Instrumenting phenotypic immunological responses to toxicants that threaten human reproduction

EPA Grant Number: R839501
Title: Instrumenting phenotypic immunological responses to toxicants that threaten human reproduction
Investigators: Osteen, Kevin G , Bruner-Tran, Kaylon L. , Cliffel, David , McLean, John
Institution: Vanderbilt University Medical Center , Vanderbilt University
EPA Project Officer: Lasat, Mitch
Project Period: August 1, 2019 through July 31, 2022
Project Amount: $848,923
RFA: Advancing Actionable Alternatives to Vertebrate Animal Testing for Chemical Safety Assessment (2018) RFA Text |  Recipients Lists
Research Category: Safer Chemicals

Description:

Traditional human reproductive health risk assessments associated with chemical exposures do not consider the potential contribution of a preexisting disease. Furthermore, the dual goals of advancing chemical safety and reducing the use of vertebrate animals require a robust, human-cell based test system. We propose to refine our microfluidic model of the human menstrual cycle, the EndoChip, to both replace the need for vertebrate animal models and to better consider the role of preexisting disease in risk assessment.

Objective:

We will test the hypothesis that a preexsisting inflammatory disease will alter sensitivity to an environmental toxicant exposure.

Approach:

We have extensive experimental evidence, obtained using a vertebrate animal model, that developmental toxicant exposure can alter adult reproductive capacity. Based on knowledge from these studies, we will utilize the EndoChip model to examine how a preexisting inflammatory disease affects cellular response(s) to an environmental toxicant. Similarly, we will examine the impact of toxicant exposure on the subsequent endometrial response to an inflammatory challenge. Importantly, the disease-toxicant interactions in EndoChips will utilize cell-type specific biosensors combined with advanced metablomic analysis via IM-MS. Finally, we will perform Case Studies to assess the EndoChip as an alternative to vertebrate animal testing to identify reproductive toxicants.

Expected Results:

It is significant that the human endometrium is the only adult tissue that routinely undergoes a development-like process. Thus, our proposed EndoChip is expected to provide a robust and reproducible human cell-based model that mirrors the functional physiology of the reproductive tract. Use of the EndoChip will enable accurate identification of environmental chemical-disease interactions that represent a threat to human reproduction. Furthermore, the EndoChip is expected to dramatically reduce the reliance on vertebrate animal modeling for similar endpoints.

Supplemental Keywords:

Dioxin, Reproductive Toxicology, Susceptibility, Bioengeneering