Stress Drivers of Glucose Dynamics during Ozone Exposure Measured Using Radiotelemetry in Rats

Stress-related neurobehavioral and metabolic disorders are associated with altered circulating adrenal-derived hormones and hyperglycemia. Temporal assessment of glucose and these hormones is critical for insights on an individual’s health. Here we use implantable-telemetry in rats to assess real-time changes in circulating glucose during and after exposure to the air pollutant ozone, and link responses to circulating neuroendocrine stress and metabolic hormones. Rodent glucose and corticosterone (cortisol in humans) responses were compared to humans exposed to ozone. First, using a cross-over design, glucose levels were monitored during single or repeated ozone exposures (0.0, 0.2, 0.4 and 0.8-ppm) and non-exposure periods in male Wistar-Kyoto-rats implanted with glucose-telemeters. Ozone (0.8-ppm) caused hyperglycemia and hypothermia beginning 90-min into exposure, with reversal of effects 4-6 hours post-exposure. Glucose monitoring during four daily 4-hour ozone exposures revealed duration of hyperglycemia, adaptation, and diurnal variations. A second cohort of un-implanted rats was exposed to ozone (0.0, 0.4 or 0.8-ppm) for 30-min, 1-hour, 2-hour, or 4-hour with hormones measured immediately afterwards. Ozone-induced hyperglycemia was preceded by increased adrenocorticotropic hormone, corticosterone, and epinephrine, but depletion of thyroid-stimulating, prolactin, and luteinizing hormones. There was coherence among rats and humans in ozone-induced corticosterone/cortisol increases. Using adrenalectomy and pharmacological interventions of adrenergic and glucocorticoid receptors, we demonstrated a causal link between hyperglycemia and adrenal-derived hormones. These findings revealed for the first time the neuroendocrine-stress-mediated pathological sequalae responsible for ozone-induced metabolic dysfunction as exposure occurs. Real-time glucose monitoring with stress hormones assessment may be useful in identifying interactions among pollutants and stress-related illnesses.

Impact/Purpose

Environmental exposures are linked to neuropsychiatric and cardiometabolic diseases. Individuals with these diseases have altered dynamics of circulating adrenal-derived stress hormones and glucose. The assessment of stress dynamic by measuring circulating glucose and cortisol can provide insights into causality, chronicity, and host vulnerability. Here we demonstrate the use of real-time continuous glucose monitoring for determining inhaled ozone-induced stress linked to increased circulating corticosterone and epinephrine in a rat model. Through interventional approaches, we provide causal evidence linking circulating stress hormones and ozone-induced hyperglycemia. We demonstrate similar ozone-induced increases in cortisol in humans. Since real-time glucose and cortisol monitoring is employed for patients with diabetes and anxiety disorders, we propose this approach for broader application in air-pollution research and disease susceptibility.

Citation

Henriquez, A., S. Snow, T. Jackson, J. House, A. Motsinger-Reif, C. Ward-Caviness, Mette C. Schladweiler, D. Aelwel, C. Miller, A. Farraj, M. Hazari, R. Grindstaff, D. Diaz-Sanchez, A. Ghio, AND U. Kodavanti. Stress Drivers of Glucose Dynamics during Ozone Exposure Measured Using Radiotelemetry in Rats. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, 130(2):127006, (2022). [DOI: 10.1289/EHP11088]

DOI: Stress Drivers of Glucose Dynamics during Ozone Exposure Measured Using Radiotelemetry in Rats