Theses and Dissertations

Issuing Body

Mississippi State University

Advisor

Howell III, George E.

Committee Member

Chambers, Janice E.

Committee Member

Ross, Matthew K.

Committee Member

Pruett, Stephen B.

Committee Member

Carr, Russell L.

Date of Degree

11-25-2020

Document Type

Dissertation - Open Access

Major

Environmental Toxicology

Degree Name

Doctor of Philosophy

College

College of Veterinary Medicine

Department

Environmental Toxicology Program

Abstract

Obesity is a prevalent disease in which, when compared to individuals of normal weight, obese individuals have noted pathophysiological alterations including increased adiposity and fat mass which may alter toxicokinetics of xenobiotics and therefore alter their toxicities. However, the effects of obesity and the altered pathophysiology accompanying this condition on the toxicity of many widely utilized pesticides have not been established. Organophosphate (OP) pesiticides, including chlorpyrifos (CPS), have historically been widely used for agricultural purposes. CPS and several other notable OPs are no longer registered for household use but still used mainly in agriculture by registered users. CPS is bioactivated to form chlorpyrifos-oxon (CPO) in liver by cytochrome P450 isozymes. Acute toxicity of CPS exposure is inhibition of acetylcholinesterase (AChE) in the central and peripheral nervous systems. The other targets following CPS exposure are the noncholinergic serine hydrolase enzymes: carboxylesterase (CES), fatty acid amide hydrolase (FAAH), and monoacylglycerol lipase (MAGL). Therefore the current study was designed to: 1) determine the time and concentration-dependent effects of CPS on noncholinergic endpoints of OP toxicity utilizing hepatoma cells under normal and steatotic conditions 2) determine if obese phenotype altered the toxicity of CPS, including both cholinergic and non-cholinergic endpoints and 3) determine the effects of high fat diet on CPS bioaccumulation and detoxication by determining CPS and 3,5,6-trichloro-2-pyridinol (TCP) levels at different time points. The current in vitro studies determined that CES is more sensitive to CPS mediated inhibition in normal and steatotic conditions compared to FAAH and MAGL. The in vivo studies determined that CPS (2 mg/kg) exposure produced a greater inhibitory effect on hepatic CES and FAAH in obese animals compared to lean animals which indicates that the obese animals may be at greater risk for CPS mediated alterations in hepatic lipid metabolism upon chronic exposure. Our toxicokinetic studies using a higher dose of CPS (25 mg/kg) did not inhibit AChE in CNS and did not alter the overall CPS levels between normal and obese animals. Peak levels of TCP were decreased in liver of obese animals at 3 hours and overall hepatic TCP levels were significantly decreased in obese animals.

URI

https://hdl.handle.net/11668/20885

Sponsorship

Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University.

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