Supervisory Research Microbiologist — Division of Genetic and Molecular Toxicology

Mugimane Manjanatha, Ph.D.
(870) 543-7121
NCTRResearch@fda.hhs.gov  

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Background

Dr. Mugimane Manjanatha (Manju) received a Bachelor of Science from Bangalore, India, a Master of Science degree in biology from West Texas A&M University, and a Ph.D. in microbiology and genetics from Iowa State University. Following his Ph.D. studies, Dr. Manjanatha joined FDA’s National Center for Toxicological Research (NCTR) in 1991 as an Oak Ridge Institute for Science and Education postdoctoral fellow. He was an FDA staff fellow from 1993-1995 and converted to a research microbiologist in NCTR’s Division of Genetic and Molecular Toxicology in 1995. Recently, Dr. Manjanatha was promoted to the position of Deputy Director, DGMT (Supervisory Research Microbiologist).

Dr. Manjanatha is a recognized leader in the field of genetic toxicology, especially in the development and use of transgenic animals for hazard identification, characterization, and risk assessment. He recently developed a transgenic hairless albino-mouse model with two reporter genes for potential application in photocarcinogenicity studies. His research interests also extend to modification of the Comet assay for assessment of the genotoxic and epigenetic mode-of-action of FDA-regulated agents, and gene expression profiling to determine mode-of-action as a tool for human risk assessment.

He serves on committees of the International Life Science Institute – Health and Environmental Sciences Institute and Environmental Mutagenesis and Genomics Society that address the application of transgenic mutational models in hazard characterization and mode-of-action of chemical agents for their carcinogenicity. Dr. Manjanatha has more than 80 publications including book chapters and mini reviews in peer-reviewed toxicology journals. He is an editor of Advances in Toxicology and Journal of the Scientific World and serves on the editorial boards of Molecular Biology Journal of International Scholarly Research and Mutation Research-Genetic Toxicology and Environmental Mutagenesis. He has received several major awards, most recently the FDA “Commendable Service Award.”

Research Interests

Dr. Manjanatha has expanded his research to include development of a new transgenic rodent (TGR) mutational model, modification of the Comet assay for the detection of changes in DNA global methylation, and, most recently, the development of a human in vitro three-dimensional (3D) liver co-culture model.

His work on chemicals of interest to FDA using TGR mutational models has demonstrated that the types of transgene mutations induced by many carcinogenic chemicals in the target tissues are remarkably like the types of cancer-gene mutations induced by these chemicals in tumor tissues. Thus, the transgenic mutation assays serve as a highly reliable tool for predicting cancer-gene mutations and are extremely useful for safety assessment of FDA-relevant chemicals and drugs. In addition, his work on TGR assays in collaboration with researchers from industry, academia, and NCTR to evaluate the mutagenic mode-of-action of carcinogenic chemicals, such as ethylene oxide, vanadium pentoxide and vinyl acetate showed that transgenic, neutral reporter genes are valuable tools that are amenable for quantitative risk analysis by hazard identification and characterization. He was recently selected to serve as an FDA expert on Organization for Economic Co-Operation and Development (OECD) TGR assay Test Guideline (TG) 488 revision for including germ cell mutagenesis.

Dr. Manjanatha led a team of researchers from NCTR and FDA’s Center for Food Safety and Nutrition in successfully establishing the Single Cell Gel Electrophoresis assay (Comet assay) at NCTR. Using enzyme-modified Comet assays, the team evaluated the genotoxic mode-of-action of several FDA-relevant food mutagens – such as methyleugenol, furan, safrole, and estragole – and pharmaceuticals – such as doxorubicin and cyproterone acetate. Dr. Manjanatha was invited as a U.S. national expert on the Comet assay to write comments on the draft Organisation for Economic Co-Operation and Development (OECD) Comet assay test guideline in July 2013. The assay guideline was adopted by OECD (489-TG) in September 2014 and the assay has become a regulatory genetox assay used world-wide. Dr. Manjanatha has continued his work on the Comet assay and recently began working with an FDA commissioner’s fellow to develop a modified Comet assay that can detect DNA damage and epigenetic modifications such as global DNA methylation alteration on a single platform. He has applied this assay to test the safety of black cohosh extract used as a supplement by pre- and post-menopausal women for relief from menopausal symptoms.

Dr. Manjanatha has successfully developed a new transgenic, hairless-albino (THA) mouse model at NCTR to test in vivo mutagenesis as a short-term end point that could replace the requirement of a long-term photocarcinogenesis bioassay. Current validation studies show that THA mice are extremely sensitive to UV radiation and low UVB doses (20-40 mJ/cm2) induced 10-12-fold and 3-5-fold increases in the mutant frequency compared to the respective controls in the guanine phosphoribosyl transferase (GPT) and sensitive to P2 interference (Spi-) selection systems. Further, molecular analysis of the GPT mutants in skin showed UV-specific, C→T signature mutations exclusively at dipyrimidine sites. Further studies with this model are underway to evaluate the carcinogenic predictivity of short-term mutagenicity assays, the UVB circadian clock in skin, and the safety of cosmetics containing nanoparticles.

