SAT-118 Untargeted Profiling of the Second Trimester Pregnancy Exposome Reveals an External Toxin Linked to Third Trimester Endocrine Disruption and Maternal Breast Cancer

Abstract Disclosure: B. Cohn: None. P. Cirillo: None. N. Krigbaum: None. S. Teeny: None. B. Minasenko: None. D. Wang: None. V. Tran: None. Y. Go: None. D. Jones: None. X. Hu: None. Background. A lower ratio of estriol to the sum of estrone and estradiol (estriol ratio) in the 3rd trimester predicted maternal breast cancer within 15 years of pregnancy (DOI: 10.1210/jc.2016-3476). Here we identify 2nd trimester metabolites that predict the 3rd trimester estriol ratio to inform the mechanism for this association. Methods. Metabolites in 2nd trimester pregnancy serum were extracted and analyzed using established untargeted metabolic profiling in 566 pregnant women residing near Oakland, California 1959-1967 (Child Health and Development Studies) of whom 36 were diagnosed with breast cancer within 15 years. High resolution mass spectrometry was performed using C18 and negative electrospray ionization. Statistical analysis and pathway enrichment screened for 2nd trimester metabolic dysfunction correlated with the 3rd trimester estriol ratio. We used Rodin for untargeted analysis (https://rodin-meta.com) to fit a linear regression model predicting the 3rd trimester estriol ratio moderated by subsequent breast cancer within 15 years. Conditional logistic regression estimated associations of maternal breast cancer with 2nd trimester metabolites, 3rd trimester estriol ratio and age. Results. An exogenous pathway in the 2nd trimester for the degradation of the insecticide parathion associated with the 3rd trimester estriol ratio in future cases compared to controls (p=0.0004). Three compounds in this pathway include a feature with m/z 138.0197, retention time 276 s, annotated as 4-nitrophenol (PNP) with high confidence, a metabolite of parathion and known to disrupt androgen and estrogen signaling in breast cells. Other significant compounds (p<0.01) include m/z 153.0307, 127 s; m/z 153.0307, 284 s, annotated as amino-nitrophenols. In logistic regression models, increased intensity of the most significant of these amino-ntirophenols in the 2nd trimester significantly strengthened the association of the 3rd trimester estriol ratio with subsequent maternal breast cancer. Conclusion. In logistic regression models, increased intensity of 2nd trimester amino-nitrophenol significantly strengthened the association of the 3rd trimester estriol ratio with subsequent maternal breast cancer, suggesting that endocrine disruption contributes to the incidence of breast cancer within 15 years of pregnancy. Presentation: Saturday, July 12, 2025