ANALYSIS OF PRO-CARCINOGENIC EXPOSURES THAT IMPACT DNA REPAIR GENE EXPRESSION FROM ARSENIC TRIOXIDE, GLYPHOSATE AND THE GULF WAR WITH A FOCUS ON ANCESTRAL DISPARITY

Abstract

Studies of pro-carcinogenic exposures are ongoing in the U.S. in an attempt to prevent environmentally driven cancers. Breast cancer (BC) continues to be a significant U.S. public health concern, with 310,720 new invasive cases in 2024. Disparities in incidence and mortality disproportionately impact women of African ancestry (AA), who exhibit a higher incidence before age 40 and a 40% increased mortality risk relative to women of Non-Hispanic White (NHW) ancestry. In Florida, several zip codes in Broward and Miami-Dade counties have advanced BC diagnosis rates of 35-55%, above the national average of 30%. Within these areas live higher proportions of populations with AA. Environmental exposures, including environmental carcinogens, may contribute to these disparities of BC outcomes. Arsenic levels are elevated in the tap water of seven Broward County zip codes and in Miami Dade with increased rates of advanced BC diagnoses. Glyphosate is in widespread use in parks, and lawns and is used all year for weed control in Florida where it runs off into the water supply. We hypothesized that different ethnicities have different pharmacogenomic sensitivities to environmental exposures, leading to distinct molecular responses to environmental agents. Unique patient-derived culture explants (PDCEs) generated in the AutoNation Institute from AA (N=3) and NHW (N=3) women were exposed to 0.3 uM arsenic trioxide and 0.003 uM glyphosate. Arsenic exposure in AA PDCEs resulted in a significant reduction in all 5 DNA repair pathways [base excision repair, nucleotide excision repair, mismatch repair, homologous recombination, and non-homologous end joining] vs. NWH. AA cultures manifested dysregulation in 66–86% percentage of gene vs. 25–38% in NHW. In contrast glyphosate exposure did not manifest significant changes in DNA repair pathways in general. Instead, the most significant pathways impacted were metabolically related, diabetes related, and immune/inflammation related and were more dramatic in AA vs. NWH. Our findings matched others in that AA PDCEs showed significant upregulation of demethylating agents TET2 and TET3 gene expression. In Gulf War Illness (GWI) patient blood cells showed NER genes were significantly downregulated, despite slightly higher NER capacity compared to age-matched controls, indicating lasting dysregulation from burn pit.