Nicotinamide metabolic dysregulation plays a key role in Benzo[a]pyrene-induced adverse birth outcomes: Evidence from multi-omics profiling, experimental and epidemiological validation.

Prenatal exposure to Benzo[a]pyrene (BaP) has been shown to increase the risk of adverse birth outcomes, potentially through disruption of maternal metabolic homeostasis. However, the underlying pathways and mechanisms remain unclear. To address this knowledge gap, we employed a multi-omics approach combining experimental and epidemiological investigations. In the mouse model, untargeted metabolomics profiling revealed niacinamide (NAM) metabolism as the most significantly altered pathway in both maternal serum and placenta following BaP exposure. Mechanistically, BaP exposure reduced nicotinamide adenine dinucleotide (NAD+) synthesis while increasing its catabolism through activation of poly (ADP-ribose) polymerase 1 (PARP1) in placental tissue. Subsequent transcriptomic analysis showed that BaP-induced NAD+ depletion led to sirtuin 1 (SIRT1) suppression and consequent exacerbation of the NF-κB-mediated inflammatory response. These experimental findings were substantiated in human populations through targeted metabolomic analysis of a Chinese birth cohort, where significant NAM metabolic disturbances were observed in women with high BaP exposure experiencing preterm delivery. Our study provides novel mechanistic evidence that BaP-induced dysregulation of NAM metabolism mediates adverse birth outcomes through NAD+ deficiency and subsequent inflammatory response. These findings not only identify potential therapeutic targets but also highlight the urgent need for evidence-based environmental policy interventions and nutritional supplementation strategies to protect maternal-fetal health in high-risk populations.