Plastic associated endocrine disruptors reduce nicastrin protein and potentiate inflammation in hidradenitis suppurativa

Summary: Abstract Body: Hidradenitis Suppurativa (HS) is an inflammatory skin disorder with poorly understood etiology and few FDA approved treatments. Mutations in gamma secretase (GS), particularly the Nicastrin (NCSTN) subunit, characterize hereditary HS, but the pathophysiology of common acquired HS is unclear, despite associations with obesity and a diet containing ultra-processed foods (UPFs). Consistent with the hypothesis that the phenotypic overlap between acquired and hereditary HS suggests a shared dysfunction of NCSTN, we demonstrate that NCSTN protein is selectively lost in HS dermal fibroblasts (p<.0001, n=11 subjects) and primes them for inflammation. In particular, both HS dermal fibroblasts and siNCSTN fibroblasts express more CXCL8 RNA and protein after TNFα stimulation compared to controls (p<.0001; p<.0001). We further hypothesized the climbing incidence of acquired HS and its hormonal associations suggest Endocrine Disruptor (ED) chemicals as an environmental cause. Given the prevalence of plasticizer bisphenols and phthalates (p-EDs) in UPFs, we tested for their presence in HS skin and impact on NCSTN. p-EDs are elevated in the skin of HS patients but not controls, and persist in ex vivo cultured HS fibroblasts but not controls. p-EDs inhibit NCSTN protein expression at nanomolar concentrations in fibroblasts (p = 0.0004, n = 8), and prime for inflammation as seen in NCSTN siRNA and HS fibroblasts (p = 0.0002 overall, n = 3 per dose). These results suggest exposure to p-EDs can contribute to disease and the importance of further focus on p-ED research to mitigate HS and possibly other GS related diseases. Kaitlin L. Williams¹, Beita Badiei¹, James Reilly¹, William Andrews², Hana Minsky¹, Nina Rossa Haddad¹, Eddie Martinez¹, Mengqi Sun¹, Sam S. Lee¹, Ang Li¹, Leigh Curvin-Aquilla¹, Arieana Johnson¹, Aiden Willis¹, Charles Kirby¹, Amy van Ee¹, Yingchao Xue¹, Carrie Cox⁴, Shanmuga Rajagopalan⁴, Sewon Kang¹, Kurunthalchalam Kannan³, Julie Caffrey⁴, Nathan Archer¹, Maureen Kane², Luis A. Garza¹ 1. Dermatology, Johns Hopkins Medicine, Baltimore, MD, United States. 2. Pharmacy, University of Maryland Medical System, Baltimore, MD, United States. 3. Environmental Health Sciences, Wadsworth Center, Albany, NY, United States. 4. Plastic Surgery, Johns Hopkins Medicine, Baltimore, MD, United States. Innate Immunity, Microbiology, and Microbiome