Assistant Research Professor of Biological Sciences
PhD, 2002 Hokkaido University, Japan
Environmentally-induced developmental origins of adult abnormalities and epigenetic transgenerational inheritance
Research descriptionMy current research interests are to understand: 1) epigenetic mechanisms underlying environmentally-induced developmental origins of adult diseases, 2) mechanisms of transgenerational inheritance of abnormal phenotype that occurs via germline transmission to subsequent generations, and 3) impact of transgenerational inheritance of abnormal phenotype on a population.
My research focuses on the epigenetic basis of environmentally-induced phenotype evolution. I integrate molecular biology, biochemistry, cell biology, ecology, evolutionary biology, and mathematics to address issues in environmental health using non-human, vertebrate models. If the genome is compared to the hardware in a computer, the epigenome would be the operating system that runs a variety of software on it. Epigenetic signals are chemical modifications that instruct the genome to turn the genes “on” or “off” at exactly the right time. Epigenetic alterations are heritable and often behave similarly to genetic mutations in terms of their stability. Altered epigenetic modifications have been found in cancer and various other diseases. Because of their reversible properties, there is the potential for these alterations to be manipulated therapeutically. Environmental stressors, such as chemicals and nutrition, have been found to alter the epigenetic status of a cell and to cause abnormalities that predispose organisms to diseases such as metabolic disorders and cancer. Environmentally-induced epigenetic alterations in germ cells cause reproductive pathologies in exposed individuals. Additionally, these alterations are transmitted to subsequent generations with adverse health outcomes. It is believed that those environmental effects which are amplified in offspring and subsequently produce a multitude of adverse outcomes may cause a population crash. In the event of such a population crash, those individuals who survive the crash may evolve as a new phenotype with altered characteristics and sensitivity to environmental changes.
Germ line stem cells and other precursor stem cell types that give rise to gametes and hormone producing tissues, respectively, are susceptible to environmental stressors, including chemicals that are used in everyday life. Germ line stem cells, also called primordial germ cells (PGCs) or spermatogonial stem cells, are precursors of eggs and sperm. They undergo epigenetic reprogramming at the time of sex determination. A global erasure of DNA methylation marks gives rise to a stem cell state in PGCs, and de novo methylation initiates a controlled gene expression pattern in a gender-specific manner. Any perturbations of global epigenetic reprogramming events in PGCs may result in reproductive consequences later in life as well as adverse health outcomes in descendants. Epigenetic alterations can be permanently programmed and transmitted to subsequent generations via both sperm and eggs. Environmental endocrine disrupting chemicals (EDCs) can influence epigenetic programming of germ cells with adverse outcomes in later generations. Examples of such transgenerational effects are: obesity, early onset of puberty in females, reduced sperm count, polycystic ovaries, prostate disease, kidney disease, various cancers, and behavioral abnormalities. However, information about what epigenetic marks are initially established by environmental chemicals, whether these marks are consistently inherited by subsequent generations, and their direct functional link with disease state is currently lacking.
Current Research Project
It is important to find the very first changes that environmental stressors make in a cell, the germ line stem cell in particular, after exposure. Cascades of events that follow the initial change generate endpoints that are usually measured. Significant damage should already have occurred by the time these endpoints are detectable. Children born from a mother on birth control pills and offspring exposed gestationally to chemicals of plastic origin are likely to develop adult-onset diseases and these abnormalities have been found to be transmitted to subsequent generations. My current research is focused on finding the initial events that are imprinted/established in germline stem cells and carried to subsequent generations via eggs and sperm. I am taking a comparative approach to identify common biomarkers of these environmental estrogenic chemical-induced transgenerational diseases using fish and mice as models. My projects are designed to use high throughput epigenomic and genomic techniques, especially BisulfiteSeq, Histone ChIP-Seq, RNAseq, and bioinformatics. Objectives are: 1) to identify chemical exposure and phenotype-specific epigenetic and transcriptomic biomarkers in germline cells and affected somatic tissues, and 2) to understand the role of the identified alterations in disease onset. The long-term goals of my research are to understand: 1) the impact that the environmental stressor-induced transgenerational inheritance would have on a population, and 2) whether the transgenerational phenotype is able to evolve as a new species adapted to a chemically-polluted environment.
Bhandari, R.K. (2016). Medaka as a model for studying environmentally induced epigenetic transgenerational inheritance of phenotypes. Environmental Epigenetics. 2:1-9 (doi: http://dx.doi.org/10.1093/eep/dvv010)
Skinner, M.K., Bhandari, R.K., Hoque, M.M., Nilsson, E.E. (2016). Environmentally induced epigenetic transgenerational inheritance of altered SRY genomic binding during gonadal sex determination. Environmental Epigenetics 1:1-10 (doi: 10.1093/eep/dvv004)
Bhandari R.K., vom Saal, F.S., Tillitt, D. E. (2015). Transgenerational effects from early developmental exposures to bisphenol A or 17α-ethinylestradiol in medaka, Oryzias latipes. Scientific Reports, 5 : 9303.
