Obesity is a multifactorial disorder that has reached epidemic proportions. The recent dramatic rise in obesity rates is an alarming global health trend that consumes an increasing portion of health care budgets in the EU. The recent research implicates our environment as a major contributing factor. In this project, we focused on di-2-(ethylhexyl) phthalate (DEHP) that is a ubiquitous chemical used as plasticizer e.g. in polyvinyl chloride (PVC) products. Phthalates can disrupt endocrine systems and more recently, epidemiological and experimental studies associate phthalates with the high body weight in humans. To fully understand the mechanisms and to address the multifaceted nature of chemical induced metabolic disruption, the study focused on several key regulators involved in metabolism: the host gut and associated gut microbiome. To study these complex mechanisms, we used a zebrafish (ZF) as a model organism which is a novel powerful tool in translational biomedical research.
We successfully investigated the effect of DEHP on wide array of physiological functions including metabolism, gut integrity and homeostasis and immune function. Using the latest bioinformatics approaches, such as sub-network enrichment analysis, we were able to identify the adverse effects on cell processes and identify the expression targets responsible for the observed effects in detail. Among the genes, the signaling cascade dealing with the PPAR genes were altered, which is a very specific group of genes that may play an important role in lipid processes that lead to alterations in gut energy homeostasis, a possible link to DEHP-induced obesity. In addition, we identified novel molecular targets that show the link between dysregulated intestinal immune system and host microbiome in the adverse effects. More specifically, we bring the evidence, that metabolic disruptors can act via the effect on an adaptive part of the immune system, such as Th cells. Phthalates can thus contribute to diseases and dysfunctions that are based on dysregulated immune system such as Crohn's disease and ulcerative colitis.
To determine the alteration of microbiome with DEHP, we analyzed the composition and diversity of microbiome using NextGen sequencing. We also applied several novel bioinformatics approaches to predict metagenome functional content from marker gene (e.g. 16S rRNA) and thus predict the functional changes in the microbiome. In addition, we identified the microbial bioactive metabolites that are modulated by DEHP and have an adverse effect on host (e.g. dysregulation of adaptive part of the immune system). Further, the project helped the uncover the potency of ZF embryonic model to identify metabolic disruptors and suggested several sensitive endpoints dealing with metabolism and mitochondrial performance.
The project is actively discussing the results with scientific community via publications and with public via series of presentations and lectures. The project has both major scientific and public health significance. Scientifically, our knowledge of the molecular targets of phthalates is still limited, and this project was poised to uncover these mechanisms which could lead to the development of novel therapeutic interventions. Technologically, this research will establish zebrafish model as a tool to address mechanistic questions related to metabolic disruption and to study emerging chemicals of concern. From the public health perspective, diseases like obesity and metabolic disruption are a major cause of disability and a lesser quality of life.
