Prenatal Exposure to PM_2.5 Increased Vulnerability to a Second Hit of a High-Fat Diet in Mouse Offspring

Emerging evidence indicates that prenatal exposure to fine particulate matter (PM_2.5) may program metabolic syndrome (MS) in adult offspring. However, the metabolic response to the second hit of a high-fat diet (HFD) (prenatal PM_2.5 exposure as the first hit) in adult offspring and its underlying mechanisms remain poorly understood. Using a whole-body inhalational exposure system, we achieved the following observations. First, prenatal PM_2.5 exposure significantly increased the fat mass, inhibited the insulin signaling pathway in chow diet (CD)-fed offspring, and exacerbated HFD-induced metabolic disorders evidenced by impaired insulin signaling in metabolic organs like liver, epididymal white adipose tissue (eWAT), and brown adipose tissue (BAT). Second, prenatal PM_2.5 exposure enhanced hepatic lipid accumulation and hypertrophy of adipocytes in eWAT and BAT, accompanied by lipid metabolic disorders in the liver and eWAT. Finally, prenatal exposure to PM_2.5 exaggerated HFD-induced cellular senescence in both hepatic and eWAT, as well as cell cycle arrest in BAT, which ultimately led to the activation of chronic inflammation in offspring. In conclusion, prenatal exposure to PM_2.5 increased the vulnerability to the second hit of HFD feeding in adult offspring, in which chronic inflammation triggered by cellular senescence may be involved. These findings underscore the heightened vulnerability to metabolic diseases in individuals following early life exposure to air pollution, particularly in the setting of compounding with a high-fat dietary pattern.