Semester

Spring

Date of Graduation

2022

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Grazyna D. Szklarz

Committee Co-Chair

Jeffrey S. Fedan

Committee Member

John Hollander

Committee Member

Tim Nurkiewicz

Committee Member

Vince Castranova

Committee Member

Dale Porter

Abstract

The exposome encompasses the concept that an individual’s health is a combination of genetic, environmental, and occupational exposures. A worker’s exposomal profile could potentially influence their susceptibility to hazardous occupational exposures. Over 35% of adults in the United States have metabolic dysfunction (MetDys), yet interactions between MetDys and hazardous occupational exposures are generally unknown. MetDys is associated with HFWD-consumption and obesity and induces a chronic low grade systemic inflammation and alters serum adipokine profiles. Silicosis, a progressive inflammatory lung disease, results from occupational inhalation exposure to respirable crystalline silica particles. This research tests the hypothesis “Inflammation resulting from HFWD-induced MetDys increases silica-induced lung injury and impairment”. Simply stated, at its end, this research will have demonstrated that HFWD-induced MetDys is an exposomal risk factor for increased susceptibility to silicosis.

In our pilot study, a HFWD-induced MetDys F344 animal model was characterized. Six-wk old male Fischer rats (F344/DuCrl) were fed a HFWD (45 kcal % fat, sucrose 22.2 % by weight) or standard rat chow (STD, control) for 16 wk. HFWD-induced MetDys was confirmed after 16 wk of HFWD consumption indicated by body and epididymal fat pad weight gain, elevated fasting glucose, increased serum insulin and leptin levels, and altered blood BUN/Creatine, amylase, and high-density lipoprotein levels. For the combined exposure study, six-wk old male Fischer rats were fed a HFWD (45 kcal % fat, sucrose 22.2% by weight) or standard rat chow (STD, controls) for 16 wk, and then subsequently exposed to silica (6 h/d, 5 d/wk, 39 d; Min-U-Sil 5®, 15 mg/m3) or filtered air. Repeated measures of body weight, fasting blood glucose and tail artery laser doppler flowmetry were taken every 2 wk; endpoint measures to determine changes in pulmonary inflammation and fibrosis, peripheral vascular function, and metabolic and blood chemistry indices were made at 0, 4 and 8 wk. Animals remained on their assigned diet for the duration of this study.

The most significant findings of this study were that HFWD-consumption exacerbated pulmonary inflammation and fibrosis at 8 wk, increased BAL cells and LDH, and altered arterial pulse compared to STD+silica exposed groups. HFWD+silica exposure also reduced serum proinflammatory cytokine levels at 8 wk compared to HFWD+air, but levels were still greater than STD+silica and control groups. Silica-inhalation (STD+silica) resulted in progressive pulmonary inflammation and fibrosis, increased arterial pulse over time from preexposure to 8 wk, but produced no differences in obesity measures or blood chemistry. At 8 wk, silica exposure reduced serum leptin and adiponectin levels, and reduced serum proinflammatory cytokine levels regardless of diet compared to air control. In the lung, HFWD-consumption (HFWD+air) increased the number of BAL cells and proinflammatory cytokine levels (KC/GRO, IL-6, and IL-5) compared to STD+air but did not result in pulmonary injury. HFWD-consumption induced MetDys confirmed by body and epidydimal fat pad weight gain, increased serum proinflammatory cytokine levels, altered serum adipokines levels, blood lipid, and blood chemistry panel, and increased arterial pulse over time from preexposure to 0 wk.

In conclusion, HFWD-consumption exacerbates silica-induced pulmonary inflammation and fibrosis and alters arterial function responses in the F344 rat. In addition, silica inhalation has been identified as an adipose endocrine disrupter. These studies demonstrate HFWD-consumption increases susceptibility to silica-induced effects in the F344 rat, and, therefore, further investigation in necessary to determine whether HFWD-consumption is an exposomal risk factor for increased susceptibility to silica-induced disease in silica-exposed workers. Reminiscent of the World Trade Center first responder studies where MetDys biomarkers were indicative of increased risk for severe lung injury, further investigation of the interactions between MetDys and crystalline silica inhalation are warranted. Identification of exposomal risk factors within the various subpopulations of American workers are needed to ensure worker protection, safety, and health.

Embargo Reason

Patent Pending

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