Pyrethroid Insecticides & the Gastrointestinal Environment Pubblico

Abstract

Pyrethroid insecticides are one of the most used classes of insecticides in the world. Derived from a type of chrysanthemum flower, they now represent a family of chemicals that is found in products throughout homes, medical offices, and agricultural settings. Many pyrethroids resist photodegradation, making them invaluable to farmers for large-scale use on vegetables and crops. Their primary mechanism of action is to induce neurotoxicity via actions on voltage-gated sodium channels. While pyrethroids are not nearly as toxic to humans as they are to insects, it is important to understand their potential impact on human health as we expose ourselves to them on a regular basis. In fact, the primary route of exposure to pyrethroids among the general population is through ingestion. However, most studies investigating the role of pyrethroids in human health have looked at their effects in the central nervous system, so knowledge of pyrethroid toxicity in the gastrointestinal (GI) tract is limited. The gut is comprised of several layers, the innermost of which is the gut epithelium. Scattered along the epithelial layer are enteroendocrine cells (EECs), a rare and unique cell type that have many neuronal properties. Coupled with their physical proximity to ingested contents, the gut epithelial environment is highly susceptible to pyrethroid-induced neurotoxicity. Therefore, we investigated the effects of the common pyrethroid deltamethrin on EECs in vitro and intestinal function and status in vivo. Given the numerous indicators that pyrethroids like deltamethrin are capable of disrupting monoamine signaling pathways, we went on to determine the extent to which longer-term oral exposure to deltamethrin may contribute to neurological dysfunction in a Parkinsonian manner. We found that while chronic exposure to deltamethrin did not induce Parkinsonism, acute exposure paradigms induced intestinal dysmotility and suppressed levels of several GI-related hormones including serotonin, insulin, and leptin. Moreover, we found that deltamethrin interferes with stimulus-induced hormone release by EECs in vitro. Thus, it is plausible that deltamethrin could be acting through similar mechanisms to induce intestinal dysmotility. Our findings provide novel insight into the potential for low-dose, oral, pyrethroid exposure to affect GI function and raise important questions about the extent to which such exposures contribute to intestinal dysmotility in humans.             

Table of Contents

Table of Contents

Chapter 1: Introduction

1.1.      General anatomy and functions of the gastrointestinal tract

1.2.      Enteroendocrine cells and the intestinal-luminal interface

1.3.      Modeling enteroendocrine cells in vitro

1.4.      Gastrointestinal hormones

1.5.      Intestinal monoamines

1.6.      Intestinal dysmotility

1.7.      A brief introduction to pyrethroid insecticides

1.8.      Pyrethroid-monoamine interactions

1.9.      Susceptibility of the GI tract to pyrethroids

1.10.    Intestinal dysmotility as an early indicator of neurological disease: an example of Parkinson’s disease

1.11.    Pesticides in Parkinson’s disease

1.12.    Pyrethroids, intestinal dysfunction, & neurological outcomes

Chapter 2: The pyrethroid insecticide deltamethrin disrupts neuropeptide and monoamine signaling pathways in the gastrointestinal tract

2.1 Abstract

2.2 Introduction

2.3 Materials and methods

Chemicals and treatments

Animal husbandry

Oral exposures

Intestinal behaviors

Cell culture

Cytotoxicity & cell viability assays

Gene expression analysis

Bulk RNA sequencing

Protein quantifications

High Performance Liquid Chromatography (HPLC)

Statistical Analyses

2.4 Results

Deltamethrin dysregulates monoamine pathways in EECs

Deltamethrin inhibits epinephrine-evoked GLP-1 release in STC-1 cells

Oral deltamethrin exposure induces acute constipation in mice

Deltamethrin interferes with nutrient-stimulated intestinal hormone signaling in vivo

2.5 Discussion

2.6 Limitations of this study

2.7 Conclusion

2.8 Acknowledgments

2.9 Figures

2.10. Supplementary Figures

Chapter 3: Discussion

3.1 The pyrethroid deltamethrin affects enteroendocrine cell status & function in vitro.

3.2 Deltamethrin-induced gut dysmotility and potential mechanisms.

3.3 Deltamethrin dampens the postprandial hormonal response in mice

3.4 Chronic exposure to deltamethrin does not induce Parkinsonism

3.5 Conclusions and future directions

3.6 Figures

Acknowledgements

References.

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Cell Environmental Health Biology, Neuroscience
Parola chiave	gastrointestinal tract pesticide neurotoxicology
Committee Chair / Thesis Advisor	Timothy R. Sampson, Emory University W. Michael Caudle, Emory University
Committee Members	Shanthi Srinivasan, Emory University James G. Greene, Emory University Leah Roesch, Emory University

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