Experimental Cellular Approaches to Genotype × Environment Interaction

PROJECT SUMMARY Genotype×environment interactions (GEIs) lead to interindividual differences in the response to environmental stressors that are genetically mediated (i.e., the phenotypic response to the stressor is heritable), though most medically relevant phenotypes are not simply inherited but are influenced by many genes, many environmental factors, and GEIs. Such genetic components of the human response to environmental stress are widely invoked, but relatively poorly studied. Aflatoxins, including aflatoxin B1 (AFB1), aflatoxin B2 (AFB2), aflatoxin G1 (AFG1), and aflatoxin G2 (AFG2), are produced by Aspergillus flavus and Aspergillus parasiticus (Asao et al., 1963). They commonly contaminate various agricultural products such as maize (corn), peanuts, cottonseed, tree nuts, spices, and some cereal grains (Cao et al., 2022). Many of these products help to shape the dietary environment of South Texas. AFB1 and its three variants, AFB2, AFG1 and AFG2 are all recognized as the most toxic to both human and animals, with chronic exposure through contaminated food sources being the most common cause. Aflatoxin exposure is linked to a range of adverse health effects. This project will leverage an existing human resource, the Mexican American Family Study (MAFS) from South Texas. We will use existing cryo-preserved iPSC lines from 20 MAFS participants for the generation of well-characterized hepatocytes to identify transcriptional responses influenced by AFB1 exposure. We will also quantify aflatoxins and their metabolites in the existing plasma samples of 500 MAFS participants, all with extensive genomic and phenotypic data to search for potential genotype×aflatoxin interactions influencing liver health. Our specific aims are: 1) develop an assay for the identification and quantification of aflatoxins; 2) determine the transcriptional response of aflatoxin B1 exposure in hepatocytes; and 3) obtain individual-level measures of aflatoxins and search for genotype×aflatoxin interactions influencing liver health.