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Defining the Molecular Effects of Ar...

Beck, Rowan Far.

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Defining the Molecular Effects of Arsenic Exposure in Circulation and in Pancreatic Beta Cells.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Defining the Molecular Effects of Arsenic Exposure in Circulation and in Pancreatic Beta Cells./
作者:	Beck, Rowan Far.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	153 p.
附註:	Source: Dissertations Abstracts International, Volume: 82-01, Section: B.
Contained By:	Dissertations Abstracts International82-01B.
標題:	Molecular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27735159
ISBN:	9798607314002

Defining the Molecular Effects of Arsenic Exposure in Circulation and in Pancreatic Beta Cells.
Beck, Rowan Far.

Defining the Molecular Effects of Arsenic Exposure in Circulation and in Pancreatic Beta Cells. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 153 p.

Source: Dissertations Abstracts International, Volume: 82-01, Section: B.

Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2020.

This item must not be sold to any third party vendors.

Type 2 diabetes (T2D) is a complex metabolic disorder characterized by hyperglycemia. Exposures to environmental toxicants are less studied in the context of T2D, but these toxicants, alone or in conjunction with other environmental and lifestyle factors, may play a contributing role to the development of T2D. Numerous population studies have found an association between exposure to inorganic arsenic (iAs) in drinking water and an increased incidence or prevalence of T2D. These studies also indicate that metabolism of iAs into monomethyl-As (MAs) and dimethyl-As (DMAs) metabolites, which facilitates clearance of iAs from the body, influences individual susceptibility to adverse effects of iAs exposure. Population studies of iAs exposure point to defects in insulin secretion as being the primary cause of metabolic dysfunction, and the impairment of insulin secretion has been validated in lab studies. While the exact mechanism by which iAs affects pancreatic beta cells and insulin secretion is unknown, microRNAs (miRNAs) have emerged as potential drivers. MiRNAs are environmentally responsive, short non-coding RNAs that are important components of gene regulatory networks involved in T2D. While miRNA expression changes have been observed in the presence of some metals including arsenic, and have specifically been shown to play a role in metabolism and glucose homeostasis, the role of miRNAs in the pancreas in the context of environmental metal exposures remains highly understudied. To address this gap in knowledge, I utilized a cohort exposed to iAs through drinking water, as well as an in vitro cell line to identify miRNAs that link iAs exposure to diabetes. I identified a novel association between a methylated metabolite of iAs and 6 circulating plasma miRNAs, several of which have known links to diabetes. I also found that the inhibition of insulin secretion from beta cells exposed to iAs was concurrent to the upregulation of miR-146, an important regulator of several genes involved in the pathogenesis of T2D. Lastly, I examined the enhancer profile of pancreatic beta cells exposed to iAs or MAs and found that both exposures were associated with decreased activity of transcriptional regulatory elements enriched in binding sites for important transcription factors critical in maintaining pancreatic beta cell identity and function, including Pdx1. The results from this body of work contribute to the field of toxicology and environmental health by addressing major knowledge gaps in gene regulation and noncoding RNAs, and warrant further study and validation in the context of metabolic diseases such as T2D.

ISBN: 9798607314002Subjects--Topical Terms:

517296
Molecular biology.
Subjects--Index Terms:

Arsenic

Defining the Molecular Effects of Arsenic Exposure in Circulation and in Pancreatic Beta Cells.
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500 $a Source: Dissertations Abstracts International, Volume: 82-01, Section: B.
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506 $a This item must not be sold to any third party vendors.
520 $a Type 2 diabetes (T2D) is a complex metabolic disorder characterized by hyperglycemia. Exposures to environmental toxicants are less studied in the context of T2D, but these toxicants, alone or in conjunction with other environmental and lifestyle factors, may play a contributing role to the development of T2D. Numerous population studies have found an association between exposure to inorganic arsenic (iAs) in drinking water and an increased incidence or prevalence of T2D. These studies also indicate that metabolism of iAs into monomethyl-As (MAs) and dimethyl-As (DMAs) metabolites, which facilitates clearance of iAs from the body, influences individual susceptibility to adverse effects of iAs exposure. Population studies of iAs exposure point to defects in insulin secretion as being the primary cause of metabolic dysfunction, and the impairment of insulin secretion has been validated in lab studies. While the exact mechanism by which iAs affects pancreatic beta cells and insulin secretion is unknown, microRNAs (miRNAs) have emerged as potential drivers. MiRNAs are environmentally responsive, short non-coding RNAs that are important components of gene regulatory networks involved in T2D. While miRNA expression changes have been observed in the presence of some metals including arsenic, and have specifically been shown to play a role in metabolism and glucose homeostasis, the role of miRNAs in the pancreas in the context of environmental metal exposures remains highly understudied. To address this gap in knowledge, I utilized a cohort exposed to iAs through drinking water, as well as an in vitro cell line to identify miRNAs that link iAs exposure to diabetes. I identified a novel association between a methylated metabolite of iAs and 6 circulating plasma miRNAs, several of which have known links to diabetes. I also found that the inhibition of insulin secretion from beta cells exposed to iAs was concurrent to the upregulation of miR-146, an important regulator of several genes involved in the pathogenesis of T2D. Lastly, I examined the enhancer profile of pancreatic beta cells exposed to iAs or MAs and found that both exposures were associated with decreased activity of transcriptional regulatory elements enriched in binding sites for important transcription factors critical in maintaining pancreatic beta cell identity and function, including Pdx1. The results from this body of work contribute to the field of toxicology and environmental health by addressing major knowledge gaps in gene regulation and noncoding RNAs, and warrant further study and validation in the context of metabolic diseases such as T2D.
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653 $a Metals
653 $a Toxicity
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