Pandit, N.P., Bhandari, R.K., Kobayashi, Y., Nakamura, M. (2015). High temperature-induced sterility in the female Nile tilapia, Oreochromis niloticus. General and Comparative Endocrinology, 213:110-117.
Bhandari RK, Deem SL, Holliday DK, Jandegian CM, Kassotis CD, Nagel SC, Tillitt DE, Vom Saal FS, Rosenfeld CS. (2015) Effects of the environmental estrogenic contaminants bisphenol A and 17α-ethinylestradiol on sexual development and adult behaviors in aquatic wildlife species. General and Comparative Endocrinology. 214:195-219.
Jandegian, C.M., Deem, S.L., Bhandari, R.K., Holliday, C.M., Nicks, D., Rosenfeld, C.S., Selcer, K.W., Tillitt, D.E., vom Saal, F.S., Vélez-Rivera, V., Yang, Y., Holliday, D.K. (2015) Developmental exposure to bisphenol A (BPA) alters sexual differentiation in painted turtles (Chrysemys picta). General and Comparative Endocrinology 216: 77-85.
Bhandari, R.K., Nagahama, Y., Nakamura, M. (2013). Selective inhibition of estrogen production, but not androgen treatments, causes sex reversal of terminally differentiated female tilapia. (Submitted)
Paul-Prasanth B*., Bhandari R.K*., Kobayashi, T., Horiguchi, R., Kobayashi, Y., Nakamoto, M., Shibata, Y., Sakai, F., Nakamura, M., Nagahama, Y. (2013). Estrogen depletion causes functional sex reversal of adult female gonochoristic fish, Nile Tilapia and Medaka (*Equally contributing first authors). Nature Scientific Reports, Oct 7; 3:2862.
Skinner M.K., Haque M.M., Nilsson E., Bhandari R.K., McCarrey J.R. (2013). Environmentally induced transgenerational epigenetic reprogramming of primordial germ cells and the subsequent germ line. PLoS One. 2013 Jul 15;8(7):e66318
Bhandari, RK and Tillitt, D.E. (2014). Environmental chemical contaminants and transgenerational fish phenotype. (in preparation)
Miura, S., Kobayashi, Y., Bhandari, R.K., and Nakamura, M. (2013). Estrogen favors differentiation of ovary in the ambisexual gonads of Anemone fish. Journal of Experimental Zoology A Ecological Genetics and Physiology. 319, 10:560-568.
Bhandari, R.K., Schinke, E.N., Haque, MM, and Skinner, M.K. (2012). SRY-induced TCF21 genome- wide targets and cascade of bHLH factors during Sertoli cell differentiation and male sex determination in the rat. Biology of Reproduction, 87: 131-136.
Bhandari RK, Haque MM, Skinner MK. (2012). Global genome analysis of the downstream binding targets of testis determining factor SRY and SOX9. PLoS One. 2012;7(9):e43380
Bhandari, R.K., Clement, T., Sadler-Riggleman, I., and Skinner, M.K. (2011). Basic helix-loop- helix transcription factor Tcf21 is a downstream target of male sex determining gene Sry. PLoS One, 6(5): e19935. pp1-11.
Bhandari, R.K*., Clement, T*., Riggleman, I., and Skinner, M.K. (2011). Sry directly regulates Neurotrophin-3 promoter during male sex determination and testis development (*Equally contributing first authors). Biology of Reproduction. 85: 277-284.
Skinner, M.K., Nilsson, E.E., and Bhandari, R.K. (2010). Cell-Cell Signaling in the Testis and Ovary. In: Handbook of Cell Signaling Third Edition (Ralph A Bradshaw and Edward Dennis, Eds.) Academic Press/Elsevier Science Publishing. pp. 2663-2678.
Kojima, Y. Bhandari, R.K., Kobayashi, Y. and Nakamura M. (2008). Male-to-female sex reversal of primary male wrasse with estrogen treatment. General and Comparative Endocrinology. 156:628-632.
Westring, C.G., Ando, H., Kitahashi, T., Bhandari, R.K., Ueda, H., Urano, A., Dores, R.M., Sher, A.A. and Danielson, P.B. (2008). Seasonal changes in CRF-I and urotensin I transcript levels in masu salmon: Correlation with cortisol secretion during spawning. General and Comparative Endocrinology, 155: 126-140.
Bhandari, R.K., Alam, M.A.,, Soyano K., and Nakamura, M., (2006). Induction of female-to- male sex change in the honeycomb grouper (Epinephelus merra) by 11-ketotestosterone treatments. Zoological Science 23: 65-69.
Bhandari, R.K., Nakamura, M., Kobayashi, T., and Nagahama, Y. (2006). Suppression of steroidogenic enzyme expression during androgen-induced sex reversal in Nile tilapia (Oreochromis niloticus). General and Comparative Endocrinology 145: 20-24.
