Role of constitutive androstane receptor in developmental toxicology: linking chemical exposure, nutrition, and disease susceptibility.

Abstract

The constitutive androstane receptor (CAR) is a xenobiotic-sensing nuclear receptor that regulates gene transcription involved in drug metabolism, especially in the liver. CAR activation influences detoxification pathways and disrupts endocrine homeostasis, notably thyroid hormone (TH) signaling. THs are crucial for neurodevelopment, skeletal maturation, and metabolic regulation. When activated by antiseizure medications, such as phenobarbital, or environmental chemicals, such as perfluoroalkyl substances, CAR induces hepatic enzymes, including UDP-glucuronosyltransferases (UGTs), which increase the clearance of THs and raise thyroid-stimulating hormone levels. Developmental exposure to CAR activators in rodents has been linked to reduced circulating and brain TH levels, resulting in impaired neurodevelopmental outcomes. Given that CAR expression is very low in fetal and neonatal livers, maternal CAR activation may significantly disrupt fetal TH signaling. Additionally, CAR modulates host gene expression affecting microbial composition and bile acid homeostasis, with emerging evidence connecting it to early-life metabolic programming, including low birth weight. Epigenetic changes caused by CAR agonists during the neonatal period can persist into adulthood at least in rodents, suggesting a potential role of CAR in the developmental origins of health and disease, or DOHaD. While it is essential to consider species differences in ligand specificity and UGT isoform expression when extrapolating findings from rodents into humans, CAR is increasingly recognized as a mediator between environmental exposure and endocrine-metabolic disruption. This review integrates animal and human evidence to highlight the critical yet underappreciated functions of CAR in mediating developmental toxicity and long-term health outcomes.