The Maternal-Placental-Fetal Liver Axis: A Mechanistic Framework for Understanding Benzene Developmental...

Benzene is a ubiquitous environmental pollutant and a human hematotoxicant and carcinogen. Increasing epidemiological and experimental evidence links in utero benzene exposure to adverse pregnancy outcomes, altered fetal development, and increased childhood leukemia risk. Benzene toxicity is initiated through metabolism into reactive intermediates, primarily by cytochrome P450 2E1 (CYP2E1) and myeloperoxidase. These enzymes are expressed not only in the maternal liver but also in the placenta and fetal liver, indicating that multiple compartments may contribute to benzene toxicity during pregnancy. Despite these observations, the mechanisms linking maternal exposure to fetal hematotoxicity remain incompletely understood, as existing studies have largely examined maternal, placental, and fetal effects independently, with the placenta often treated as a passive barrier rather than an active regulator of developmental toxicity. We propose the maternal-placental-fetal liver axis as a mechanistic framework for understanding in utero benzene developmental hematotoxicity, and discuss three biologically plausible bioactivation routes across this axis: maternal hepatic metabolism, placental bioactivation, and direct fetal liver metabolism. We further examine how fetal injury may arise through complementary mechanisms: direct toxicity from transplacental transfer of benzene and its reactive metabolites, and indirect toxicity, whereby benzene-induced placental dysfunction alters the intrauterine environment and may drive secondary fetal injury. We suggest a model where placental dysfunction may amplify, rather than independently drive, fetal benzene toxicity. The maternal-placental-fetal liver axis integrates maternal metabolism, placental biology, and fetal susceptibility, providing a mechanistic framework for understanding the pathways underlying benzene-induced developmental hepatotoxicity and its potential contribution to childhood leukemia.