
Core Narative
Studies of Superfund toxicants require novel mouse models, sensitive analytical approaches for measures of hormones, cytokines and small molecule metabolites, and in-depth analyses of large datasets to pioneer new findings in the detection of environmental toxicants and their role in health and disease. The UC San Diego Superfund Research Center Genetics and Metabolomics Core creates tailor-made genetically altered mouse models for the Biomedical Projects, uses highly sophisticated, rapid and sensitive methods for the detection and analysis of hormones and small metabolites (metabolomics), and provides informatics for analysis of biological and environmental samples. Hormone analyses in mouse and human serum, and metabolomics analyses of serum, urine, water, soil, and plant samples provide detailed detection of toxicants and their effects in environmental and experimental systems.
Summary of Core
Studies of Superfund toxicants require novel mouse models, careful, high-throughput analyses of hormones, cytokines and small molecule metabolites, and informatics analyses of large datasets to pioneer new findings in the detection of environmental toxicants and health effects of exposure. The UC San Diego Superfund Research Center Genetics and Metabolomics Core facility will provide state-of-the-art molecular biology services for generation of murine models of toxicant exposure as well as cutting-edge analytical services for sensitive, high-throughput assay of hormones and small molecule metabolites and their informatic analyses. This Core will interface with all six proposed research projects. Comprehensive approaches for modifying the mouse genome are provided including DNA microinjection, embryonic stem cell homologous recombination, CRISPR/Cas9 mutagenesis, and blastocyst injection, specifically tailored to UCSD Superfund projects. Furthermore, metabolomics services will be provided, allowing for measure of hormones, growth factors, and thousands of small molecule metabolites (both targeted and untargeted) using a Luminex magnetic bead analyzer and liquid chromatography-mass spectrometry based approaches. Samples for analysis will include human and mouse biospecimens (plasma, urine, and stool) as well as community plant, water, and soil samples. Bioinformatics services will provide in-depth analyses of large datasets resulting from transcriptomics, cistromics, and metabolomics. This core provides centralized, cost-effective, efficient, technically sophisticated services that are crucial to the success of all six projects in the UC San Diego Superfund Research Center.
Publications
Lavalle SN, Chou T, Hernandez J, Naing NCP, He MY, Tonsfeldt KJ, Mellon PL. Deletion of the homeodomain gene Six3 from kisspeptin neurons causes subfertility in female mice. Mol Cell Endocrinol. 2022 Feb 2;546:111577. doi: 10.1016/j.mce.2022.111577. Epub ahead of print.
Qin Y, Havulinna AS, Liu Y, Jousilahti P, Ritchie SC, Tokolyi A, Sanders JG, Valsta L, Brożyńska M, Zhu Q, Tripathi A, Vázquez-Baeza Y, Loomba R, Cheng S, Jain M, Niiranen T, Lahti L, Knight R, Salomaa V, Inouye M, Méric G. Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort. Nat Genet. 2022 Feb;54(2):134-142. doi: 10.1038/s41588-021-00991-z. Epub 2022 Feb 3.
Meadows JD, Breuer JA, Lavalle SN, Hirschenberger MR, Patel MM, Nguyen D, Kim A, Cassin J, Gorman MR, Welsh DK, Mellon PL, Hoffmann HM. Deletion of Six3 in post-proliferative neurons produces weakened SCN circadian output, improved metabolic function, and dwarfism in male mice. Mol Metab. 2022 Mar;57:101431. doi: 10.1016/j.molmet.2021.101431. Epub 2021 Dec 31.
Tonsfeldt KJ, Mellon PL, Hoffmann HM. Circadian Rhythms in the Neuronal Network Timing the Luteinizing Hormone Surge. Endocrinology. 2022 Feb 1;163(2):bqab268. doi: 10.1210/endocr/bqab268.
Ho EV, Shi C, Cassin J, He MY, Nguyen RD, Ryan GE, Tonsfeldt KJ, Mellon PL. Reproductive Deficits Induced by Prenatal Antimüllerian Hormone Exposure Require Androgen Receptor in Kisspeptin Cells. Endocrinology. 2021 Dec 1;162(12):bqab197. doi: 10.1210/endocr/bqab197.
Ward C, Nallamshetty S, Watrous JD, Acres E, Long T, Mathews IT, Sharma S, Cheng S, Imam F, Jain M. Nontargeted mass spectrometry of dried blood spots for interrogation of the human circulating metabolome. J Mass Spectrom. 2021 May 27;56(8):e4772. doi: 10.1002/jms.4772. Epub ahead of print. Erratum in: J Mass Spectrom. 2022 Feb;57(2):e4780.
Hoffmann HM, Meadows JD, Breuer JA, Yaw AM, Nguyen D, Tonsfeldt KJ, Chin AY, Devries BM, Trang C, Oosterhouse HJ, Lee JS, Doser JW, Gorman MR, Welsh DK, Mellon PL. The transcription factors SIX3 and VAX1 are required for suprachiasmatic nucleus circadian output and fertility in female mice. J Neurosci Res. 2021 Oct;99(10):2625-2645. doi: 10.1002/jnr.24864. Epub 2021 Jul 2.
