Guo-Xiang Yang, MD, PhD – Department of Internal Medicine

Role of Environmental Chemicals in the Pathogenesis of Autoimmune Disease Although it is well known that environmental pollution poses significant health hazards, data on the environment and human autoimmunity are limited. This study will examine the effects of a group of well-defined environmental pollutants on the immune functions of patients with systemic lupus erythematosus (SLE), a classical, systemic autoimmune disease. Data from this work will enhance our understanding on how chemical pollutants contribute to the development of SLE and provide insights on the etiology and clinical management of environmental-triggered autoimmune disease.

Zeljka Smit-McBride, PhD – Ophthalmology and Vision Science

Dysregulation of MicroRNAs in Ocular Tissue Exposed to Cigarette Smoke Age-related macular degeneration (AMD), a blinding disease having both genetic and environmental components, is the most common form of visual impairment in elderly individuals of the Western world, and smoking is the leading identified associated environmental insult. Recently, a central regulatory role for a novel type of molecule, microRNA (miRNA), had been discovered in many human diseases. MiRNAs are considered to be master regulatory switches, playing roles in stem cell differentiation, aging, epigenetics, etc. Although knowledge about miRNAs and their functions is rapidly accumulating, their roles in healthy ocular aging vs. age-related pathologies in the eye is lacking. Our long-term goal is to elucidate the regulatory role of miRNAs in the eye during normal aging and disease. The goal of this project is to address how circulatory miRNA populations change during normal eye aging, and how that process is accelerated and dysregulated during heightened level of environmental insult such as chronic exposure to cigarette smoke. Our central hypothesis is that normal age-related homeostatic processes whose failure causes/allows the transition from healthy aging to disease are regulated by miRNAs. We will determine which miRNAs show aging-related change of expression using a

Carolyn Slupsky, PhD – Department of Nutrition

Maternal Metabolome, PON1 Status, Organophosphate Exposure and Childhood Autism With the rapid rise in autism spectrum disorder (ASD) diagnoses over the last three decades, identification of the causes and mechanisms of this condition is urgently needed. Building on recent findings that children prenatally exposed to pesticides have an increased risk of an ASD diagnosis, serum from children was previously analyzed. A distinct metabolic pattern was found in children with ASD who were exposed to pesticides in utero that revealed associations with insulin regulation. Given the correlation between insulin resistance and decreased activity of paraoxonase 1 (or PON1, an enzyme involved in detoxification), we hypothesize that exposure to pesticides during pregnancy coupled with reduced maternal PON1 activity is associated with the metabolic health of the mother and the neurological outcome and metabolic health of her child. Most of the evidence about environmental factors in autism provides sparse information about the biologic mechanisms of neurodevelopment. This project seeks to generate preliminary data on perturbations in basic biochemical pathways and reduced PON1 status as a consequence of pesticide exposure, and its association with autism in children.

Colin Reardon, PhD – Department of Anatomy, Physiology and Cell Biology

Postnatal Neuroimmune Integration of Environmental Stresses Over the last 40 years, epidemiological studies have shown a disturbing trend of increasing incidence of allergic asthma in children. A wide range of stressors in the womb or during early life can increase the risk of developing allergic childhood asthma. Given the broad spectrum of stressors, it is likely that numerous systems in the body (i.e., the nervous and immune systems) contribute to the observed increase in allergic childhood asthma. Specialized tissues in the body serve to coordinate immune responses and are required for the development of allergic asthma. These tissues are still developing in the lung during early life and receive signals from various systems that control body functions. We hypothesize that the developing tracheal- and bronchial-associated mediastinal lymph nodes are critical sites where environmental exposures change normal development and set the stage for allergic asthma. The stages of development in humans and other primates is not clear; this study will first examine normal development and the consequences of environmental exposures on immune cells.

Stuart Meyers, DVM, PhD – Anatomy, Physiology and Cell Biology

Environmental Oxidants and the Aging Male: Sperm Function and Embryo Development Age-dependent accumulation of testicular oxidative insult very likely leads to declining sperm function and fertility, cellular damage to spermatogenic stem cells, inefficiency of sperm production, inefficient mitochondrial metabolism, and mutations in nuclear and mitochondrial DNA. Paternal age has been associated with a number of diseases that have mitochondrial etiologies or components, including autism spectrum disorder, schizophrenia and bipolar disorder. We hypothesize that environmental toxins that cause oxidative insult to the testis contribute to these effects. We propose studies that will utilize a highly relevant model of human reproductive health — the rhesus macaque — that will encompass testicular endocrine health, sperm function and embryo development to assess immediate post-fertilization and developmental landmarks in rhesus embryos. We will expose monkey sperm in vitro with known oxidants and assess sperm function as a necessary first step. With pilot project funding, we propose a comprehensive study to determine specific effects on testicular and gamete health from exposures to environmental toxins, including ozone, forest fire/tobacco smoke and other oxidants.

Melanie Gareau, PhD – Department of Anatomy, Physiology and Cell Biology

Gastrointestinal Pathophysiology Following Early Life Environmental Exposure The microbiota-gut-brain axis (MGB axis) is an important pathway for maintaining health and well-being. Disruptions in the axis have been identified in numerous disease states, including inflammatory bowel disease, diabetes and autism spectrum disorder. Early development is an important life stage for normal establishment of the microbiota, development of the gastrointestinal (GI) tract and neurobiological growth and maturation, which together modulate the MGB axis. Exposure to pathophysiological stimuli, for example neurotoxicants, during this important developmental period can have long-term consequences on overall health and well-being. We propose to study GI function following exposure to polychlorinated biphenyls (PCB) during gestation and lactation in mice. We will use samples collected from animals used in ongoing studies funded to examine cognition following developmental exposures. We hypothesize that PCB exposure during early development will lead to GI and microbiota defects. These studies will determine whether environmental exposures to potential neurotoxicants can lead to changes in GI physiology and contribute to long-lasting changes in the MGB axis.

Keith Bein, PhD – Air Quality Research Center

Facilitating Real-Time Exposure Studies on Traffic Related Air Pollution Toxicological studies continue to demonstrate causal relationship between exposures to traffic related air pollution (TRAP), including gases and particles, and various metrics of adverse pulmonary, cardiovascular and neurological health effects. The key challenge in these studies is replicating true human exposure in models that mimic human biology on accelerated time scales with sufficient resolution in physiological and/or behavioral response to demonstrate statistical significance. A core need is an exposure paradigm that addresses these issues in a robust and dependable manner. It is hypothesized that a roadway tunnel system provides a platform that maximizes signal-to-noise ratio and minimizes bias by allowing for real-time exposure to concentrated ambient TRAP. The objective of this project is to design, construct, implement and characterize a mobile vivarium. The expected outcome from this project is a facility that will reliably and accurately assess the health effects of exposure to TRAP. Concomitant with this facility will be core services providing full physical and chemical characterization of the exposure environment.