Maternal exposure to bisphenol A has transgenerational effects on the development of experimental asthma through bromodomain-containing protein 4–zinc finger DHHC-type containing 1–stimulators of interferon genes axis

Perinatal exposures to the environmental estrogen bisphenol A (BPA) are associated with increased asthma prevalence. We tested the hypothesis that perinatal BPA exposure transgenerationally enhances allergic asthma development through the bromodomain-containing protein 4 (BRD4) - zinc finger HHC-1 (ZDHHC1) - stimulators of IFN genes (STING) axis. Female BALB/c mice (F0) were exposed to 10 μg/mL BPA in their drinking water during pregnancy until F1 pups were weaned. Pups were sensitized with low doses of ovalbumin (OVA) on postnatal day 4 (PND 4) and 1% OVA inhaler on PND 18-20. Asthma phenotype was assessed on PND 22. Non-sensitized female pups were bred with non-exposed male mice at 8 weeks of age. Subsequent pups were sensitized, and asthma phenotypes were examined for four generations (F1-F4). Maternal BPA exposure significantly enhanced airway hyperresponsiveness, eosinophilic inflammation, and allergen-specific IgE production in F1-3 pups. Further, treatment of F0 dams with STING inhibitor C-176 yielded pups with decreased response to sensitization. Thus, prenatal exposure to environmental estrogens such as BPA may promote development of experimental asthma through the BRD4-ZDHHC1-STING axis, causing immune alterations with multigenerational effects.