Show simple item record

Impact of Perinatal Bisphenol A and High Fat Diets on Non-Alcoholic Fatty Liver Disease

dc.contributor.authorMarchlewicz, Elizabeth
dc.date.accessioned2018-10-25T17:40:18Z
dc.date.availableNO_RESTRICTION
dc.date.available2018-10-25T17:40:18Z
dc.date.issued2018
dc.date.submitted2018
dc.identifier.urihttps://hdl.handle.net/2027.42/145959
dc.description.abstractNon-alcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease among youth in the United States. This recent rise of NAFLD may be partially due to perinatal programming, where in utero exposures alter the lifelong health trajectory of offspring. Maternal pregnancy diet and endocrine disrupting chemical exposure have been identified as drivers of perinatal programming. However, the potential for maternal diet to modify the impact of perinatal chemical exposure is not well understood. This dissertation examined whether perinatal exposure to two common environmental toxicants, bisphenol A (BPA) and high fat diets (HFDs), would affect NAFLD incidence in offspring. A longitudinal mouse exposure study and a human birth cohort were used to investigate this hypothesis and to evaluate the translation of findings across species. Oral exposure to one of six diets: Control, Western HFD, Mediterranean HFD or each diet with 50ug BPA/kg added, occurred pre-gestation through lactation. All mice were weaned onto the Control diet, thus isolating exposure to the perinatal period. Offspring NAFLD was assessed via hepatic steatosis and hepatic oxidative response at postnatal day 10 (PND10) and 10-months. Hepatic triglyceride (TG) levels were altered by perinatal HFD in dams, but in offspring perinatal exposures affected metabolic outcomes not hepatic TGs. Hepatic histology from 10-month offspring highly correlated with hepatic TG levels, validating the TG findings. Hepatic 8-isoprostane (8-iso) levels differed by perinatal exposure in PND10 and 10-month offspring, but alterations were age and sex-specific. Perinatal HFD and BPA minimally impacted offspring redox parameters (EhGSH, EhCys, S-glut), suggestive of greater homeostatic control of these parameters compared to lipid oxidation. Dam metabolic phenotype significantly altered offspring hepatic steatosis and oxidative response, even when perinatal HFD and BPA did not, emphasizing the critical role of the maternal environment on offspring health. The impact of maternal BPA exposure and gestational Mediterranean diet adherence (MDS) on the metabolic health of peripubertal youth was examined in a well-established human birth cohort. Youth metabolic and oxidative health was assessed via metabolic risk score (MRS) and serum 8-iso. Maternal pregnancy average and Trimester 2 BPA were associated with a suggestive decrease in youth MRS driven by boys, but a suggestive increase in 8-iso levels driven by girls. Maternal MDS did not affect youth MRS, but altered youth serum 8-iso in opposite directions based on sex. Additional youth characteristics (peripubertal BPA, MDS, vigorous activity, and pubertal status) contributed to predictive models of MRS and 8-iso, underscoring the impact healthy lifestyle behaviors may have, potentially even modifying perinatal programming. The unexpected lack of protection exerted by the Mediterranean diet in both mouse and human studies, suggests the beneficial effect observed in adults may not apply to perinatal exposure. Greater impact of HFDs in mice but BPA in humans highlights the need to carefully scrutinize findings before translating across species. Despite this difference, sex-specific effects occurred in both species, emphasizing the importance of investigating perinatal programming in all offspring. This research suggests that perinatal BPA and HFD exposure may be insufficient to induce perinatal programming of NAFLD. The significant impact of dam metabolic phenotype in mice and peripubertal behaviors in humans on metabolic and oxidative outcomes suggest NAFLD risk can be altered and potentially prevented at multiple life stages.
dc.language.isoen_US
dc.subjectdevelopmental programming
dc.subjectnutrition
dc.subjecttoxicology
dc.subjectmaternal & child health
dc.subjectpublic health
dc.titleImpact of Perinatal Bisphenol A and High Fat Diets on Non-Alcoholic Fatty Liver Disease
dc.typeThesisen_US
dc.description.thesisdegreenamePhDen_US
dc.description.thesisdegreedisciplineEnvironmental Health Sciences
dc.description.thesisdegreegrantorUniversity of Michigan, Horace H. Rackham School of Graduate Studies
dc.contributor.committeememberDolinoy, Dana
dc.contributor.committeememberSong, Peter Xuekun
dc.contributor.committeememberBurant, Charles
dc.contributor.committeememberHarris, Craig
dc.contributor.committeememberPeterson, Karen Eileen
dc.subject.hlbsecondlevelPublic Health
dc.subject.hlbtoplevelHealth Sciences
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/145959/1/marcheh_1.pdf
dc.identifier.orcid0000-0001-6023-0236
dc.identifier.name-orcidMarchlewicz, Elizabeth; 0000-0001-6023-0236en_US
dc.owningcollnameDissertations and Theses (Ph.D. and Master's)


Files in this item

Show simple item record

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.