Komatsu, T. Bhandari, R.K., Nakamura, M. (2006). Acceleration of precocious spermatogenesis in under- yearling Golden Rabbitfish (Siganus guttatus, Bloch) by GnRHa treatments. Aquaculture 257: 558-565.
Alam, M.A., Bhandari, R.K., Kobayashi, Y., Soyano K., and Nakamura, M., (2006). Induction of sex change within two full moons during breeding season and spawning in grouper. Aquaculture 255: 532-535.
Alam, M.A., Bhandari, R.K., Kobayashi, Y., Soyano, K., and Nakamura, M. (2006). Changes in androgen-producing cell size and circulating 11-ketotestosterone levels during female-to- male sex change in Honeycomb grouper (Epinephelus merra). Molecular Reproduction and Development. 73(2):206-14.
Jodo, A., Kitahashi, T., Taniyama, S., Bhandari, R.K., Ueda, H., Urano, A. and Ando, H. (2005). Seasonal variations in expression of five subtypes of gonadotropin-releasing hormone receptor genes in the brain of masu salmon from immaturity to spawning. Zoological Science 22: 1331-1338.
Luo, Q., Ban, M., Ando, H., Kitahashi, T., Bhandari, R.K., McCormick, S.D. and Urano, A. (2005). Distinct effects of 4-nonylphenol and estrogen-17beta on expression of estrogen receptor a gene in smolting sockeye salmon. Comparative Biochemistry and Physiology.140C: 123-130.
Alam, M.A., Komuro, H., Bhandari, R.K., Nakamura, S., Soyano, K., and Nakamura, M. (2005). Immunohistochemical evidence identifying the site of androgen production in the ovary of the protogynous grouper Epinephelus merra . Cell and Tissue Research 320: 323- 329.
Bhandari, R.K., Alam, M.A., Higa, M. Soyano, K., Nakamura, M. (2005). Evidence that estrogen regulates the sex change of honeycomb grouper (Epinephelus merra), a protogynous hermaphrodite fish. Journal of Experimental Zoology 330A: 497-503.
Bhandari, R.K., Higa, M., Nakamura, S. and Nakamura, M. (2004). Aromatase inhibitor induces complete sex change in a protogynous honeycomb grouper, Epinephelus merra. Molecular Reproduction and development, 67(3): 303-307.
Bhandari, R.K., Komuro, H., Higa, M., and Nakamura, M. (2004). Sex inversion of sexually immature honeycomb grouper (Epinephelus merra) by aromatase inhibitor. Zoological Science 21 (3): 305-310.
Bhandari, R.K., Higa, M., Komuro, H., Nakamura, S. and Nakamura, M. (2003). Treatments with an aromatase inhibitor induces complete sex change in protogynous honeycomb grouper (Epinephelus merra). Fish Physiology and Biochemistry 28: 141-142.
Bhandari, R.K., Taniyama, S., Kitahashi, T., Ando, H., Yamauchi, K., Zohar, Y., Ueda, H., and Urano, A. (2003). Seasonal changes of responses to gonadotropin-releasing hormone analog in expression of growth hormone/prolactin/somatolactin genes in the pituitary of masu salmon. General and Comparative Endocrinology 130: 55-63.
Miura, S., Komatsu, T., Higa, M., Bhandari, R.K., Nakamura, S. and Nakamura, M. (2003).Gonadal sex differentiation in protandrous anemone fish, Amphiprion clarkii. Fish Physiology and Biochemistry 28: 165-166.
Nakamura, M., Bhandari, R.K. and Higa, M. (2003). The role estrogens play in sex differentiation and sex changes of fish. Fish Physiology and Biochemistry 28: 113-117
Bhandari, R.K. Komuro, H., Nakamura, S., Higa, M., and Nakamura (2003). Gonadal restructuring and correlative steroid hormone profiles during natural sex change in protogynous honeycomb grouper, Epinephelus merra. Zoological Science 20: 1399-1404.
Bhandari, R.K., Ushikoshi, I., Fukuoka, H., Koide, N., Yamauchi, K., and Ueda, H. (2002). Effects of Rhizopus extract administration on somatic growth and sexual maturation in lacustrine sockeye salmon, Oncorhynchus nerka. Fisheries Science. 68 (4): 776-782.
Honors & Awards
Selected honors and awards
Junior Faculty Travel Grant | University of Florida 2012
Travel Award for Junior Faculty | Society for Developmental Biologists 2012
Outstanding Postdoctoral Presentation | CRB | Washington State University 2011
Lalor Foundation Merit Award | Society for Study of Reproduction 2011
Lalor Foundation Merit Award | Society for Study of Reproduction 2008
Young Researcher Award | Zoological Society of Japan 2007
Research grant and Fellowship | Japan Society for the Promotion of Science 2002
Ph.D. Scholarship | Ministry of Education (Monbusho), Government of Japan 1998
April 17, 2015
April 8, 2015
March 30, 2015
March 30, 2015
March 24, 2015
March 24, 2015