Environmental Programming of Insulin Resistance

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ABSTRACT The goal of this K22 Career Development Award is to facilitate the path to independence to Dr. Veiga-Lopez, an environmental endocrinologist, and provide with the means towards her long-term goal; become a leader in the field of environmental developmental programming. The short-term goals of this proposal are to acquire the necessary training, mentoring, and skills in the following areas: 1) oxidative stress / mitochondrial function methods, 2) inflammatory pathways, and 3) state of the art genomics and systems biology approaches. For that, a detailed Career Development Plan (CDP) has been developed with Dr. Norbert Kaminski, Sponsor of the current proposal and expert in immune-toxicology, and a multidisciplinary team of investigators that are members of the Advisory Committee. The CDP includes course work, workshops, seminars, and conferences, and meetings with the Sponsor and Advisory Committee, which along with the Research Plan will enable the candidate to successfully generate preliminary data for a competitive R01 application within 3 years of the K22 award. To that effect, as a new Assistant Professor at Michigan State University, the candidate has the necessary facilities to develop a strong research program focusing on environmental research. In 2012, the American Diabetes Association estimated that 22.3 million Americans were diagnosed with diabetes. Insulin resistance is one of the early signs in the pathophysiology of type 2 diabetes. Staggering numbers in type 2 diabetes cases over the past decades may relate to environmental exposures. Recent evidence suggests an association between exposure to the endocrine disruptor bisphenol A (BPA) and insulin resistance in humans. Animal studies further supports this evidence. However, the mechanisms by which BPA may induce such disruptions remain unknown. The central hypothesis of this proposal is that prenatal exposure to BPA leads to changes in microRNAs responsible for increased oxidative stress, pro-inflammatory state, and intracellular energy pathways dysfunction leading to the onset of insulin resistance, the first step in the development of type 2 diabetes. This hypothesis aligns with the first goal in the 2012-2017 NIEHS Strategic Plan: “Identify and understand fundamental shared mechanisms…, e.g., inflammation, epigenetic changes, oxidative stress, mutagenesis, etc., underlying a broad range of complex diseases, in order to enable the development of applicable prevention and intervention strategies”. This proposal will examine the underlying mechanisms by which BPA can induce tissue specific oxidative stress and inflammation via changes in miRNAs during prenatal life, using a large animal model. In vitro approaches will also be used to investigate if BPA leads to disruption in intracellular energy pathways triggering the onset of oxidative stress and contributing to the development of insulin resistance. Understanding the underlying mechanisms by which a ubiquitous endocrine disruptor such as BPA, induces these disruptions will enable prevention strategies during one of the most vulnerable periods of exposure - early fetal development.