The Investigation of Chlorpyrifos Exposure on Hypertension and Metabolic Syndrome Prevalence and its Dysregulatory Effects within Hypothalamic Blood Pressure and Metabolism Pathways Restricted; Files Only

Glover, Frank (Spring 2022)

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Hypertension (HTN) is the leading cause of morbidity and mortality associated with cardiovascular diseases, and the global prevalence of HTN is predicted to increase over the ensuing decades. Hypertension is also a component of the metabolic syndrome (MetS), a cluster of conditions that significantly increases the risk of heart disease, stroke and Type II diabetes. While strong risk factors for HTN and MetS have been identified including age, smoking, and high-salt diets, the complete etiology remains to be fully understood. Recently, the contribution of environmental toxicants such as OP insecticides in the etiology of HTN and MetS has come to light.

Organophosphate (OP) insecticides are a group of environmentally ubiquitous chemicals that have been in use for decades to increase crop yield and lower transmissions of vector-borne diseases. They function primarily to disrupt synaptic function in insects via acetylcholinesterase inhibition, resulting in paralysis and death. Despite their utility, OPs have been strongly associated with several adverse health outcomes, most notably central nervous system (CNS) dysregulation linked with cognitive delay in children, and neurodegenerative diseases in adults. Organophosphates have also been demonstrated to have off-target consequences in not only the CNS, but also peripheral organs including the heart, liver, and kidneys. These adverse outcomes have been observed at concentrations below the threshold to induce acute toxicity, and may reflect concentration levels representing everyday exposures.

While several in vitro and in vivo studies have found associations between OP exposure, HTN, and MetS, the generalizability of these studies is lacking, and their results remain conflicting and inconclusive. Additionally, the biological mechanisms underlying the association between OPs, HTN, and MetS remain to be elucidated. Our group hypothesized that exposure to OP insecticides at environmentally relevant concentrations are associated with the risk of HTN and MetS, and that these associations are related to effects of OPs on hypothalamic pathway targets.

Using a nationally representative cohort of U.S. adults from the NHANES 2013-2016 survey cycles, we quantified the association between general population exposure of OP insecticides, HTN, and MetS. Our findings revealed significant associations between OP exposure and systolic blood pressure, diastolic blood pressure, odds of abnormal pulse pressure, and the odds of MetS and MetS components, specifically low high-density lipoprotein (HDL) and hypertriglyceridemia. Using a murine hypothalamic cell line, we performed a targeted in vitro investigation of the effects by chlorpyrifos, the most used OP insecticide, on the mRNA and protein expression of well-established blood pressure and metabolism-regulating pathways components. Hypothalamic cells were exposed to a range of environmentally relevant concentrations of chlorpyrifos and chlorpyrifos-oxon, at either 24 hour or 4-day timepoints. We observed both concentration and time-dependent changes in the mRNA and protein expression of our hypothalamic targets. Computational benchmark dose (BMD) modeling was used to estimate points of departure for fold changes of mRNA and protein expression of pathway targets at various concentrations, and a value of 10% change in expression relative to the control was set as the predetermined BMD response. We were able to successfully calculate BMD and benchmark lower limit (BMDL) values for monotonic dose-response curves, and these values can ultimately be to calculate daily reference doses and to inform public health policies.

Our findings support previous studies implicating OP insecticides in the pathogenesis of HTN and MetS. This study contributes important novel information to the toxicological profile of OP insecticides like chlorpyrifos using a BMD model, and provides unique insights into the pathogenesis of OP-related HTN and metabolic dysfunction, specifically related to the hypothalamus. Furthermore, we have demonstrated that OP insecticides are associated with blood pressure changes and MetS at everyday levels of exposure, findings which support initiatives to reduce exposure to OPs and to develop safer alternatives. Future studies are warranted to corroborate our results, test these associations in whole organisms, and to expand on the proposed biological mechanisms underlying these associations.

Table of Contents

Abstract. 10

Chapter 1: Introduction. 11

Hypertension Background. 12

Blood Pressure Control by Organ Systems. 15

Metabolic Syndrome. 24

Metabolism Regulation by Organ Systems. 26

The Immune System, Blood Pressure, and Metabolism.. 30

Hypertension, Metabolic Syndrome, and Environmental Exposures. 33

Chlorpyrifos Background. 35

Chlorpyrifos and Hypertension. 44

Chlorpyrifos and Metabolic Dysfunction. 45

Chlorpyrifos and the Hypothalamus. 46

Study Population (NHANES) and in Vitro Model 47

Chapter 2: The Association between Organophosphate Insecticides and Blood Pressure Dysregulation: NHANES 2013-2014. 52

Abstract 53

Introduction. 55

Research Design/Methods. 58

Results. 61

Discussion. 70

Conclusion. 74

Chapter 3: Organophosphate Insecticides are Associated with Blood Pressure Dysregulation and Metabolic Syndrome among U.S. Adults: NHANES 2015-2016. 77

Abstract 78

Introduction. 79

Research Design/Methods. 82

Results. 87

Discussion. 93

Strengths. 96

Limitations. 97

Conclusion. 97

Chapter 4: Chlorpyrifos Influences the Expression of Hypertension and Metabolic Syndrome-Related Pathway Targets in a Hypothalamic Cell Line. 101

Abstract 102

Introduction. 104

Methods. 107

Results. 115

Discussion. 140

Weaknesses. 146

Future Directions/Conclusion. 147

Chapter 5: Summary. 148

Summary. 149

References. 155

References. 156

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