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BME Seminar: Kyongbum Lee, Using metabolomics to investigate biological responses to environmental chemicals

Kyongbum Lee, Professor and Chair, Department of Chemical and Biological Engineering, Tufts University

River Campus, Robert B. Goergen Hall, Sloan Auditorium (Room 101)

Abstract

We are interested in the study of cellular metabolism and its role in shaping biological function. Metabolism refers to the biochemical processes that extract chemical energy from nutrients and generate the basic building blocks for biosynthesis. Metabolism is thus life-essential, and critical for virtually every cellular function. Our research goals are to develop new methods for analyzing and manipulating metabolic pathways, and use the insights enabled by these methods to devise strategies for rational manipulation of metabolic pathways to direct biological function. Central to our research is the idea that metabolism involves the concerted actions of many enzymes, reactants, and products that together form a complex reaction network. In this light, useful insights may be gained through “systems” oriented studies that examine metabolism as a whole.

This presentation focuses on the fate of consequence of exposure to environmental chemicals, which has emerged as a potentially significant public health threat. We examine several representative chemicals that are found in household and industrial products: bisphenol A, a phthalate, and an organotin compound. The effects of these chemicals are studied in two model systems, cultured fat cells and bacteria isolated from murine intestine.

In cultured fat cells, repeated exposure to low, physiologically relevant doses of mono-ethylhexyl phthalate (MEHP) over several days led to significant changes in metabolite and enzyme levels indicating elevated lipogenesis and lipid oxidation. The chemical exposure also increased expression of major inflammatory cytokines, including chemotactic factors. Proteomic and gene expression analysis revealed significant alterations in pathways regulated by peroxisome proliferator activated receptor-γ (PPAR-γ). Inhibiting the nuclear receptor’s activity using a chemical antagonist abrogated not only the alterations in PPAR-γ regulated metabolic pathways, but also the increases in cytokine expression.  Our results show that MEHP can induce a pro-inflammatory state in differentiated, adult fat cells. This effect is at least partially mediated by PPAR-γ.

We next examined the intestinal microbiota as a potential source of MEHP as well as another site of action. Using 16S ribosomal RNA sequencing and untargeted metabolomics, we found that exposing a mixed culture of murine cecal isolates to diethylhexyl phthalate (DEHP), the industrial chemical from which MEHP is derived, directly alters both the microbiota community structure as well as metabolite profile. Comparisons with control cultures lacking the cecal isolate inoculum confirmed that metabolite level changes are due to microbial metabolic activity. Correlation analysis of community composition and metabolite data using predicted metagenomes of the cecal cultures showed that changes in specific metabolite levels can be attributed to the depletion or enrichment of specific bacterial subgroups. Notably, DEHP induced alterations in neuromodulators and immune cell activators. Our results to date suggest that environmental chemicals could cause significant dysbiosis in the gut microbiota leading to an altered milieu of bioactive metabolites, consistent with other recent studies linking environmental chemical exposure to developmental disorders involving gastrointestinal conditions.