Carcinogenicity Health Effects Innovation Research Program

National Institute Of Environmental Health Sciences

Investigators

Linked publications & trials

Abstract

A summary of the projects in support of the major objectives described above are included below. A. Studies to understand the environmental contributions leading to early onset colorectal cancer: The studies on early onset colorectal cancer (EO-CRC) include several projects that are aligned with the Division of Translational Toxicology (DTTs) Translational Toxicology Pipeline. This pipeline leverages data from various modalities as well as biological organization with increasing complexity, such as mining existing scientific literature to obtain actionable information and employ in silico, in vitro, and short-term in vivo methods to generate research data that provide insights into the environmental contributions related to EO-CRC. The data mining project involves bioinformatic analysis of whole genome/whole exome sequencing data from human colorectal cancers deposited in various national and international genomic data repositories, such as the TCGA, ICGC, Hartwig, and Genomics England. In addition to partnering with the Drs. Jian-liang Li and Ashley Brooks from the NIEHS bioinformatics core, we have also established national and international collaborations with research teams that are focusing on the same objective. These collaborators include Dr. Scott Kopetz from MD Anderson Cancer Center, Dr. David Adams from the Sanger Institute, UK. A manuscript summarizing this data has been submitted to JNCI Cancer Spectrum. We have derived human colonoids from human embryonic stem cells (H9) and validation of these cultures is in progress to allow for investigation of genomic landscapes resulting from various exposures implicated in the etiology of EO-CRC. We plan to compare the underlying molecular alterations in these complex in vitro cultures to the genomic alterations observed in corresponding human tumors. Some of this work is being done in collaboration with Dr. Jatin Roper at Duke University. We have established a breeding colony comprised of a rat model (Polyposis in rat colon (PIRC)) with mutated APC gene to conduct animal studies to test various environmental exposures that potentially contribute to EO-CRC. By leveraging the translational toxicology pipeline to study EO-CRC, we aim to obtain mechanistic knowledge that is actionable and translationally relevant for public health. We have recently completed a PIRC rat animal study where the animals were exposed to Western diet (30% fat) or high fructose corn syrup to examine tumor latency and multiplicity associated with these translationally relevant exposures. These data have been presented at regional and national meetings. A manuscript is under preparation and expected to be submitted in the 4th quarter of 2025. B. Investigate the etiologic role of environment in human cancers using multi-omics technologies: While the NTP is mainly known for generating high quality in vitro and in vivo mechanistic toxicity and carcinogenicity data using rodents and in vitro systems, no major efforts were directed to study tissues/fluids derived directly from human cancers to understand the influence of the environment on human cancers. As a part of this objective, Carci-HEI has three projects aimed at generating multi-omics data from human cancers. Project #1: DODSR proteomics/miRNA project to understand the mechanisms and identify predictive biomarkers related to breast cancer and potential exposures related to deployment in military personnel. This work is being done in collaboration with Dr. Craig Shriver from the Murtha Cancer Center; Dr. Kangmin Zhu from the Uniformed Services University of the Health Sciences and the metabolomics core at the Pacific Northwest National Labs. Metabolomics testing is currently in progress on 2100 serum samples (700 cases and 1400 controls). Project #2: DODSR proteomics/miRNA project to understand the mechanisms and identify predictive biomarkers related to early onset-colorectal cancer in military service members. Testing is currently in progress on 1200 serum samples (600 cases and 600 controls). Canopy biosciences (Bruker) is assessing miRNA alterations, Texas A&M University and University of North Carolina at Chapel Hill are assessing the exposomics/metabolomics alterations. Project #3: Whole exome sequencing of human tumors from the Agent Orange tumor registry to decipher exposure-specific mutation signatures. This work is a collaboration between the DTT and the Joint Pathology Center (Drs. Joel Moncur and Michael Lewin-Smith). This pilot next generation sequencing project was completed successfully and the data support expanding the study with additional samples from the registry. Project #4: Whole exome sequencing of renal cell carcinomas and other tumors from Camp Lejeune/Camp Pendleton to identify exposure specific mutation signatures: Tumors from Camp Lejeune are suspected to result from ground water contamination while tumors from Camp Pendleton have no known environmental exposures. A reassessment of the cancer incidences in the service members associated with both the marine bases are in progress. This project is a collaboration with the Veterans Affairs (Drs. Jeffrey Smith, Julie Lynch, and Michael Kelley). C. Evaluation of the genomic and epigenomic alterations in chemical carcinogenesis studies using in vitro and in vivo models: We have recently completed a multi-omics study on mouse hepatocellular carcinomas (HCCs) resulting from chronic exposure to various genotoxic and non-genotoxic carcinogens. The manuscripts summarizing these data are currently under progress. A paper summarizing whole exome sequencing of mouse hepatocellular carcinomas has been recently published (Xu et al., 2025). We have generated similar data from rodent tumors from recent NTP bioassays, examples include tris(Chloropropyl)phosphate (mouse HCCs), and alpha-pinene (mouse HCCs and alveolar/bronchiolar carcinomas and rat mammary fibroadenomas and mammary adenocarcinomas). In addition to these studies, several omics studies are in progress in collaboration with various national and international partners. The DTT has a long-standing collaboration with Dr. Daniele Mandrioli, Ramazzini Institute, Italy as well as Dr. David Adams, Sanger Institute, UK. An important goal of these collaborations is to understand the mutation signatures of rodent tumors resulting from chronic exposures to known and probable human carcinogens that may operate through a genotoxic and/or non-genotoxic mode of action. These rodent cancer -omics data will be compared to the -omics data from the corresponding chemical exposures implicated in human cancers, such as vinyl chloride, benzene, trichloroethylene, etc., to establish the translational relevance of these exposures in human cancers. Whole exome data from rat tumors resulting from exposure to Vinyl chloride has been generated and the bioinformatics analysis is in progress. In addition, the rodent specific cancer driver gene information will be used to generate targeted duplex sequencing panel to screen non-tumor tissues from short term animal studies to predict a potential carcinogenic response.