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Exploration of the Role of Organophosphates in Depression by Epidemiological, Biochemical, Behavioral, and Epigenetic Means /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Exploration of the Role of Organophosphates in Depression by Epidemiological, Biochemical, Behavioral, and Epigenetic Means // Alyssa Rose Daniel.
Author:	Daniel, Alyssa Rose,
Description:	1 electronic resource (141 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
Contained By:	Dissertations Abstracts International86-12B.
Subject:	Toxicology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31931332
ISBN:	9798286433841

Exploration of the Role of Organophosphates in Depression by Epidemiological, Biochemical, Behavioral, and Epigenetic Means /
Daniel, Alyssa Rose,

Exploration of the Role of Organophosphates in Depression by Epidemiological, Biochemical, Behavioral, and Epigenetic Means /Alyssa Rose Daniel. - 1 electronic resource (141 pages)

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

Pesticides, specifically organophosphates (OPs) such as chlorpyrifos (CPF), have been widely known to cause adverse health outcomes. It has been shown that environmental toxins such as OPs are associated with psychiatric and neurological outcomes such as neurodevelopmental problems, behavioral deficits, depression, and suicide.Epidemiological analyses have previously shown that agricultural workers are at increased risk for depression, and research suggests that environmental exposures, particularly to pesticides, may be on the causal pathway of depression. Neurotoxic OP pesticides have been previously linked to psychiatric disorders including major depressive disorder. Although OPs have been associated with depression diagnosis, mechanistic understanding is lacking. We hypothesize that the chronic mechanism of OP exposure leads to depressive symptoms in agricultural populations and is epigenetic in nature, mediated by interactions between environmental factors and DNA. In this dissertation, incidence of depressive symptoms associated with OP exposure is explored by epidemiological, biochemical, and behavioral analyses, and DNA methylation (DNAm) is explored as a sub-chronic mechanism of toxicity.The first goal of this dissertation was to use ordinal logistic regression modeling to analyze epidemiological data from male pesticide applicators enrolled in the Agricultural Health Study (AHS) to estimate the effect of OP intensity on the severity of depressive symptoms. The second goal was to assess a mouse model of sub-chronic CPF exposure through biochemical and behavioral means and assess DNAm as a potential epigenetic mechanism of toxicity. After 21-day sub-chronic exposure, behavior was observed via the Open Field Test, Tail Suspension Test, Forced Swim Test, and Sucrose Preference Test. DNAm was then measured in hippocampal DNA using mouse methylation array technology and, finally, Gene Set Enrichment Analysis (GSEA) was used to determine which pathways may be implicated in CPF-induced behavioral effects.The long-term goal of this research is to identify those at risk for depression and to reduce environmental exposure to OPs to protect the mental health of those who may be exposed. The overall objective is to identify the chemical impact of OPs on populations at risk for depression at both the biological and the population level. The central hypotheses were that 1) participants exposed to OPs in the AHS would have an increased risk for depressive symptoms with increasing OP intensity 2) CPF exposure would lead to depressive-like behavior and differential DNAm in a dose-dependent manner, highlighting DNAm as a possible sub-chronic mechanism of toxicity.Results showed that high-intensity exposure to each of the OPs diazinon, dichlorvos, and parathion, was associated with more severe depressive symptoms in the AHS, indicating a dose-specific effect on behavior in male pesticide applicators. Increased risk for mild but not severe symptoms was observed with high exposure to malathion and CPF. Ultimately, the epidemiological work presented here suggests increased risk for depressive symptoms after OP exposure in an occupational cohort. Our mouse model showed that after CPF exposure at occupationally relevant levels, enzymatic activity was recovered in females at low exposure, but not among male or female mice with high exposure. Behavioral changes in distance traveled over time were observed among treated mice and could indicate cognitive function or habituation differences, but no depressive-like behavior was observed at this timepoint. Significant differential DNAm was observed at 3,538 CpG sites, and GSEA showed that the mitogen-activated protein kinase (MAPK) pathway was the most enriched, suggesting that the inflammatory response may be implicated in the differences observed between treatment vs. control mice.Overall, the work presented in this dissertation has resulted in expanded epidemiological, chemical, behavioral, and epigenetic knowledge surrounding depressive-like behaviors related to long-term OP exposure.

