Grantee Research Project Results
Assessment of Underlying Molecular Mechanisms Promoting Adipogenic Outcomes in Complex Mixtures
EPA Grant Number: R840459Title: Assessment of Underlying Molecular Mechanisms Promoting Adipogenic Outcomes in Complex Mixtures
Investigators: Kassotis, Christopher Dennis , Ghosh, Samiran
Current Investigators: Kassotis, Christopher Dennis , Korzeniewski, Steven
Institution: Wayne State University
EPA Project Officer: Aja, Hayley
Project Period: September 1, 2022 through May 12, 2025
Project Amount: $598,487
RFA: Development of Innovative Approaches to Assess the Toxicity of Chemical Mixtures Request for Applications (RFA) (2022) RFA Text | Recipients Lists
Research Category: CSS , Chemical Safety for Sustainability , Early Career Awards , Endocrine Disruptors , Health Effects , Human Health , Mixtures , New Approach Methods (NAMs) , Non-Vertebrate Animal Testing , Safer Chemicals
Description:
This proposal will directly interrogate the comparability of joint toxicity as well as the development of methods focused across several levels of biological organization.
Objective:
The objectives are to evaluate mixtures of increasing complexity for ability to promote fat cell development (adipogenesis). Specifically, this project will examine mixtures of increasing complexity for their deviations from expected adipogenic effects using concentration addition and independent action models. Researchers hypothesize that mixtures of increasing complexity will shift towards independent action, but that the most complex mixtures will not be well predicted by either model. The research team will also develop an effect-based model to predict adipogenic activity based on component bioactivities, which they hypothesize will provide a chemical agnostic approach to risk assessments of environmental mixtures.
Approach:
The proposed research will rigorously assess available mixture models through controlled assessments of contaminants predicted to promote adipogenesis through shared, distinct, and mixed molecular mechanisms (selected through in silico approach). The research team will use in vitro and in vivo models of metabolic health disruption to assess both individual chemicals and their mixtures and will then compare these responses with predicted outcomes based on concentration addition and independent action models. Lastly, researchers will utilize environmental samples (household dust) to develop a receptor bioactivity component model to predict adipogenic outcomes.
Expected Results:
The results will promote a greater functional understanding of complex mixture effects that can be utilized to bolster risk assessments of diverse contaminant exposures. By using this stepwise approach of increasing mixture complexity, researchers expect a primary output of clearly describing the weaknesses and strengths of these standard mixture models. Through testing of dust extracts, the research team expects that they can support a new method of mixture risk assessments through using component mechanistic effect levels to determine cooperative effects on complex health endpoints and/or outcomes.
Supplemental Keywords:
Adipocyte; Metabolic Health; Obesogen; Mixture; Dust; Chemicals; Organics; Cumulative Effects; Organism; Cellular; Animal; ZebrafishProgress and Final Reports:
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.