Lavalle SN, Chou T, Hernandez J, Naing NCP, Tonsfeldt KJ, Hoffmann HM, Mellon PL. Kiss1 is differentially regulated in male and female mice by the homeodomain transcription factor VAX1. Mol Cell Endocrinol. 2021 Aug 20;534:111358. doi: 10.1016/j.mce.2021.111358. Epub 2021 Jun 4.
Koponen KK, Salosensaari A, Ruuskanen MO, Havulinna AS, Männistö S, Jousilahti P, Palmu J, Salido R, Sanders K, Brennan C, Humphrey GC, Sanders JG, Meric G, Cheng S, Inouye M, Jain M, Niiranen TJ, Valsta LM, Knight R, Salomaa VV. Associations of healthy food choices with gut microbiota profiles. Am J Clin Nutr. 2021 Aug 2;114(2):605-616. doi: 10.1093/ajcn/nqab077.
Ryan GE, Bohaczuk SC, Cassin J, Witham EA, Shojaei S, Ho EV, Thackray VG, Mellon PL. Androgen receptor positively regulates gonadotropin-releasing hormone receptor in pituitary gonadotropes. Mol Cell Endocrinol. 2021 Jun 15;530:111286. doi: 10.1016/j.mce.2021.111286. Epub 2021 Apr 17.
Bohaczuk SC, Cassin J, Slaiwa TI, Thackray VG, Mellon PL. Distal Enhancer Potentiates Activin- and GnRH-Induced Transcription of FSHB. Endocrinology. 2021 Jul 1;162(7):bqab069. doi: 10.1210/endocr/bqab069.
Ruuskanen MO, Åberg F, Männistö V, Havulinna AS, Méric G, Liu Y, Loomba R, Vázquez-Baeza Y, Tripathi A, Valsta LM, Inouye M, Jousilahti P, Salomaa V, Jain M, Knight R, Lahti L, Niiranen TJ. Links between gut microbiome composition and fatty liver disease in a large population sample. Gut Microbes. 2021 Jan-Dec;13(1):1-22. doi: 10.1080/19490976.2021.1888673.
Zhou R, Llorente C, Cao J, Zaramela LS, Zeng S, Gao B, Li SZ, Welch RD, Huang FQ, Qi LW, Pan C, Huang Y, Zhou P, Beussen I, Zhang Y, Bryam G, Fiehn O, Wang L, Liu EH, Yu RT, Downes M, Evans RM, Goglin K, Fouts DE, Brenner DA, Bode L, Fan X, Zengler K, Schnabl B. Intestinal α1-2-Fucosylation Contributes to Obesity and Steatohepatitis in Mice. Cell Mol Gastroenterol Hepatol. 2021;12(1):293-320. doi: 10.1016/j.jcmgh.2021.02.009. Epub 2021 Feb 22.
Rosenthal SB, Liu X, Ganguly S, Dhar D, Pasillas MP, Ricciardelli E, Li RZ, Troutman TD, Kisseleva T, Glass CK, Brenner DA. Heterogeneity of HSCs in a Mouse Model of NASH. Hepatology. 2021 Aug;74(2):667-685. doi: 10.1002/hep.31743. Epub 2021 Aug 10.
Schoeller EL, Tonsfeldt KJ, Sinkovich M, Shi R, Mellon PL. Growth Hormone Pulses and Liver Gene Expression Are Differentially Regulated by the Circadian Clock Gene Bmal1. Endocrinology. 2021 Apr 1;162(4):bqab023. doi: 10.1210/endocr/bqab023.
Ma HY, Yamamoto G, Xu J, Liu X, Karin D, Kim JY, Alexandrov LB, Koyama Y, Nishio T, Benner C, Heinz S, Rosenthal SB, Liang S, Sun M, Karin G, Zhao P, Brodt P, Mckillop IH, Quehenberger O, Dennis E, Saltiel A, Tsukamoto H, Gao B, Karin M, Brenner DA, Kisseleva T. (2019) IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease. J Hepatol. Dec 31.
doi: 10.1016/j.jhep.2019.12.016
Pandolfi, E.C., Breuer, J.A., Nguyen Huu, V.A., Talluri, T., Nguyen, D., Lee, J.S., Hu, R., Bharti, K., Skowronska-Krawczyk, D., Gorman, M.R., Mellon, P.L., Hoffmann, H.M. (2019) The Homeodomain Transcription Factors Vax1 and Six6 Are Required for SCN Development and Function. Mol Neurobiol. doi: 10.1007/s12035-019-01781-9. (https://link.springer.com/article/10.1007%2Fs12035-019-01781-9) [Epub ahead of print]
Pandolfi, E.C., Tonsfeldt, K.J., Hoffmann, H.M., Mellon, P.L. (2019) Deletion of the Homeodomain Protein Six6 From GnRH Neurons Decreases GnRH Gene Expression, Resulting in Infertility. Endocrinology. 160(9):2151-2164. doi: 10.1210/en.2019-00113. (https://academic.oup.com/endo/article/160/9/2151/5519301)
Tonsfeldt, K.J., Schoeller, E.L., Brusman, L.E., Cui, L.J., Lee, J., Mellon, P.L. (2019) The Contribution of the Circadian Gene Bmal1 to Female Fertility and the Generation of the Preovulatory Luteinizing Hormone Surge. J Endocr Soc. 3(4):716-733. doi: 10.1210/js.2018-00228. (https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30906911/) eCollection 2019 Apr 1.
