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Interaction between the Aryl Hydrocarbon Receptor (AhR) and Tryptophan on the Hepatic and Microbial Toxicity of Polychlorinated Biphenyl 126 (PCB126).

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Interaction between the Aryl Hydrocarbon Receptor (AhR) and Tryptophan on the Hepatic and Microbial Toxicity of Polychlorinated Biphenyl 126 (PCB126)./
作者:	Dean, Laura.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
面頁冊數:	193 p.
附註:	Source: Dissertations Abstracts International, Volume: 83-09, Section: B.
Contained By:	Dissertations Abstracts International83-09B.
標題:	Toxicology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28866122
ISBN:	9798790627323

Interaction between the Aryl Hydrocarbon Receptor (AhR) and Tryptophan on the Hepatic and Microbial Toxicity of Polychlorinated Biphenyl 126 (PCB126).
Dean, Laura.

Interaction between the Aryl Hydrocarbon Receptor (AhR) and Tryptophan on the Hepatic and Microbial Toxicity of Polychlorinated Biphenyl 126 (PCB126). - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 193 p.

Source: Dissertations Abstracts International, Volume: 83-09, Section: B.

Thesis (Ph.D.)--The University of Iowa, 2021.

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

We are exposed to persistent organic, man-made pollutants, also called forever chemicals, in our daily lives. Many have a structure that allows them to bind with a cellular receptor known as the aryl hydrocarbon receptor (AhR). Ligands for this receptor include dioxins, polychlorinated biphenyls (PCBs), polybrominated biphenyls, and pesticides. Dioxin-like compound exposures, such as that to PCB126 (3, 3', 4, 4',5-pentachlorobiphenyl), cause many different bodily dysfunctions primarily related to the activation of the AhR. Activation of the AhR by PCB126 can alter gene expression in the host and modulate the gut microbiota, and lead to toxicity throughout the body including disturbed energy homeostasis, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), immune dysfunction, and cachexia. Other AhR ligands, such as tryptophan (Trp) and its metabolites can interact with the AhR in beneficial ways. For instance, Trp is an essential amino acid found in many food sources that acts as a nutrient enhancer. Activation of the AhR by Trp and/or Trp metabolites can help regulate energy metabolism. Co-exposure to both a beneficial and a toxic AhR ligand has been shown to reduce toxicity.Gene expression can be altered by many environmental factors, including exposure to dioxin-like compounds such as PCB126 and Trp. Gene expression can be mediated through transcription factors such as the AhR, which is ligand activated. When activated, the AhR will bind with the co-activator ARNT and form a complex. The ligand bound AhR-ARNT complex will then move from the cytoplasm to the nucleus and bind with xenobiotic response elements. This leads to regulation of the transcription of many genes, including those involved in energy metabolism, glucose homeostasis, fatty acid oxidation, and carbohydrate metabolism. The gut microbiome is sensitive to diet and environmental exposures and its mutualistic relationship with the host body can lead to changes in metabolism leading to alterations in metabolism, compromised immune function, and diseases such as NAFLD, inflammatory bowel disease, type 2 diabetes, and colorectal cancers. For instance, exposure to PCB126 and Trp can directly (oral exposure) or indirectly (all other exposures) impact the colon microbiome. While PCB126 causes detrimental effects to the colon microbiome, Trp is a key player in balancing intestinal immune tolerance and gut microbiota maintenance.There were several hypotheses addressed throughout this work. The first two studies focused on PCB126 alone, and the effect on both hepatic gene expression and the colon microbiome. We hypothesized that the toxic effects caused by PCB126 to the three major energy metabolism pathways (carbohydrate metabolism, fatty acid oxidation, and glucose homeostasis), as well as changes in the colon microbiome, would be mediated by the AhR. The present studies also introduced Trp as a potential supplementation to reduce the toxic effects of PCB126 on hepatic and microbial systems. Therefore, we hypothesized that supplementation with Trp would decrease the toxicity of PCB126. Overall, the present studies aimed to determine 1) the effects of PCB126 on hepatic energy metabolism, 2) the effects of PCB126 on the colon microbiome, 3) whether