Long-term effects of developmental exposure to a mixture of thyroid disruptors associated with hydrofracking on T cell development and antimicrobial immunity

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This exploratory research proposal addresses growing concerns about the threats of endocrine disruptor (EDC) water pollutants released during unconventional oil and gas extraction (UOG) to human health. Specifically, these studies focus on how a mixture of 4 UOG chemicals with thyroid hormone (TH) disrupting activity affect the immune system, for which there is no systematic assessment to date. We have developed a reliable, sensitive and cost-effective model system in the amphibian Xenopus that is uniquely suited to investigate the effects of early life exposure to waterborne mixtures of UOG toxicants on immunity later in life. We propose a comparative biology approach in Xenopus to define how postembryonic exposure to a representative mixture of UOG water contaminants with TH activity impacts T cell development and weaken antimicrobial immune response later in life. Our rationale is that (1) a mixture of several EDCs acting toward one hormone axis will allow us to address cellular mechanism leading to acute and persistent effects of this mixture of chemicals on T cell development and function; (2) Although TH axis affects the immune system, little is still known about the long-term biological impacts of TH disruptors on immunity; and (3) Xenopus is a reliable, extensively characterized and widely recognized model of human perinatal endocrinology and biomedical research on the TH axis, including dependence of TH signaling for the differentiation of adult-type T cell immunity during metamorphosis. Other features advantageous for achieving our goal are the external development of tadpoles, which are free of maternal influence and easily accessible to exposure during postembryonic development, and the cost effectiveness of exposing tadpoles in large numbers to EDCs. To test the hypothesis that developmental exposure to a mixture of TH-disruptors associated with UOG alters T cell development, resulting in long-term perturbation of immune homeostasis and poorer antimicrobial immunity, we will determine: (1) acute effects of UOG-EDCs on tadpole T cell differentiation and immune homeostasis , by defining the impact of tadpole exposure on homeostatic lymphocyte populations using flow cytometry, histology and transcriptomics; (2) long-term effects on immune homeostasis and anti-microbial immunity of developmental exposure to a mixture of TH-disruptors persisting after metamorphosis , by measuring changes at steady state and in response to the ranavirus FV3 (similar to poxviruses such as vaccinia, a strong CD8 T cell inducer) and Mycobacterium marinum (a pathogen of frogs and humans, a strong CD4 T cell inducer); and (3) TH-disruptor activity of each of the 4 UOG-EDC alone and their potential additive and synergistic actions. Innovative convergent findings from infection with two different types of pathogens (pox-like FV3 and Mycobacteria) in Xenopus whose TH axis and immune system are remarkably conserved with those of mammals will provide novel and compelling evidence regarding effects of UOG-EDCs on the immune system function relevant to human health.