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Developmental Exposures to Phthalates and Phthalate Mixtures and Life-course Metabolic Outcomes: Using a Mouse Model to Inform Human Studies and Elucidate Mechanisms.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Developmental Exposures to Phthalates and Phthalate Mixtures and Life-course Metabolic Outcomes: Using a Mouse Model to Inform Human Studies and Elucidate Mechanisms./
作者:	Neier, Kari Elizabeth.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	215 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-08, Section: B.
Contained By:	Dissertations Abstracts International81-08B.
標題:	Environmental health. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27614459
ISBN:	9781392410141

Developmental Exposures to Phthalates and Phthalate Mixtures and Life-course Metabolic Outcomes: Using a Mouse Model to Inform Human Studies and Elucidate Mechanisms.
Neier, Kari Elizabeth.

Developmental Exposures to Phthalates and Phthalate Mixtures and Life-course Metabolic Outcomes: Using a Mouse Model to Inform Human Studies and Elucidate Mechanisms. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 215 p.

Source: Dissertations Abstracts International, Volume: 81-08, Section: B.

Thesis (Ph.D.)--University of Michigan, 2019.

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

Nearly 40 percent of US adults and 20 percent of US children are obese. Given obesity's multiple dangerous comorbidities, this presents a significant concern for public health. A growing body of evidence suggests that exposures to environmental chemicals may be contributing to the obesity epidemic. Such chemicals have been termed "obesogens" and among them are phthalates, endocrine disrupting chemicals (EDCs) that are present in food packaging, children's toys, and personal care products. Exposures to phthalates during development have been linked to adverse metabolic health outcomes in both animal and human studies, but findings from human studies are less consistent. One possible reason is humans are co-exposed to many phthalates, and these mixture exposures are difficult to interpret. Additionally, the vast majority of animal studies to date have focused on examining metabolic impacts of diethylhexyl phthalate (DEHP), despite the recent introduction of newer phthalates on the market to replace it, including diisononyl phthalate (DINP). Furthermore, mechanisms linking developmental exposures and later-life health outcomes, such as epigenetic reprogramming via DNA methylation, are still poorly understood.The overall objective of this dissertation was to utilize an animal model of perinatal phthalate exposures to investigate long-term metabolic impacts in a manner that would inform human studies and infer underlying mechanisms. We incorporated exposures to three individual phthalates (DEHP, DINP, and dibutyl phthalate (DBP)), as well as two phthalate mixtures (DEHP+DINP and DEHP+DINP+DBP). We then took phenotypic and molecular measurements on the offspring at two time points: at weaning on postnatal day 21 (PND21) at the end of the exposure period and at 10 months of age, >9 months after exposure had ceased. In Aim 1, we investigated early-life metabolic phenotypes by measuring body weight and relative liver weights and examined biomarkers of whole-genome DNA methylation alterations at PND21. In Aim 2, we evaluated metabolic phenotypes longitudinally at two and eight months of age to determine whether developmental exposures to phthalates influenced metabolism across the life course. Finally, in Aim 3, we measured the transcriptome and DNA methylation in liver and white adipose tissue (WAT) at both PND21 and 10 months to elucidate a molecular mechanism.We found that developmental exposures to individual phthalates and phthalate mixtures were associated with increased body weights in males and females in early postnatal life. Females, but not males, perinatally exposed to DINP-only and a mixture of DEHP+DINP also had increased relative liver weights at PND21. We also observed a sex-specific effect on tail DNA methylation at repetitive elements in mice exposed to individual phthalates and phthalate mixtures, indicating a sexually dimorphic effect on the epigenome. Developmental exposures to DEHP-only and DINP-only resulted in increased body fat percentage and glucose intolerance, respectively, across the life course. However, we did not observe longitudinal adverse metabolic impacts in mice perinatally exposed to phthalate mixtures, suggesting a potential adaptive response in these mice. In females perinatally exposed to DINP, we identified several persistently up-regulated PPAR target genes in the liver that could lead to increased fatty acid synthesis. Fatty acid synthase (Fasn) also exhibited increased promoter region DNA methylation at both PND21 and 10 months of age, implicating a role for epigenetic reprogramming. Taken together, the work here demonstrates short-term and long-term metabolic impacts following perinatal exposures to phthalates, and presents a new potential mechanism describing the underlying biology in the liver.

