Date of Award

2024

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Sue M Ford

Second Advisor

Louis Trombetta

Third Advisor

Raymond Ochs

Abstract

Due to the rising occurrence of diabetes in the population and the prevalence of OTA exposure via ingestion of contaminated foodstuffs, there is a need to assess the possible renal interaction of a diabetic disease state in concurrence with OTA exposure. Sprague Dawley rats were treated with streptozotocin to induce experimental diabetes and then orally exposed to 0.5 mg/kg body weight OTA once a day for 21 days. Renal biomarkers and light microscopy were evaluated to assess the interaction between diabetic nephropathy and OTA exposure. LLC-PK1 proximal tubule cells were used as an in vitro model to assess the potential mechanism involved in this interaction. Numerical data were analyzed with t-test or ANOVA with Tukey’s post-hoc. All indications of significance were at p < 0.05. Histopathological findings of diabetic animals treated with OTA showed increased inflammation, tubular degeneration, glomerular degeneration, interstitial fibrosis, necrosis and cast formation. Classic and novel biomarker assessment indicated that the interaction between DN and OTA exposure exacerbated renal damage and significant tubular damage. These assessments support that the interaction between diabetic nephropathy and OTA exposure exacerbated renal damage and inflammation. The LLC-PK1 porcine proximal tubule cell line was used to assess the interaction of glucose levels and OTA exposure on cell viability. LC50 of the high glucose groups (17.5 mM glucose, 30 mM glucose, and 5 mM/30 mM glucose) were significantly lower from that of the 5 mM group indicating enhanced toxicity of OTA. The effects of the combination treatment (STZ/OTA) were greater than for animals exposed to either treatment alone. These findings were supported by biomarker profiles which reveal greater effects on serum creatinine, serum protein, KIM-1, and NGAL in the STZ/OTA-treated animals compared to those treated with STZ or OTA alone. These results indicate that exposure to environmental mycotoxins such as OTA may represent an increased risk to diabetics compared to non-diabetic individuals. The demonstration that kidney cells grown in high glucose media were more sensitive to OTA suggests that increased glucose levels of plasma and/or urine may contribute directly to such interactive toxicity of diabetes and OTA exposure.

Download

Included in

Toxicology Commons

Share

COinS