an oral subacute exposure to PCB126 with or without a co-exposure to a 2% Trp diet could significantly a) alter the hepatic energy metabolism or b) alter the gut microbiome, and 4) if any or all of the alterations could also be linked to the aryl hydrocarbon receptor (AhR). Additional questions were a) the exact role of the AHR and/or existence of non-AhR mediated effects, b) differences between the sexes, and c) how the mode of exposure would influence the effects.To test our hypotheses, we utilized two animal studies. Both studies utilized 4-week-old male and female wild-type (WT) and CRISPR/Cas9-created AhR knockout (KO) rats. In the first study each rat received 1 intraperitoneal (IP) injection of either PCB126 (5 µmol/kg) or corn-oil (control). Four weeks later rats were sacrificed, livers were removed for total mRNA extraction, and fecal pellets from the colon were used for microbial DNA extraction. In the second study rats were first put on either a 2% Trp or a control diet for one week to acclimate them to the new diet. On day 7 of the study, the rats were given a weekly oral exposure of either PCB126 (1.25 µmol/kg) or corn-oil (control) for each of the remaining 4 weeks. Rats were then sacrificed, livers removed for total mRNA extraction, and colon fecal samples were utilized once again for microbial DNA extraction. Hepatic differentially expressed genes were analyzed by Ingenuity Pathway Analysis (IPA) utilizing log(FC), p-values, and FDRs. 16S rRNA sequencing was employed to determine the impact of PCB126 and/or Trp on the microbiome. A single IP injection of PCB126 altered gene expression as well as the colon microbiome. WT rats showed significant changes in gene expression levels after PCB126 exposure while KO rats had far fewer genes altered. Additionally, PCB126 exposure caused many changes in genes related to energy metabolism pathways. PCB126 caused a larger number of changes in gene expression which led to more sub-pathway alterations in WT females than any other genotype. Key elements of energy metabolism, glucose homeostasis, and fatty acid oxidation, were significantly altered in WT rats after PCB126 exposure while carbohydrate metabolism displayed a similar number of changes in both PCB126 exposed WT and KO rats. Changes in gene expression were reflected as a greater effect on sub-pathways in males than in females. Knocking out AhR, without exposure to PCB126, resulted in changes in expression of genes involved in energy homeostasis remarkably in males. Additionally, a single IP injection of PCB126 led to specific taxa abundance alterations but did not alter alpha and beta diversity or Firmicutes to Bacteroidetes ratios. A sub-acute oral exposure to PCB126 and Trp caused many genes and microbiota abundances to be altered as well. Overall, Trp did not significantly alter the principal component analysis (PCA) of genes in WT rats exposed to PCB126. However, Trp reduced the effects of PCB126 on glucose homeostasis and fatty acid oxidation but not carbohydrate metabolism in WT females. KO rats showed very few changes across all analyses. Trp decreased the number of genes altered by PCB126 in WT rats but increased the number of dysregulated genes in KO rats. 16S rRNA sequencing showed that overall diversity of the microbiomes and the Firmicutes to Bacteroidetes ratios were once again not altered after oral exposure to PCB126 and/or Trp. However, oral exposure to PCB126, alone or with Trp, and knocking out the AhR led to specific phyla and genera alterations. Interestingly, these alterations have been reported to cause changes in energy metabolism of the host.These studies demonstrate the essential role of AhR in energy homeostasis pathways even during normal conditions and the significant disturbance by an AhR agonist like PCB126. Also, males may be at higher risk of adverse effects on energy homeostasis while females may respond in a broader, more adaptive way. The second study with an IP injection implies that the enterohepatic circulation of PCB126 can lead to microbial dysbiosis even when the route of exposure is not through ingestion. The third study demonstrates the effects of PCB126 and Trp through the AhR in energy homeostasis pathways; Trp reduced the effects of PCB126 in females but did not significantly benefit males. Finally, the last study's results demonstrate the effects of AhR ligands on the colon microbiota through oral exposure and how Trp can help mediate some of the responses and cause responses alone to the gut microbiome.

