Environmental Pollution Is Associated with Higher Risk MDS in a Diverse Urban Cohort and Triggers Inflammation in a Murine Models

Introduction

Environmental pollution due to increased industrialization and automobile exhaust has long been associated with adverse effects on human health. While smoking has been associated with clonal hematopoiesis, no studies have comprehensively evaluated the effect of environmental pollutants MDS/myeloid malignancies.

Methods

A retrospective cohort was developed of patients diagnosed with MDS at Montefiore Health System (Bronx, NY) between 2000-2017 (n=138) using the Montefiore Electronic Data Warehouse. Patient addresses were then used to geospatially estimate Outdoor Air Pollution (OAP) exposures from 2000-2018 using land use regression models as previously performed (Wysota M et al, Abstract 531, ASH 2023). Associations with environmental Black Carbon (BC) and PM2.5 exposures, clinical parameters, and disease characteristics were assessed by Pearson's correlation statistics. A novel mouse model was developed for studying the effects of chronic intratracheal administration of black carbon pollutants in vivo. Mice cohorts were evaluated for hematopoietic alterations and signs of systemic inflammation.

Results

Our MDS patient cohort was highly diverse, as patients were 29% (40/138) Black, 27% (37/138) White, and 41% (57/138) identifying as Hispanic. Median age at diagnosis was 65. Correlation with high resolution geospatial mapping demonstrated that both BC in 2016 and PM2.5 in all years correlated positively with IPSS disease severity scores (P=0.0006 and P=0.01, respectively). BC content also correlated positively with prevalence of high risk TP53 mutations and negatively with lower risk SF3B1 mutations (P<0.05). However, BC exposure was not associated with worse survival, except in the year 2013 when lower overall survival with BC exposure was noted (median OS of 1455 and 2642 days for high and low BC groups; Log rank P val= 0.009).

To further determine the neighborhood exposure of specific PM 2.5 matter in high resolution, we performed 24 hour measurements of airborne pollutants in 3 separate regions of the Bronx and an area of Westchester County with less industrialization. We used an industrial pump (TE-1000 PUF) to force gallons of air through a sponge that traps pollutants at the level of PM 2.5uM. Chemical analysis was performed in certified analytical lab (Airzone One, Ontario, CA) and revealed that significantly elevated levels of Phenanthrene (10ng/m3), Pyrene (4ng/m3), Fluoranthene (3ng/m3) and Benzopyrene (0.6ng/m3) were seen in the Bronx with 2-5 fold increase when compared to control region. To mimic exposure to environmental pollution, we developed a formulation containing nano sized black carbon particles smaller than 2.5 microns containing the same chemicals. We observed that mouse lung derived macrophages engulfed Black Carbon pollutant particles in vitro, suggesting a mechanism via which these chemicals enter the blood stream after inhalation.

C57B6 mice were exposed to Black Carbon loaded with pollutants via intratracheal administration 3 times a week for 4 weeks. Exposure to BC-pollutants led to inflammation in vivo as evident from increased levels of pro-inflammatory IL-1β and histamine and decreased levels of anti-inflammatory IL-10 detected at 4 weeks of administration. Blood counts were monitored serially and showed a significant decrease in white cell counts upon chronic dosing demonstrating bone marrow suppression. Compensatory increase in hematopoietic stem cells compartments was seen suggesting a differentiation block mimicking alterations seen in MDS. Furthermore, exposure to BC loaded with pollutants on primary human CD34+ stem and progenitors resulted in a decreased production of differentiated hematopoietic colonies validating the murine findings.

Conclusion

In conclusion, we demonstrate that high levels of PM2.5 and BC pollutants correlate with higher disease severity and shorter overall survival in an urban diverse cohort of MDS patients. An in vivo model of chronic exposure of BC pollutants leads to inflammation and bone marrow suppression in vivo. These data demonstrate that environmental exposures can affect MDS diseases phenotypes adversely and are a potential casual factor for disease severity. Though the sample size limits the power of this study, we observed important correlations that certainly warrant further analysis.

Verma:Throws Exception: Current equity holder in publicly-traded company; Bakx: Current equity holder in publicly-traded company; Janssen: Honoraria; Stelexis: Honoraria; Eli Lilly: Research Funding; Curis: Research Funding; Medpacto: Research Funding; Incyte: Research Funding; BMS: Research Funding; prelude: Research Funding. Shastri:NACE & PeerView: Honoraria; Jassen: Consultancy; Gilead, Rigel, Kymera: Consultancy; Kymera: Research Funding; Ryvu therapeutics: Research Funding; Geron: Speakers Bureau.