Dr. Manjanatha is interested in the development of a human in vitro 3D liver co-culture model (or kidney systems containing primary parenchymal and non-parenchymal cells on a 3D scaffold). The 3D liver model containing hepatocytes, stellate, Kupffer, and endothelial cells should be able to maintain liver function for at least up to 3 months and produce albumin, fibrinogen, transferrin and urea. Additionally, 3D liver co-cultures should maintain cytochrome P450 inducibility, form bile canaliculi-like structures and respond to inflammatory stimuli. Upon incubation with selected hepatotoxicants, including drugs which have been shown to induce idiosyncratic toxicity, this model should be able to detect in vivo drug-induced toxicity, including species-specific drug effects, when compared to monolayer hepatocyte cultures. In conclusion, in vitro cell-culture models that contain all liver-cell types and allow repeated drug-treatments for detection of in vivo-relevant adverse drug effects will be ideal.

Professional Societies/National and International Groups

Association of Scientists of Indian Origin
Member
2013 – Present

Central Arkansas Chapter of Sigma Xi
Member
1992 – Present

Environmental and Molecular Mutagenesis Society
Member
1991 – Present 

European Environmental Mutagenesis and Genomics Society
Member
2014 – Present

Genetic Toxicology Association
Member
2014 – Present

International Life Sciences Institute – Health and Environmental Sciences Institute
Member
2010 – Present

Society of Toxicology
Member
2000 – Present

Select Publications

Appropriate In Vivo Follow-Up Assays to an In Vitro Bacterial Reverse Mutation (Ames) Test Positive Investigational Drug Candidate (Active Pharmaceutical Ingredient), Drug-Related Metabolite, and Frug-Related Impurities.
Robison T.W., Heflich R.H., Manjanatha M.G.,  Elespuru R., Atrakchi A., Mei N., and Ding W. 
Mutation Research. 2021, DOI: 10.1016/j.mrgentox.2021.503386.

Night Shift Schedule Causes Circadian Dysregulation of DNA Repair Genes and Elevated DNA Damage in Humans.
Koritala B.S.C., Porter K.I., Arshad O.A., Gajula R.P., Mitchell H.D., Arman T., Manjanatha M.G., Teeguarden J., Van Dongen P.A., McDermott J.A., and Gaddameedhi S. 
Journal of Pineal Research. 2021, https://doi.org/10.1111/jpi.12726, First published: 27 February 2021. 

Mechanistic Evaluation of Black Cohosh Extract-Induced Genotoxicity in Human Cells.
Seo J-E., Guo X., Petibone D., Shelton S., Chen Y., Li X., Tryndyak V., Smith-Roe S.L., Witt K.L., Mei N., and Manjanatha M. 
Tox. Sci. 2021, fab044,  https://doi.org/10.1093/toxsci/kfab044, Published:15 April 2021.

Performance of High-Throughput CometChip Assay Using Primary Human Hepatocytes: A Comparison of DNA Damage Responses with In Vitro Human Hepatoma Cell Lines.
Seo J.-E., Wu Q., Bryant M., Ren L., Shi Q., Robison T.W., Mei N., Manjanatha M.G., and Guo X
Archives of Toxicology. 2020, 94:2207-2224. PMID 32318794.

Evaluation of Pyrrolizidine Alkaloid-Induced Genotoxicity Using Metabolically Competent TK6 Cell Lines.
Li X., He X., Chen S., Bryant M.S., Guo L., Manjanatha M.G., Zhou T., Witt K.L., and Mei N. 
Food and Chemical Toxicology. 2020, 145:11662.

Development and Application of TK6-Derived Cells Expressing Human Cytochrome P450s for Genotoxicity Testing.
Li X., Chen X., Guo X., Wu Q., Seo J-E., Guo L., Manjanatha M.G., Zhou T., Witt K.L., and Mei N. 
Toxicological Sciences. 2020, 175(2):251-265. PMID 32159784.

In Vivo Genotoxicity Testing Strategies: Report from the 7th International Workshop on Genotoxicity Testing (IWGT).
Kirkland D., Uno Y., Luijten M., Beevers C., van Benthem J., Burlinson B., Dertinger A., Douglas G.R., Hamada S., Horibata K., Lovell D.P., Manjanatha M., Martus H.J., Mei N., Morita T., Ohyama W., and Williams A. 
Mutation Research-Genetic Toxicology and Environmental Mutagenesis. 2019, 847:403035.