English

ISBN: 9798286433841Subjects--Topical Terms:

556884
Toxicology.
Subjects--Index Terms:

Chlorpyrifos

Exploration of the Role of Organophosphates in Depression by Epidemiological, Biochemical, Behavioral, and Epigenetic Means /
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520 $a Pesticides, specifically organophosphates (OPs) such as chlorpyrifos (CPF), have been widely known to cause adverse health outcomes. It has been shown that environmental toxins such as OPs are associated with psychiatric and neurological outcomes such as neurodevelopmental problems, behavioral deficits, depression, and suicide.Epidemiological analyses have previously shown that agricultural workers are at increased risk for depression, and research suggests that environmental exposures, particularly to pesticides, may be on the causal pathway of depression. Neurotoxic OP pesticides have been previously linked to psychiatric disorders including major depressive disorder. Although OPs have been associated with depression diagnosis, mechanistic understanding is lacking. We hypothesize that the chronic mechanism of OP exposure leads to depressive symptoms in agricultural populations and is epigenetic in nature, mediated by interactions between environmental factors and DNA. In this dissertation, incidence of depressive symptoms associated with OP exposure is explored by epidemiological, biochemical, and behavioral analyses, and DNA methylation (DNAm) is explored as a sub-chronic mechanism of toxicity.The first goal of this dissertation was to use ordinal logistic regression modeling to analyze epidemiological data from male pesticide applicators enrolled in the Agricultural Health Study (AHS) to estimate the effect of OP intensity on the severity of depressive symptoms. The second goal was to assess a mouse model of sub-chronic CPF exposure through biochemical and behavioral means and assess DNAm as a potential epigenetic mechanism of toxicity. After 21-day sub-chronic exposure, behavior was observed via the Open Field Test, Tail Suspension Test, Forced Swim Test, and Sucrose Preference Test. DNAm was then measured in hippocampal DNA using mouse methylation array technology and, finally, Gene Set Enrichment Analysis (GSEA) was used to determine which pathways may be implicated in CPF-induced behavioral effects.The long-term goal of this research is to identify those at risk for depression and to reduce environmental exposure to OPs to protect the mental health of those who may be exposed. The overall objective is to identify the chemical impact of OPs on populations at risk for depression at both the biological and the population level. The central hypotheses were that 1) participants exposed to OPs in the AHS would have an increased risk for depressive symptoms with increasing OP intensity 2) CPF exposure would lead to depressive-like behavior and differential DNAm in a dose-dependent manner, highlighting DNAm as a possible sub-chronic mechanism of toxicity.Results showed that high-intensity exposure to each of the OPs diazinon, dichlorvos, and parathion, was associated with more severe depressive symptoms in the AHS, indicating a dose-specific effect on behavior in male pesticide applicators. Increased risk for mild but not severe symptoms was observed with high exposure to malathion and CPF. Ultimately, the epidemiological work presented here suggests increased risk for depressive symptoms after OP exposure in an occupational cohort. Our mouse model showed that after CPF exposure at occupationally relevant levels, enzymatic activity was recovered in females at low exposure, but not among male or female mice with high exposure. Behavioral changes in distance traveled over time were observed among treated mice and could indicate cognitive function or habituation differences, but no depressive-like behavior was observed at this timepoint. Significant differential DNAm was observed at 3,538 CpG sites, and GSEA showed that the mitogen-activated protein kinase (MAPK) pathway was the most enriched, suggesting that the inflammatory response may be implicated in the differences observed between treatment vs. control mice.Overall, the work presented in this dissertation has resulted in expanded epidemiological, chemical, behavioral, and epigenetic knowledge surrounding depressive-like behaviors related to long-term OP exposure.
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