Maternal nutrition as a key determinant of placental and developing blood-brain barrier xenobiotic protective...

The placenta and the developing blood-brain barrier (BBB) function as two complementary fetal protective interfaces ensuring nutrient delivery at the same time as limiting fetal brain xenobiotic overexposure. In this review, we integrate evidence from animal and human studies demonstrating that the spectrum of maternal malnutrition, from undernutrition/underweight to overnutrition/obesity, profoundly remodels placental morphology and compromises placental barrier efficiency. Maternal undernutrition reduces placental exchange surface area, impairs villous vascular development and alters syncytiotrophoblasts maturation, whereas maternal overnutrition/obesity promotes villous immaturity, inflammation and limits vascular exchange capacity, thus impairing fetal xenobiotic protection. These nutritional insults also consistently impair expression and activity of protective efflux transporters, P-glycoprotein (P-gp/ABCB1), breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance protein 2 (MRP2/ABCC2), weakening xenobiotic defence. Concurrently, solute carrier transporters for glucose (GLUT1), amino acids (SNATs and LATs) and fatty acid (FATP/CD36) are dysregulated with malnutrition, further debilitating these barriers and increasing risk for adverse developmental programming. The developing BBB may be similarly sensitive, with maternal nutritional adversity linked to increased permeability, diminished efflux capacity and reduced tight junction integrity. Moreover, micronutrients, including copper, folate, iron, vitamin A, vitamin B12, vitamin D and zinc emerge as pivotal regulators of these protective systems, directly modulating BBB efflux transporter activity, and junctional stability. This evidence demonstrates that maternal nutrition imbalance impairs fetal protection, with consequences for neurodevelopment. Optimizing maternal diet before and during pregnancy represents a strategy to reinforce placental and developing BBB function, safeguard the fetal brain, and improve long-term offspring health.