ISBN: 9798790627323Subjects--Topical Terms:

556884
Toxicology.
Subjects--Index Terms:

Aryl hydrocarbon receptor

Interaction between the Aryl Hydrocarbon Receptor (AhR) and Tryptophan on the Hepatic and Microbial Toxicity of Polychlorinated Biphenyl 126 (PCB126).
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300 $a 193 p.
500 $a Source: Dissertations Abstracts International, Volume: 83-09, Section: B.
500 $a Advisor: Ludewig, Gabriele.
502 $a Thesis (Ph.D.)--The University of Iowa, 2021.
506 $a This item must not be sold to any third party vendors.
520 $a We are exposed to persistent organic, man-made pollutants, also called forever chemicals, in our daily lives. Many have a structure that allows them to bind with a cellular receptor known as the aryl hydrocarbon receptor (AhR). Ligands for this receptor include dioxins, polychlorinated biphenyls (PCBs), polybrominated biphenyls, and pesticides. Dioxin-like compound exposures, such as that to PCB126 (3, 3', 4, 4',5-pentachlorobiphenyl), cause many different bodily dysfunctions primarily related to the activation of the AhR. Activation of the AhR by PCB126 can alter gene expression in the host and modulate the gut microbiota, and lead to toxicity throughout the body including disturbed energy homeostasis, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), immune dysfunction, and cachexia. Other AhR ligands, such as tryptophan (Trp) and its metabolites can interact with the AhR in beneficial ways. For instance, Trp is an essential amino acid found in many food sources that acts as a nutrient enhancer. Activation of the AhR by Trp and/or Trp metabolites can help regulate energy metabolism. Co-exposure to both a beneficial and a toxic AhR ligand has been shown to reduce toxicity.Gene expression can be altered by many environmental factors, including exposure to dioxin-like compounds such as PCB126 and Trp. Gene expression can be mediated through transcription factors such as the AhR, which is ligand activated. When activated, the AhR will bind with the co-activator ARNT and form a complex. The ligand bound AhR-ARNT complex will then move from the cytoplasm to the nucleus and bind with xenobiotic response elements. This leads to regulation of the transcription of many genes, including those involved in energy metabolism, glucose homeostasis, fatty acid oxidation, and carbohydrate metabolism. The gut microbiome is sensitive to diet and environmental exposures and its mutualistic relationship with the host body can lead to changes in metabolism leading to alterations in metabolism, compromised immune function, and diseases such as NAFLD, inflammatory bowel disease, type 2 diabetes, and colorectal cancers. For instance, exposure to PCB126 and Trp can directly (oral exposure) or indirectly (all other exposures) impact the colon microbiome. While PCB126 causes detrimental effects to the colon microbiome, Trp is a key player in balancing intestinal immune tolerance and gut microbiota maintenance.There were several hypotheses addressed throughout this work. The first two studies focused on PCB126 alone, and the effect on both hepatic gene expression and the colon microbiome. We hypothesized that the toxic effects caused by PCB126 to the three major energy metabolism pathways (carbohydrate metabolism, fatty acid oxidation, and glucose homeostasis), as well as changes in the colon microbiome, would be mediated by the AhR. The present studies also introduced Trp as a potential supplementation to reduce the toxic effects of PCB126 on hepatic and microbial systems. Therefore, we hypothesized that supplementation with Trp would decrease the toxicity of PCB126. Overall, the present studies aimed to determine 1) the effects of PCB126 on hepatic energy metabolism, 2) the effects of PCB126 on the colon microbiome, 3) whether an oral subacute exposure to PCB126 with or without a co-exposure to a 2% Trp diet could significantly a) alter the hepatic energy metabolism or b) alter the gut microbiome, and 4) if any or all of the alterations could also be linked to the aryl hydrocarbon receptor (AhR). Additional questions were a) the exact role of the AHR and/or existence of non-AhR mediated effects, b) differences between the sexes, and c) how the mode of exposure would influence the effects.To test our hypotheses, we utilized two animal studies. Both studies utilized 4-week-old male and female wild-type (WT) and CRISPR/Cas9-created AhR knockout (KO) rats. In the first study each rat received 1 