I. Metabolism Reprograming by PBDE via mTOR Pathway 

What is mTOR?

Serine/threonine protein kinase mTOR (mechanistic target of rapamycin) has emerged over the last decade as a critical signaling node that links nutrient sensing to the coordinated regulation of cellular metabolism. Deregulation of the mTOR signaling pathway has now been linked to aging and to the development of human diseases, including cancer, obesity, Type 2 diabetes, neurodevelopmental and neurodegenerative diseases. The mTOR-centered pathway is a metabolic master-switch, which at starvation suppresses biosynthetic programs and increases the recycling of proteins and organelles to provide an internal resource of metabolites. Conversely, stimulation of the pathway by nutrients and growth factors causes activation of biosynthesis and suppression of autophagy. In our experiments with rats and mice we have discovered that developmental exposure to polybrominated diphenyl ethers (PBDE) results in a long lasting reprograming of the mTOR pathway. The potential ability of PBDEs to reprogram mTOR signaling may be linked to significant public health threats.

What are PBDEs?

PBDEs are flame-retardant additives used in a wide range of polymers. PBDEs in human blood, milk, and tissues have increased exponentially over the last 30 years. Accumulation of toxicological evidence pushed withdrawal of PBDE from the North American market by 2013. The long-term persistence of human PBDE exposure all over the world has been attributed to many factors: waste and recycling sites; indoor use of PBDE-containing products; global circulation of PBDE; and high potency of PBDE for bioaccumulation and bioconcentration in food chains. Given the high lipophilicity of PBDE, exposure to small daily doses throughout life leads to substantial accumulation of the substance in tissues with high lipid content. The half-life of PBDE in human tissues is estimated at 1.8-6.5 years. During pregnancy, accumulated PBDE mobilizes, causing high-dose exposure of the developing organism via cord blood and breast milk. Toddlers are exposed to high PBDE doses due to dust ingestion and high food intake per kilogram of body weight. Hence, PBDE exposure peaks at early stages of development (in utero, early postnatal) when biological plasticity is high and even modest exposure to environmental stressors may result in dramatic and long-term health effects.

What are our research questions?

We now try to answer to the following questions:

1. What are the molecular mechanisms of mTOR activity reprograming by PBDE?
2. What is the developmental window of sensitivity for the long-term mTOR programming by PBDE?
3. What are the long-term health consequences of mTOR reprograming in laboratory animals?
4. What tissues are most sensitive for mTOR reprograming by PBDE?
5. Can other modulators of mTOR activity produce long-lasting changes in its activity if administered during a sensitive developmental window?
6. What interventions may be used to reverse/compensate abnormal activity of mTOR due to early life exposure to PBDE?

What methods do we use?

In our research we use a broad range of methods of molecular biology and toxicology including, among others, exposure experiments with laboratory rodents (rats and mice) and cell cultures, analysis of gene expression by RT-PCR and NextGen RNA-seq technology, expression of proteins by Western blotting and immunohistochemistry, analysis of epigenome using ChIP-seq (histone modifications), DHS-seq (chromatin rearrangement) and RRBS-seq (DNA methylation). We use diverse bioinformatics instruments to analyze results of our sequencing-based experiments and to reanalyze published high-throughput data.

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II. Developmental Exposures and Social Behavior

We would like to dissect the interaction between early life exposures to environmental endocrine disruptors and trade-offs between social behavior and physiology. Given that in human population almost everyone is exposed to a cocktail of endocrine disruptors throughout life, including the period of embryogenesis, we hypothesize that social behavior of every member of a community may be affected, resulting in altered performance of communities themselves. Here are 2 examples of projects:

Body Weight and Social Dominance

We have developed an animal model in which low social status and high body weight are linked via a positive feedback loop. We now plan to use this model to understand the role of different environmental stressors, diet regime and social environments on the establishment and stability of these feedbacks and interventions that may interrupt them.

Hypothetical scheme of positive feedback loop linking social status of an organism with its body weight. Interior blue cycle depicts possible elements and causative links in human population (SES – socio-economic status). Exterior red cycle illustrates our animal model.

Social Dominance and Reproductive Strategies

In the course of evolution, simultaneous perfection of every adaptation is impossible. In other words, evolutionary change is always a trade-of between multiple conflicting vectors of natural selection. For example, it was shown in several studies that in closely related species of mammals the levels of development of those physiological traits that help establishing dominance between males, correlate negatively with sperm production and vise a versa. In our experiments with laboratory rodents we have found the same relations at the level of interspecific variation. We further hypothesize that individual ontogenesis trajectory towards dominant animal or high-sperm-producer is determined by environmental factors at early stages of development and is mediated by hormonal signaling. We plan to discover what environmental factors and what hormonal signals play a major role in the determination of individual trajectories.