ISBN: 9781392410141Subjects--Topical Terms:

543032
Environmental health.
Subjects--Index Terms:

Endocrine disrupting chemicals

Developmental Exposures to Phthalates and Phthalate Mixtures and Life-course Metabolic Outcomes: Using a Mouse Model to Inform Human Studies and Elucidate Mechanisms.
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520 $a Nearly 40 percent of US adults and 20 percent of US children are obese. Given obesity's multiple dangerous comorbidities, this presents a significant concern for public health. A growing body of evidence suggests that exposures to environmental chemicals may be contributing to the obesity epidemic. Such chemicals have been termed "obesogens" and among them are phthalates, endocrine disrupting chemicals (EDCs) that are present in food packaging, children's toys, and personal care products. Exposures to phthalates during development have been linked to adverse metabolic health outcomes in both animal and human studies, but findings from human studies are less consistent. One possible reason is humans are co-exposed to many phthalates, and these mixture exposures are difficult to interpret. Additionally, the vast majority of animal studies to date have focused on examining metabolic impacts of diethylhexyl phthalate (DEHP), despite the recent introduction of newer phthalates on the market to replace it, including diisononyl phthalate (DINP). Furthermore, mechanisms linking developmental exposures and later-life health outcomes, such as epigenetic reprogramming via DNA methylation, are still poorly understood.The overall objective of this dissertation was to utilize an animal model of perinatal phthalate exposures to investigate long-term metabolic impacts in a manner that would inform human studies and infer underlying mechanisms. We incorporated exposures to three individual phthalates (DEHP, DINP, and dibutyl phthalate (DBP)), as well as two phthalate mixtures (DEHP+DINP and DEHP+DINP+DBP). We then took phenotypic and molecular measurements on the offspring at two time points: at weaning on postnatal day 21 (PND21) at the end of the exposure period and at 10 months of age, >9 months after exposure had ceased. In Aim 1, we investigated early-life metabolic phenotypes by measuring body weight and relative liver weights and examined biomarkers of whole-genome DNA methylation alterations at PND21. In Aim 2, we evaluated metabolic phenotypes longitudinally at two and eight months of age to determine whether developmental exposures to phthalates influenced metabolism across the life course. Finally, in Aim 3, we measured the transcriptome and DNA methylation in liver and white adipose tissue (WAT) at both PND21 and 10 months to elucidate a molecular mechanism.We found that developmental exposures to individual phthalates and phthalate mixtures were associated with increased body weights in males and females in early postnatal life. Females, but not males, perinatally exposed to DINP-only and a mixture of DEHP+DINP also had increased relative liver weights at PND21. We also observed a sex-specific effect on tail DNA methylation at repetitive elements in mice exposed to individual phthalates and phthalate mixtures, indicating a sexually dimorphic effect on the epigenome. Developmental exposures to DEHP-only and DINP-only resulted in increased body fat percentage and glucose intolerance, respectively, across the life course. However, we did not observe longitudinal adverse metabolic impacts in mice perinatally exposed to phthalate mixtures, suggesting a potential adaptive response in these mice. In females perinatally exposed to DINP, we identified several persistently up-regulated PPAR target genes in the liver that could lead to increased fatty acid synthesis. Fatty acid synthase (Fasn) also exhibited increased promoter region DNA methylation at both PND21 and 10 months of age, implicating a role for epigenetic reprogramming. Taken together, the work here demonstrates short-term and long-term metabolic impacts following perinatal exposures to phthalates, and presents a new potential mechanism describing the underlying biology in the liver.
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653 $a Epigenetics
653 $a Transcriptomics
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