Hoffmann, H.M., Larder, R., Lee, J.S., Hu, R.J., Trang, C., Devries, B.M., Clark, D.D., Mellon, P.L. (2019) Differential CRE Expression in Lhrh-cre and GnRH-cre Alleles and the Impact on Fertility in Otx2-Flox Mice. Neuroendocrinology. 108(4):328-342. doi: 10.1159/000497791. Epub 2019 Feb 10.
Hoffmann, H.M., Pandolfi, E.C., Larder, R., Mellon, P.L.. (2019) Haploinsufficiency of Homeodomain Proteins Six3, Vax1, and Otx2 Causes Subfertility in Mice via Distinct Mechanisms. Neuroendocrinology. 109(3):200-207. doi: 10.1159/000494086. Epub 2018 Sep 27. Review.
Que, X., Hung, M.Y., Yeang, C., Gonen, A., Prohaska, T.A., Sun, X., Diehl, C., Määttä, A., Gaddis, D.E., Bowden, K., Pattison, J., MacDonald, J.G., Ylä-Herttuala, S., Mellon, P.L., Hedrick, C.C., Ley, K., Miller, Y.I., Glass, C.K., Peterson, K.L., Binder, C.J., Tsimikas, S., Witztum, J.L. (2018) Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice. Nature. 558(7709):301-306. doi: 10.1038/s41586-018-0198-8. Epub 2018 Jun 6.
Pandolfi, E.C., Hoffmann, H.M., Schoeller, E.L., Gorman, M.R., Mellon, P.L. (2018) Haploinsufficiency of SIX3 Abolishes Male Reproductive Behavior Through Disrupted Olfactory Development, and Impairs Female Fertility Through Disrupted GnRH Neuron Migration. Mol Neurobiol. 55(11):8709-8727. doi: 10.1007/s12035-018-1013-0. Epub 2018 Mar 27.
Shalapour, S., Lin, X.J., Bastian, I.N., Brain, J., Burt, A.D., Aksenov, A.A., Vrbanac, A.F., Li, W., Perkins, A., Matsutani, T., Zhong, Z., Dhar, D., Navas-Molina, J.A., Xu, J., Loomba, R., Downes, M., Yu, R.T., Evans, R.M., Dorrestein, P.C., Knight, R., Benner, C., Anstee, Q.M., Karin, M. (2017). Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature. 551, 340-345. doi: 10.1038/nature24302.
Xie H., Hoffmann H.M., Iyer A.K., Brayman M.J., Ngo C., Sunshine M.J., Mellon P.L. (2017) Chromatin status and transcription factor binding to gonadotropin promoters in gonadotrope cell lines. Reprod Biol Endocrinol. 15(1):86. doi: 10.1186/s12958-017-0304-z.
Hoffmann H.M., Gong P., Tamrazian A., Mellon P.L. (2018) Transcriptional interaction between cFOS and the homeodomain-binding transcription factor VAX1 on the GnRH promoter controls Gnrh1 expression levels in a GnRH neuron maturation specific manner. Mol Cell Endocrinol. 461:143-154. doi: 10.1016/j.mce.2017.09.004. Epub 2017 Sep 7.
Schoeller E.L., Clark D.D., Dey S., Cao N.V., Semaan S.J., Chao L.W., Kauffman A.S., Stowers L., Mellon P.L. (2016) Bmal1 Is Required for Normal Reproductive Behaviors in Male Mice. Endocrinology. 157:4914-4929. doi: 10.1210/en.2016-1620.
Huang P.P., Brusman L.E., Iyer A.K., Webster N.J., Mellon P.L. (2016) A Novel Gonadotropin-Releasing Hormone 1 (Gnrh1) Enhancer-Derived Noncoding RNA Regulates Gnrh1 Gene Expression in GnRH Neuronal Cell Models. PLoS One. 11(7):e0158597. doi: 10.1371/journal.pone.0158597. eCollection 2016.
Hoffmann, H. M., Trang, C., Gong, P., Kimura, I., Pandolfi, E. C., and Mellon, P. L. (2016) Deletion of Vax1 from GnRH Neurons Abolishes GnRH Expression and Leads to Hypogonadism and Infertility. Journal of Neuroscience. 36: 3506-3518. doi: 10.1523/JNEUROSCI.2723-15.2016.
Main Contact Information
Core Leaders
- Dr. Pamela Mellon
Professor, Department of Reproductive Endocrinology and Infertility, UCSD School of Medicine - Dr. Mohit Jain
Assistant Professor, Departments of Pharmacology and Medicine, UCSD School of Medicine - Dr. Christopher Benner
Assistant Professor, Department of Medicine, UCSD School of Medicine
Contact
UCSD Superfund Research Center
University of California, San Diego
Pharmacology Department
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722