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.