Blumberg, Bruce - University of California, Irvine - Department of Developmental and Cell Biology

研究领域

One long-standing interest in the laboratory concerns the interactions between nuclear receptor and growth factor signaling in important developmental patterning processes. Retinoic acid (RA) and fibroblast growth factors (FGFs) are critical factors that interact to mediate a variety of developmental processes. RA and FGF pathways are mutually inhibitory and this inhibition is important for key developmental processes such as sensory placode formation, neuronal differentiation, somite differentiation, anteroposterior and dorsoventral patterning and the proliferation of stem cells and cancer cells. The Blumberg lab seeks to understand the genetic program and molecular interactions underlying the mutual antagonism between RA and FGF signals in embryonic development and in stem cell differentiation. A second major interest in the Blumberg laboratory concerns gene-environment interactions and the developmental basis of health and disease. Two receptors are of particular interest in this research, the steroid and xenobiotic receptor, SXR, and the peroxisome proliferator activated receptor gamma (PPARγ). SXR is the key mediator of the body’s response to endobiotics, dietary and xenobiotic chemicals. Differences in SXR underlie some of the known differences between humans and animals and among individuals in their ability to metabolize drugs and chemicals. SXR is also an important mediator of immune function and loss of SXR function leads to widespread inflammation and cancer. Activation of SXR leads to apoptosis of breast cancer cells and may have anti-cancer effects in other tissues. Obesity and obesity-related disorders such as type 2 diabetes and coronary artery disease have become an epidemic of global proportions. Excessive consumption of calorie-dense food and diminished physical activity (the “Couch Potato model”) are the generally accepted causal factors for obesity. But can environmental factors play a role in exposing preexisting genetic differences or amplifying the effects of diet and excerise? Our “obesogen hypothesis” proposes the existence of environmental chemicals that can perturb lipid homeostasis, adipocyte development and adipose tissue function. We identified organotins as bona fide obesogens that cause adipocyte differentiation in vitro and fat accumulation in vivo. Moreover, prenatal exposure to organotins reprograms metabolism such that affected animals are predisposed to weight gain later in life, despite a normal diet. Understanding the role of these environmental obesogens in regulating fat cell development will provide important insights into a novel contributing factor for obesity.

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Lille-Langoy R, Goldstone JV, Rusten M, Milnes MR, Male R, Stegeman JJ, Blumberg B, Goksoyr A. (2015) Environmental contaminants activate human and polar bear (Ursus maritimus) pregnane X receptors (PXR, NR1I2) differently. Toxicol Appl Pharmacol 284(1): 54-64. PMCID: 4387200r PMID:25680588. Legler J, Fletcher T, Govarts E, Porta M, Blumberg B, Heindel JJ, Trasande L. (2015) Obesity, diabetes, and associated costs of exposure to endocrine-disrupting chemicals in the European union. J Clin Endocrinol Metab 100(4): 1278-88. PMCID: 4399302r PMID:25742518. Janesick A, Wu SC, Blumberg B. (2015) Retinoic acid signaling and neuronal differentiation. Cell Mol Life Sci 72(8): 1559-76. PMID:25558812. Heindel JJ, Vom Saal FS, Blumberg B, Bovolin P, Calamandrei G, Ceresini G, Cohn BA, Fabbri E, Gioiosa L, Kassotis C, Legler J, La Merrill M, Rizzir L, Machtinger R, Mantovani A, Mendez MA, Montanini L, Molteni L, Nagel SC, Parmigiani S, Panzica G, Paterlini S, Pomatto V, Ruzzin J, Sartor G, Schug TT, Street ME, Suvorov A, Volpi R, Zoeller RT, Palanza P. (2015) Parma consensus statement on metabolic disruptors. Environ Health 14(1): 54. PMCID: 4473834r PMID:26092037. Bavik C, Henry SH, Zhang Y, Mitts K, McGinn T, Budzynski E, Pashko A, Lieu KL, Zhong S, Blumberg B, Kuksa V, Orme M, Scott I, Fawzi A, Kubota R. (2015) Visual Cycle Modulation as an Approach toward Preservation of Retinal Integrity. PLoS One 10(5): e0124940. PMCID: 4430241r PMID:25970164. Azuma K, Casey SC, Urano T, Horie-Inoue K, Ouchi Y, Blumberg B, Inoue S. (2015) Pregnane X receptor knockout mice display aging-dependent wearing of articular cartilage. PLoS One 10(3): e0119177. PMCID: 4352085r PMID:25749104. Ortiz L, Nakamura B, Li X, Blumberg B, Luderer U. (2014) Reprint of “In utero exposure to benzo[a]pyrene increases adiposity and causes hepatic steatosis in female mice, and glutathione deficiency is protective”. Toxicol Lett 230(2): 314-21. PMID:24291350. Kamstra JH, Hruba E, Blumberg B, Janesick A, Mandrup S, Hamers T, Legler J. (2014) Transcriptional and epigenetic mechanisms underlying enhanced in vitro adipocyte differentiation by the brominated flame retardant BDE-47. Environ Sci Technol 48(7): 4110-9. PMCID: 3983330r PMID:24559133. Janesick AS, Shioda T, Blumberg B. (2014) Transgenerational inheritance of prenatal obesogen exposure. Mol Cell Endocrinol 398(1-2): 31-5. PMCID: 4262625r PMID:25218215. Janesick A, Schug TT, Heindel JJ, Blumberg B. (2014) Environmental pollutants and obesity. Handbook of obesity : epidemiology, etiology, and physiopathology, Third Edition 1: 471-88.