Research

The overall goal of our research program is to understand how gene-environment interactions lead to reproductive and metabolic diseases. To understand this broad question, we consider chemicals and nutrition to which humans and other non-human vertebrate organisms are exposed as environment, epigenetic mechanisms as drivers, and altered health outcomes, mainly reproductive and metabolic health, as phenotypic traits. The following are our current research projects.

Medaka fry (female, 3 days post-hatch) with GFP in germ cells

Epigenetic Mechanisms Underlying Germ Cell Reprogramming

Sex differences in germ cells are believed to be epigenetically regulated, as distinct differences in DNA methylation and histone modifications have been found in germ cells during sex determination. We are studying epigenetic regulation of germ cell development, including epigenetic reprogramming of primordial germ cells (PGCs), using olvasGFP transgenic medaka as a model organism. Our research shows that medaka PGCs undergo reprogramming of DNA methylation profiles (methylome) similarly to mammals. We are investigating the role of the Y chromosome in the epigenetic reprogramming of germ cells, as fish without the Y chromosome seem to lack this pattern of epigenetic reprogramming of genome methylome profile.

Programming parental methylomes is essential for embryo development and primordial germ cells (PGCs) for gender-specific germ cell development from their pluripotent state. Although varying results have been reported recently regarding reprogramming in fish using the results obtained from later stages of cleavages in embryos, our results from DNA methylation ELISA and whole methylome sequencing of eggs, sperm, and early stage embryos (1 cell-, 2 cell-, 4 cell-, 8 cell-, 16 cell--, 32 cell-, and blastula-stage) of medaka strongly suggest that medaka reprogram their methylomes in early embryos and PGCs the same way mammals do. This makes medaka fish an ideal organismal model for studying epigenetic regulation of transcription in health and disease and the inheritance of environmentally induced epigenetic signals.

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Fig. Cyp19a1b-GFP transgenic medaka.

Epigenetic Mechanisms Underlying Brain Sex Differences

In model organisms, mate selection and mating behaviors have been found to be affected by developmental exposure to environmental estrogenic or anti-androgenic chemicals, suggesting that current environmental levels of chemicals could be affecting the health and behavior of the exposed organisms. Our team is striving to understand the epigenetic basis for brain sexual dimorphism, environmentally induced sex-specific behaviors, and neuroendocrine disruption. Current projects: 

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Fig. An example of transgenerational phenotype in humans and fish, especially for exposure occurring during early embryonic development.

Intra-, Inter- and Transgenerational Inheritance of Environmentally Induced Health Effects

The window of early embryonic development is susceptible to environmental chemical stressors. Exposures during gonadal sex determination may lead to reproductive defects in adulthood. These effects can be transgenerationally transmitted to subsequent generations via the germline (sperm and eggs).  Transgenerational effects appear in individuals, not because of direct exposure but due to ancestral exposure, and have been thought to be contributing to declining reproductive fitness and the emergence of endangered species in natural populations. We are studying molecular alterations occurring during the transgenerational inheritance of phenotypes to identify chemical and phenotype-specific biomarkers associated with adverse reproductive outcomes using medaka fish (d-rR medaka, Oryzias latipes) as a model organism. We anticipate the biomarkers to be reliably predictive of the history of exposure and associated transgenerational phenotypes.

” In model organisms and humans, studies have shown that nutritional restriction or exposure to hormone-mimicking chemicals during early gestation cause alterations in adult and offspring health across several generations”. The picture below shows the molecular signatures established by direct exposure may be translated into adverse health outcomes in the exposed individual or may not be expressed at all. 

However, studies have shown that such direct effects may remain latent for quite a long time and emerge as multiple adverse health outcomes in individuals in subsequent generations. In humans, it is difficult to study such effects directly. Studies in animal models may provide important insights into the mechanisms underlying such effects. We are developing a comparative model using mice and fish as organismal models to identify conserved mechanisms that are specific to environmental stressors and adverse health phenotypes.

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Fig. A current understanding of transgenerational inheritance of acquired traits in vertebrates.

Figure: 5mC methylation of mouse estrogen receptor alpha core promoter in the prostate mesenchymal stem cells by different concentrations of BPA and EE2.


Environmentally Induced Epigenetic Memory in Germ Cells

Gene-environment interactions can lead to the emergence of phenotypes. Environmental stressors are able to induce epigenetic changes (chemical modifications on DNA structure) that are mitotically (or meiotically) stable. Environmental stressor-induced chemical modifications, such as DNA methylation or histone modifications, may or may not survive epigenetic reprogramming events that occur during the early cleavage stage of an embryo or during the re-specification of primordial germ cells (PGCs) at the time of sex determination. We hypothesize that the epigenetic modifications that survive reprogramming serve as epigenetic memories and that these memories are associated with adverse health outcomes. 

Our research is focused on unraveling epigenetic memories established by estrogenic chemicals that humans and aquatic wildlife are exposed to. We take in vitro cell culture, in vivo animal models, next-generation high throughput miRNA/RNA/methylome sequencing and histone profiling, and bioinformatic approaches to dissect the molecular underpinning of environmentally induced health effects across three generations using medaka and mice as model organisms. We anticipate finding permanent epigenetic memories that alter fine-tuned developmental transcriptional wiring leading to altered health conditions.

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Image source: http://www.nationalmssociety.org/ and Encyclopedia Britannica

Epigenetic Effects of Early Developmental Exposure to Emerging Environmental Contaminants

A growing number of studies reveal the fact that the aquatic environment is threatened by an increasing rate of chemical contamination. As a result, aquatic fauna is impacted by the ubiquitous presence of these chemicals in water bodies. Our research suggests that developmentally established epigenetic changes can survive in the body throughout the lifetime of the exposed individual and are associated with adverse health effects later in life. We aim to develop an adverse outcome pathway (AOP) incorporating epigenetic effects and associated phenotypic traits using medaka fish as an animal model. In the near future, regulatory agencies will need scientific information to classify chemicals that are transgenerationally harmful to humans and the ecosystem.

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Lab: 219 Lefevre Hall

@theBhandariLab

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Division of Biological Sciences
University of Missouri Columbia1200 University Avenue
Columbia, MO 65211, U.S.A.