Genotoxicity Assessment of Nanomaterials: Recommendations on Best Practices, Assays and Methods.
Elespuru R., Pfuhler S., Aardema M., Chen T., Doak S.H., Doherty A., Farabaugh C.S., Kenny J., Manjanatha M., Mahadevan B., Moore M.M., Ouédraogo G., Stankowski L.F. Jr., and Tanir J.Y.
Toxicol Sci. 2018, doi: 10.1093/toxsci/kfy100. [Epub ahead of print].
 
The Development and Validation of EpiComet-Chip, a Modified High-Throughput Comet Assay for the Assessment of DNA Methylation Status.
Townsend T.A., Parrish M.C., Engelward B.P., and Manjanatha M.G.
Environ Mol Mutagen. 2017, 58(7):508-521. doi: 10.1002/em.22101. Epub 2017 Jul 29.
 
Dose and Temporal Evaluation of Ethylene Oxide-Induced Mutagenicity in the Lungs of Male Big Blue Mice Following Inhalation Exposure to Carcinogenic Concentrations.
Manjanatha M.G., Shelton S.D., Chen Y., Parsons B.L., Myers M.B., McKim K.L., Gollapudi B.B., Moore N.P., Haber L.T., Allen B., and Moore M.M.
Environ Mol Mutagen. 2017, 58(3):122-134. doi: 10.1002/em.22080. Epub 2017 Mar 22.
 
Evaluation of cII Gene Mutation in the Brains of Big Blue Mice Exposed to Acrylamide and Glycidamide in Drinking Water.
Li H.F., Shelton S.D., Townsend T.A., Mei N., and Manjanatha M.G.
J Toxicol Sci. 2016, 41(6):719-730.
 
In Vivo Alkaline Comet Assay and Enzyme-Modified Alkaline Comet Assay for Measuring DNA Strand Breaks and Oxidative DNA Damage in Rat Liver.
Ding W., Bishop M.E., Lyn-Cook L.E., Davis K.J., and Manjanatha M.G.
J Vis Exp. 2016, (111). doi: 10.3791/53833.
 
Genetic Toxicology: Opportunities to Integrate New Approaches in Genetic Toxicology: An ILSI-HESI Workshop Report.
Zeiger E., Witt K., White P., Benthem J., Thybaud V., Pfuhler S., Manjanatha M., Honma M., Gollapudi B., Aardema M., and Kim J.
Environmental Molecular Mutagenesis. 2015, 56:277-285.
 
In Vivo Genotoxicity of Estragole in Male F344 Rats.
Ding W., Levy D., Bishop M., Pearce M., Jeffrey A., Duan J., Williams G., White G., Lyn-Cook L., and Manjanatha M.
Environmental Molecular Mutagenesis. 2015, 56:356-365.
 
Neonatal Exposure of 17β-Estradiol has No Effects on Mutagenicity of 7,12-Dimethylbenz[A]Anthracene in Reproductive Tissues of Adult Mice.
Mei N., Zhang Z., Li H., Manjanatha M., and Chen T.
Genes and Environment. 2015, 37: 1-6.
 
Acrylamide-Induced Carcinogenicity in Mouse Lung Involves Mutagenicity: Acrylamide and Glycidamide-Induced cII Gene Mutations in the Lung of Big Blue Mice.
Manjanatha M., Guo L., Shelton S., and Doerge D.
Environmental Molecular Mutagenesis. 2015, 56:446-456.
 
Evaluation of cII Mutations in Lung of Male Big Blue Mice Exposed by Inhalation to Vanadium Pentoxide for up to 8 Weeks.
Manjanatha M., Shelton S., Haber L., Gollapudi B., MacGregor J., Rajendran N., and Moore M.
Mutation Research-Genetic Toxicology and Environmental Mutagenesis. 2015, 789-790:46-52.
 
Development and Validation of a New Transgenic Hairless Albino Mouse Model for Photocarcinogenicity Studies.
Manjanatha M., Shelton S., Chen Y., Gaddameedhi S., Howard P., and Boudreau M.
Mutation Research-Genetic Toxicology and Environmental Mutagenesis. 2015, 791:42-52.
 
Evaluation of Genotoxicity of Doxorubicin in F344 Rats by Combing the Comet Assay, Flow Cytometric Peripheral Blood Micronucleus Test and Pathway-Focused Gene Expression Profiling.
Manjanatha M., Bishop M., Lyn-Cook L., Kulkarni R., and Ding W.
Environmental Molecular Mutagenesis. 2014, 55:24-34.
 
Sex-Specific Dose-Response Analysis of Genotoxicity in Cyproterone Acetate-Treated F344 Rats.
Ding W., Bishop M., Pearce M., Davis K., White G., Lyn-Cook L., and Manjanatha M.
Mutation Research-Gen Tox and Enviro Mutagen. 2014, 2014774:1-7.

Lab Members

Contact information for all lab members:
(870) 543-7121
NCTRResearch@fda.hhs.gov  

Michelle Bishop, BS
Biologist

Sharon D. Shelton, BS
Biologist

Rebecca Wynne, MS
Biologist