Maternal high-protein diet impairs fetal growth through placental dysfunction in mice

Maternal dietary protein intake plays a vital role in pregnancy outcomes. However, the impact of popular high-protein diets, often accompanied by carbohydrate restriction, remains poorly understood. We investigated the effect of different levels of maternal protein during pregnancy on embryo implantation, placental development, and fetal growth in mice.

Pregnant C57BL/6 mice were fed isocaloric purified diets containing 10% (low protein, LP), 20% (medium protein, MP), or 40% (high protein, HP) protein. Implantation was assessed on day 6.5, and gestational outcomes were analyzed on day 18.5.

Maternal protein did not affect implantation number or litter size. However, HP intake reduced fetal weight and placental efficiency. Morphologically, HP intake decreased the placental labyrinth zone/total area ratio compared to LP. It was further revealed that maternal HP intake reduced fetal serum glucose, increased fetal serum urea nitrogen, and activated hepatic gluconeogenic and amino acid catabolic pathways compared to MP. Mechanistically, HP intake induced placental oxidative stress, evidenced by enhanced malondialdehyde content, and decreased the activity of placental catalase, superoxide dismutase, and glutathione peroxidase. The expression of genes involved in antioxidant defense and amino acid transport was also suppressed in placenta. Moreover, maternal HP intake reduced ATP production, lowered mitochondrial DNA copy number, and downregulated gene expression of electron transport chain components.

Excessive maternal protein intake under isoenergetic conditions disrupts placental redox homeostasis and mitochondrial function, and impairs nutrient transfer. These alterations compromise placental efficiency and fetal growth, highlighting the potential risks associated with high-protein dietary patterns during pregnancy.