Systems Biology Analysis of the Fate and Effects of Endocrine Disrupting Chemicals in Models of Adipose Tissue and the Gut Microbiota
Manteiga, Sara.
2016
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Abstract: A growing
body of evidence links exposure to endocrine disrupting chemicals (EDCs) with
obesity-related metabolic diseases. Adipose tissue (AT) plays a pivotal role in the
development of obesity. AT actively regulates whole body energy homeostasis by
orchestrating complex inter- and intra-cellular communications, effected via regulatory
molecule networks. Sustained perturbation of ... read moremetabolism by environmental factors such as
over-nutrition can override homeostatic controls, leading to a cascade of signaling
events that can result in inflammation, a hallmark of metabolic disease. In this work we
investigated the fate and effects of a subset of EDCs in cellular models related to
obesity, namely AT and the gut microbiota. Given their reported ability to interact with
regulatory molecules in AT, we hypothesized that EDCs might act by perturbing metabolic
and inflammatory signaling networks to elicit their effects. We explored this
possibility by exposing adipocytes to low concentrations of EDCs. We employed a
data-driven approach using metabolomics and proteomics methods to characterize cellular
state and determine global patterns of alterations. Our findings showed that
monoethylhexyl phthalate (MEHP) induces an inflammatory state, characterized by
elevations in free fatty acids (FFA) and cytokines. We also observed broad dysregulation
of lipid metabolism, suggesting involvement of the lipid metabolism regulator,
peroxisome proliferator-activated receptor-γ (PPAR-γ) in the observed
effects. Chemical inhibition of PPAR-γ abrogated the MEHP-induced cytokine
expression, suggesting it is a mediator of the inflammatory effect. We then used
model-driven 13C-labeling metabolic flux analysis to clarify the means by which MEHP
elevated FFA levels. Flux simulations suggested this resulted from reduced ability to
sequester FFA as triglycerides, though a clear understanding of the mechanism warrants
future investigation. We also investigated the effects of EDCs on gut microbiota
metabolism, which is intimately coupled to whole body energy metabolism in both health
and disease. When we exposed isolated cecum cultures to EDCs we observed significant
changes in 23% of the detected products of microbial metabolism, including lipids,
neuroactive chemicals, and other signaling compounds. Dysregulation of microbiota
metabolism could have negative outcomes on host
health.
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Chemical and Biological Engineering.
Advisor: Kyongbum Lee.
Committee: Arul Jayaraman, Emmanuel Tzanakakis, Kurt Pennell, and Catherine Kuo.
Keywords: Systematic biology, Endocrinology, and Chemical engineering.read less - ID:
- z029ph52q
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