Abstract The hypothalamus is essential in the regulation of metabolism, notably during critical windows of development. An abnormal hormonal and inflammatory milieu during development can trigger persistent changes in the function of hypothalamic circuits, leading to long-lasting effects on the body’s energy homeostasis and metabolism. We recently demonstrated that gestational exposure to benzene at smoking levels induces severe metabolic dysregulation in the offspring. Given the central role of the hypothalamus in metabolic control, we hypothesized that prenatal exposure to benzene impacts hypothalamic development, contributing to the adverse metabolic effects in the offspring. C57BL/6JB dams were exposed to benzene in the inhalation chambers exclusively during pregnancy (from E0.5 to E19). The transcriptome analysis of the offspring hypothalamus at postnatal day 21 (P21) revealed changes in genes related to metabolic regulation, inflammation, and neurodevelopment exclusively in benzene-exposed male offspring. Moreover, the hypothalamus of prenatally benzene-exposed male offspring displayed alterations in orexigenic and anorexigenic projections, impairments in leptin signaling, and increased microgliosis. Additional exposure to benzene during lactation did not promote further microgliosis or astrogliosis in the offspring, while the high-fat diet (HFD) challenge in adulthood exacerbated glucose metabolism and hypothalamic inflammation in benzene-exposed offspring of both sexes. These findings reveal the persistent impact of prenatal benzene exposure on hypothalamic circuits and neuroinflammation, predisposing the offspring to long-lasting metabolic health conditions.

Prenatal benzene exposure alters offspring hypothalamic development predisposing to metabolic disease in later life