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
2019
Abstract
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.Subjects
Endocrine Disrupting Chemicals Phthalates Obesity and Metabolic Syndrome Epigenetics Transcriptomics Developmental Origins of Health and Disease
Types
Thesis
Metadata
Show full item recordCollections
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.