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Human bisphenol A biomonitoring and ...

Nahar, Muna S.

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Human bisphenol A biomonitoring and biotransformation programming in the developing fetus.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Human bisphenol A biomonitoring and biotransformation programming in the developing fetus./
Author:	Nahar, Muna S.
Description:	151 p.
Notes:	Source: Dissertation Abstracts International, Volume: 75-08(E), Section: B.
Contained By:	Dissertation Abstracts International75-08B(E).
Subject:	Health Sciences, Toxicology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3619663
ISBN:	9781303890888

Human bisphenol A biomonitoring and biotransformation programming in the developing fetus.
Nahar, Muna S.

Human bisphenol A biomonitoring and biotransformation programming in the developing fetus. - 151 p.

Source: Dissertation Abstracts International, Volume: 75-08(E), Section: B.

Thesis (Ph.D.)--University of Michigan, 2014.

The ubiquitous monomer, bisphenol A (BPA), is an endocrine active compound used in the production of polycarbonate plastics and epoxy resin. Environmental biomonitoring and epidemiology studies report continuous exposure in humans that are associated with different adverse health outcomes. Although regulatory agencies are concerned with BPA's potential to harm pregnant women, fetuses, and young children, BPA's toxicity in humans remains highly debated. Animal and in vitro studies support BPA exposure-disease relationships, but metabolic, genetic and physiological differences ultimately limit translatability to humans. Thus, the objective of this dissertation was to identify BPA concentrations and early biological outcomes directly in humans, focusing on the developing fetus. Using healthy 1st-2nd trimester human clinical specimens obtained from a fetal biobank, we hypothesized that BPA concentration and biotransformation will differ across age and tissue compartments, altering biotransformation programming in the developing fetus.

ISBN: 9781303890888Subjects--Topical Terms:

1017752
Health Sciences, Toxicology.

Human bisphenol A biomonitoring and biotransformation programming in the developing fetus.
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100 1 $a Nahar, Muna S. $3 2101073
245 1 0 $a Human bisphenol A biomonitoring and biotransformation programming in the developing fetus.
300 $a 151 p.
500 $a Source: Dissertation Abstracts International, Volume: 75-08(E), Section: B.
500 $a Adviser: Dana C. Dolinoy.
502 $a Thesis (Ph.D.)--University of Michigan, 2014.
520 $a The ubiquitous monomer, bisphenol A (BPA), is an endocrine active compound used in the production of polycarbonate plastics and epoxy resin. Environmental biomonitoring and epidemiology studies report continuous exposure in humans that are associated with different adverse health outcomes. Although regulatory agencies are concerned with BPA's potential to harm pregnant women, fetuses, and young children, BPA's toxicity in humans remains highly debated. Animal and in vitro studies support BPA exposure-disease relationships, but metabolic, genetic and physiological differences ultimately limit translatability to humans. Thus, the objective of this dissertation was to identify BPA concentrations and early biological outcomes directly in humans, focusing on the developing fetus. Using healthy 1st-2nd trimester human clinical specimens obtained from a fetal biobank, we hypothesized that BPA concentration and biotransformation will differ across age and tissue compartments, altering biotransformation programming in the developing fetus.
520 $a The overall goal of this work was to characterize BPA toxicokinetic and toxicodynamic profiles that influence tissue-specific BPA biotransformation via xenobiotic metabolizing enzymes (XME) and elicit subsequent cellular changes. First, we reported BPA concentrations in N=50 fetal liver specimens (total BPA range: below limit of quantification - 96.8 ng/g), where the concentration of free BPA was three times that of BPA conjugates. Both concentrations and metabolic profiles varied across age with significant reduction in BPA-specific XME gene expression of UGT2B15, SULT1A1, and STS in fetal versus adult livers. Next, we examined matched fetal liver, kidney, and placenta in N=12 subjects and observed significant tissue-dependent differences in BPA concentrations, XME expression profiles, and global DNA methylation. Fetal livers exhibited higher BPA concentrations compared to matched tissues; however, XME expression profiles suggest an increased likelihood of BPA-glucuronide deconjugation and BPA-sulfate conjugation across the fetal compartments. With organ-specific differences in the epigenome, only placental global methylation measurements were associated with BPA. Finally, we investigated BPA's role in pathway specific biological outcomes and regulation in fetal liver. In particular, we identified 14 different XME candidate genes that were down regulated with higher BPA concentrations. After identifying common transcription factor binding sites across all candidate gene promoters, we reported increased methylation at these functionally relevant sites with higher BPA concentrations at several candidate genes.
520 $a In summary, results suggest that the 1st-2nd trimester human fetus is exposed to a considerable amount of BPA in utero, especially of the active free BPA form. XME expression profiles reveal an altered capacity for BPA biotransformation in the fetus compared to adults, with distinct metabolic profiles across different tissues. Interestingly, higher BPA concentrations in fetal liver were associated with reduced expression of novel XME candidate genes mediated by epigenetic mechanisms. These findings indicate that environmentally relevant concentrations of BPA, even across a short window of development, result in detectable changes in the host's toxicological defense system.
590 $a School code: 0127.
650 4 $a Health Sciences, Toxicology. $3 1017752
650 4 $a Environmental Health. $3 578282
650 4 $a Health Sciences, Human Development. $3 1019218
690 $a 0383
690 $a 0470
690 $a 0758
710 2 $a University of Michigan. $b Environmental Health Sciences. $3 2101074
773 0 $t Dissertation Abstracts International $g 75-08B(E).
790 $a 0127
791 $a Ph.D.
792 $a 2014
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3619663