Association of environmental chemical exposure during pregnancy with subsequent breast cancer risk

Background and Aim: Breast cancer became the most common cancer globally as of 2021, accounting for 12% of all new annual cancer cases worldwide, according to the World Health Organization. Despite epidemiologic studies establishing a number of risk factors for breast cancer, additional research is needed to elucidate environmental exposures that increase breast cancer risk. In this study, we used highly informative, existing pregnancy cohort biospecimens with an untargeted high-resolution mass spectrometry (HRMS) approach to discover possible environmental chemical exposures associated with subsequent breast cancer occurrence. Methods: Archived pregnancy samples, collected between 1959-1967, from the Child Health and Development Studies in California, one of the largest prospective pregnancy cohorts, were analyzed and searched against the Toxic Exposome Database (T3DB). The samples included 2nd (T2) and 3rd (T3) trimester archival samples of 182 women who subsequently developed breast cancer, compared to T2 and T3 samples from 384 women who did not develop breast cancer. Metabolites and environmental chemicals extracted from 50 μL aliquots of thawed pregnancy serum (n=1,148) were analyzed by HRMS with liquid chromatography followed by advanced data extraction, annotation and pathway enrichment analysis. Results: A large number of mass spectral features differed between cases and controls at p<0.05. Annotation of the discriminatory metabolites with T3DB showed increased abundance of accurate mass matches (within 5 ppm) to methylmercury and the organophosphate insecticide, tebupirimfos, in both T2 and T3 breast cancer cases compared to controls (P<0.05). Additional verification of chemical identities is ongoing. Available literature is mixed for mercury association with breast cancer; however, methylmercury has been found to stimulate proliferation of breast cancer cells in culture. Conclusions: In addition to a significant metabolic disruption, exposure to methylmercury or/and organophosphate insecticide during pregnancy is associated with subsequent breast cancer risk. Keyword: Breast cancer, environmental chemical exposure, metabolic disruption, high-resolution metabolomics, pregnancy.