intraperitoneal (IP) injection of either PCB126 (5 µmol/kg) or corn-oil (control). Four weeks later rats were sacrificed, livers were removed for total mRNA extraction, and fecal pellets from the colon were used for microbial DNA extraction. In the second study rats were first put on either a 2% Trp or a control diet for one week to acclimate them to the new diet. On day 7 of the study, the rats were given a weekly oral exposure of either PCB126 (1.25 µmol/kg) or corn-oil (control) for each of the remaining 4 weeks. Rats were then sacrificed, livers removed for total mRNA extraction, and colon fecal samples were utilized once again for microbial DNA extraction. Hepatic differentially expressed genes were analyzed by Ingenuity Pathway Analysis (IPA) utilizing log(FC), p-values, and FDRs. 16S rRNA sequencing was employed to determine the impact of PCB126 and/or Trp on the microbiome. A single IP injection of PCB126 altered gene expression as well as the colon microbiome. WT rats showed significant changes in gene expression levels after PCB126 exposure while KO rats had far fewer genes altered. Additionally, PCB126 exposure caused many changes in genes related to energy metabolism pathways. PCB126 caused a larger number of changes in gene expression which led to more sub-pathway alterations in WT females than any other genotype. Key elements of energy metabolism, glucose homeostasis, and fatty acid oxidation, were significantly altered in WT rats after PCB126 exposure while carbohydrate metabolism displayed a similar number of changes in both PCB126 exposed WT and KO rats. Changes in gene expression were reflected as a greater effect on sub-pathways in males than in females. Knocking out AhR, without exposure to PCB126, resulted in changes in expression of genes involved in energy homeostasis remarkably in males. Additionally, a single IP injection of PCB126 led to specific taxa abundance alterations but did not alter alpha and beta diversity or Firmicutes to Bacteroidetes ratios. A sub-acute oral exposure to PCB126 and Trp caused many genes and microbiota abundances to be altered as well. Overall, Trp did not significantly alter the principal component analysis (PCA) of genes in WT rats exposed to PCB126. However, Trp reduced the effects of PCB126 on glucose homeostasis and fatty acid oxidation but not carbohydrate metabolism in WT females. KO rats showed very few changes across all analyses. Trp decreased the number of genes altered by PCB126 in WT rats but increased the number of dysregulated genes in KO rats. 16S rRNA sequencing showed that overall diversity of the microbiomes and the Firmicutes to Bacteroidetes ratios were once again not altered after oral exposure to PCB126 and/or Trp. However, oral exposure to PCB126, alone or with Trp, and knocking out the AhR led to specific phyla and genera alterations. Interestingly, these alterations have been reported to cause changes in energy metabolism of the host.These studies demonstrate the essential role of AhR in energy homeostasis pathways even during normal conditions and the significant disturbance by an AhR agonist like PCB126. Also, males may be at higher risk of adverse effects on energy homeostasis while females may respond in a broader, more adaptive way. The second study with an IP injection implies that the enterohepatic circulation of PCB126 can lead to microbial dysbiosis even when the route of exposure is not through ingestion. The third study demonstrates the effects of PCB126 and Trp through the AhR in energy homeostasis pathways; Trp reduced the effects of PCB126 in females but did not significantly benefit males. Finally, the last study's results demonstrate the effects of AhR ligands on the colon microbiota through oral exposure and how Trp can help mediate some of the responses and cause responses alone to the gut microbiome.
520 $a Therefore, the role of AhR ligands in the genesis of metabolic syndrome and microbial dysbiosis, and the possibility of additive effects should be further explored.
590 $a School code: 0096.
650 4 $a Toxicology. $3 556884
653 $a Aryl hydrocarbon receptor
653 $a Energy metabolism
653 $a Microbiome
653 $a Polychlorinated biphenyls
653 $a RNA sequencing
653 $a Tryptophan
690 $a 0383
710 2 $a The University of Iowa. $b Human Toxicology. $3 3685649
773 0 $t Dissertations Abstracts International $g 83-09B.
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791 $a Ph.D.
792 $a 2021
793 $a English
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