Perinatal exposure to nonylphenol reprograms hepatic clock machinery and energy metabolism in rat offspring.

Disturbances in energy metabolism during developmental periods have long-term health consequences. Notably, the effects of perinatal exposure to nonylphenol (NP), a ubiquitous environmental contaminant, on energy metabolism remain unclear. The liver, as a central metabolic organ, relies on its intrinsic clock machinery to regulate glucose and lipid metabolism and maintain energy balance. Therefore, NP may impair hepatic metabolic regulation by disturbing the hepatic clock system. Using a perinatal NP exposure rat model with a range of environmentally relevant doses, we observed increased basal energy expenditure and fat accumulation in offspring, along with disrupted hepatic glucose and lipid metabolism. Omics analysis revealed disturbances in the PPAR signaling pathway, supported by elevated expression of PPARα, a hepatic metabolic regulator under clock control. Furthermore, NP exposure disturbed the hepatic clock system, as evidenced by Zeitgeber time-specific alterations in the expression of core clock genes and by altered circadian oscillations of enzymes and proteins involved in hepatic lipid and glucose metabolism. Melatonin supplementation partially ameliorated NP-induced metabolic disturbances by modulating the hepatic clock system. In summary, perinatal NP exposure induces profound disturbances in energy metabolism, notably disrupting hepatic glucose and lipid homeostasis, with dysfunction of the hepatic clock system contributing to these abnormalities. This study provides novel insights into how environmental pollutants disrupt energy metabolism and highlights the key role of the hepatic clock in metabolic health.