Abstract IA11: Timing of environmental contributions to cancer in a multigenerational cohort
Authors: Cohn Barbara A. 
Published: June 2022

Abstract
Transdisciplinary studies of environmental risk factors for cancer can discover paths to prevention. Using breast cancer as a case study, we review findings on the relation of a ubiquitous legacy environmental chemical, DDT, to breast cancer in three generations in the Child Health and Development Studies cohort. Although banned in the U.S. and in many places worldwide in the 1970s, the DDT story illustrates the potential role of legacy environmental chemicals in current cancer etiology. We demonstrate the importance of accounting for windows of susceptibility and induction time to cancer and provide evidence for multigenerational and transgenerational effects relevant to breast cancer risk in current generations. Findings provide proof of concept that the current environment may have lasting effects 60 years in the future. Findings support prudent management of current environmental exposures with known biologic toxicity. Waiting 60 years to understand human effects is too late to protect the public health and prevent cancer. The Child Health and Development Studies (CHDS) is a 60-year, prospective follow-up of 20,000 pregnancies that occurred in the 1960s and the resultant generations. The CHDS provides unique and valuable data to characterize how pregnancy and in utero exposures and responses contribute to disease risk in multiple generations. Maternal perinatal blood samples simultaneously provide the opportunity to measure the pregnancy exposome for Generation 1 mothers, the in utero exposome for Generation 2, and the germline exposome for Generation 3. In the CHDS we are also able to study the grandpaternal exposome in relation to granddaughters’ breast cancer risk factors, a design that estimates transgenerational effects via the paternal line. CHDS generations are tracked for place of residence, cancer risk factors, and cancer incidence to provide high quality of evidence avoiding errors of recall and accurate exposure assessment. We review breast cancer findings for Generation 1 (cohort mothers), Generation 2 (cohort daughters), and Generation 3 (cohort granddaughters). We describe perinatal DDT associations with breast cancer in mothers and daughters, with breast density in daughters, and with breast cancer risk factors in granddaughters. We show the results of next steps to uncover mechanisms, including DNA methylation patterns in breast cancer-related genes in the daughters’ generation associated with in utero DDT exposure, and the correlation of the maternal metabolome with DDT in mothers. We also compare the human, observational metabolomics data in maternal perinatal serum with parallel data from controlled experimental studies in mice designed to replicate the DDT dose and perinatal exposure in our human cohort. Along with DDT, we show findings on the relation of in utero exposure to PFASs, a class of chemicals of current concern that were also present in the 1960s. Along with grandmaternal associations, we also show early findings on some grandpaternal variables that are independently correlated with granddaughter breast cancer risk factors. We highlight findings based on high-resolution metabolomics data and exposome analyses in conjunction with epidemiologic data. These metabolomics data serve as important molecular footprints that result from gene and environmental interactions. We employ novel computational and statistical approaches to facilitate the interpretation of these high-dimensional data and integrative analysis, draw insights on the biologic effects of DDT and PFASs compounds, and explore the implication of findings on risk for breast cancer.
Citation Format: Barbara A. Cohn. Timing of environmental contributions to cancer in a multigenerational cohort [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA11.