Developmental reprogramming of cytochrome P450 enzymes in offspring by adverse maternal factors exposure: Implications for long-term metabolic disease susceptibility

The Developmental Origins of Health and Disease (DOHaD) paradigm posits that prenatal exposures program long-term health, yet its implications for the developmental regulation of xenobiotic-metabolizing enzymes remain underexplored. This review synthesizes emerging evidence demonstrating that adverse maternal environments-encompassing exposure to environmental pollutants, specific medications, and nutritional imbalances-reprogram the expression and activity of offspring cytochrome P450 (CYP) enzymes, with a specific focus on the CYP1-3 families, which were critical for the metabolism of most drugs and xenobiotics. These exposures persistently alter the developmental trajectory of hepatic CYP expression through stable epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA regulation, along with the reprogramming of nuclear receptor signaling pathways. A novel aspect of this analysis is the integration of diverse prenatal stressors within a unified developmental programming framework, extending beyond traditional views centred on genetic polymorphisms. The translational implications of such reprogramming are also examined, emphasizing its role in modifying life-stage-specific susceptibility to toxicants and drugs from infancy through adulthood, and its potential contribution to long-term disease risk. By consolidating this evidence, this review establishes a new perspective on the developmental programming of metabolic capacity and its significance for interindividual variability and precision health.