demonstrate that maternal protein resQ1triction adversely affects pulmonary health in both dams and female offspring, revealing potential mechanisms linking early-life nutritional adversity to the developmental origins of respiratory disease.