Tu104 - The Role of BRD4/ZDHHC-1/STING Axis on Allergic Asthma Development

Yoko Murakami – University Of Texas Medical Branch, Galveston; Sahar Fahmy – University Of Texas Medical Branch, Galveston; Kazuyo Kuzume – University Of Texas Medical Branch, Galveston; Kangling Zhang – University Of Texas Medical Branch, Galveston; Randall Goldblum – University Of Texas Medical Branch, Galveston

Abstract Text: Rationale: Early exposures to environmental estrogens (EEs) are associated with increased asthma prevalence. We have previously identified the enhanced expression of bromodomain-containing protein 4 (BRD4)/ zinc finger HHC-1 (ZDHHC1)/stimulators of IFN genes (STING) after EE exposure. We aimed to investigate the effects of EEs on the development of allergic asthma using our EE exposure model with the BRD4/ZDHHC1/STING axis.

Methods: Female BALB/c mice received 10 g/ml bisphenol A (BPA), bisphenol S (BPS), or vehicle control in their drinking water during pregnancy until their pups were weaned. Half of the dams received peritoneal injections of STING inhibitor, C-176. The pups were sensitized with an intentionally “suboptimal” low dose of ovalbumin (Ova) on postnatal day 4, 1% Ova inhalation on days 18-20, and asthma phenotype was assessed on day 22. Non-sensitized female pups were saved and bred with non-exposed male mice at 8 weeks of age. The subsequent pups were sensitized, and asthma phenotype was examined up to the fourth generation.

Results: F1-F4 pups from EE-exposed dams developed asthma phenotype. Pups from C-176 treated dams had decreased response to their sensitization compared to non-treated controls. Airway hyperresponsiveness and IgE anti-Ova were lower in pups with C-176 treatment.

Conclusions: Early exposure to EEs, including BPA and BPS, promotes the development of experimental asthma, possibly through the BRD4/ZDHHC1/STING axis. The immune alterations may be epigenetically perpetuated, causing multigenerational effects.