Maternal tributyltin exposure is associated with male-biased immune dysregulation across generations.

Tributyltin (TBT) is an environmental obesogen and endocrine-disrupting chemical that promotes adipogenesis and transgenerational metabolic dysfunction in mice. Although developmental TBT exposure has been linked to male-biased adiposity, insulin dysregulation, and hepatic pathology, its effects on the immune system remain unclear. We investigated whether maternal TBT exposure is associated with persistent immune dysregulation in F1 and F3 offspring. Peripheral blood immunophenotyping data generated by the German Mouse Clinic were reanalyzed in F1 offspring of control- and TBT-exposed dams. Maternal TBT exposure was associated with increased B-cell representation, reduced T-cell representation, an altered B-cell-to-T-cell balance, a reduced CD4/CD8 ratio, and decreased NK-cell frequencies. We then analyzed splenic immune-marker expression and circulating inflammatory cytokines in an independent transgenerational cohort. In F1 males, TBT exposure was associated with reduced expression of T-cell- and myeloid-associated markers and increased expression of inflammatory cytokines. Similar changes were observed in unexposed F3 male descendants of the TBT lineage, whereas F3 females showed no significant changes in the immune markers examined. Plasma TNF and IL-6 were increased in F1 and F3 males but not females. These findings identify the immune system as a potential target of developmental obesogen exposure and support a persistent, male-biased immune phenotype characterized by altered splenic immune-marker expression and elevated inflammatory cytokines across generations.