2450-P: Pyrroloquinoline Quinone Primed Human Adipose–Derived Mesenchymal Stem Cells Improves Metabolic Abnormalities Along with Gut Microbiome in Phthalates-Mixture–Exposed High-Fat Diet–Fed Mice

Introduction and Objective: Given humans' high exposure to different phthalate daily, we investigated the effect of an environmentally relevant six phthalate mixture (PM) and therapeutic efficacy of Human Adipose-Derived Mesenchymal Stem Cells (hADMSCs) in combination with Pyrroloquinoline Quinone (PQQ) in mitigating PM-induced metabolic dysregulation along with gut microbiome. Methods: Six-week male C57BL6 were used for body weight, food consumption, fasting/fed glucose, glucose tolerance, insulin resistance (IR), serum insulin, triglyceride, cholesterol levels. Set 1 (acute) were dosed with different concentration of PM or vehicle (VC) for glucose challenge. Set 2 (chronic) were exposed to PM or VC ± high-fat-diet (HFD) for 14 wks. A subset of set 2 were injected with hADMSCs or PQQ primed hADMSCs before sacrificing at 16 wks. Composition and diversity of the gut microbiome were carried out. 3T3L1, C3H/10T1/2, T37i were used to examine adipogenesis with either VC or PM ± hADMSCs-condition media (CM) or PQQ-hADMSCs-CM for differentiation (0-8 days). Oil Red O staining was performed. Results: Significant glucose intolerance was observed acutely while several metabolic abnormalities were documented in set 2 even with low doses of PM as early as wk 3. hADMSCs or PQQ-hADMSC treatment didn’t alter glucose tolerance but exhibited a significant decrease in IR compared to pre-treatment value. In all cell lines, a dose dependent increase in adipogenesis was observed with PM. hADMSCs-CM showed decreased adipogenesis while a striking decreased shown in PQQ-hADMSCs-CM. PQQ-primed hADMSCs significantly reduced body weight and improved gut microbiome in PM-exposed HFD mice. The alpha diversity was decreased at both the phylum and genus level (p <0.05). At the phylum level, the Firmicutes, was decreased and Bacteroidetes was increased. Conclusion: Investigating PM-induced metabolic dysfunction and finding therapeutic strategies will significantly advance the field. Disclosure M. Choudhury: None. S. Venkategowda: None. N. Shree: None. A.U. Ufondu: None. A. Jayaraman: None. Funding NIH (1R01ES036962-01)