Environmental & Occupational Health

Faculty Profile

  • Mingzhu Fang, PhD, DABT

  • Assistant Professor

  • Department of Environmental and Occupational Health

  • CV

Keywords
Epigenetics; DNA methylation; circadian rhythm, Environmental diseases; breast cancer; esophageal cancer.

Biography
Dr. Fang is a board certified environmental and occupational toxicologist who received Postdoctoral training in Cancer Research at the Ernest Mario School of Pharmacy in Rutgers University, following earning her PhD in Toxicology from the College of Veterinary Medicine in Seoul National University on 2001. Prior to her PhD study, she received an MS in Anatomic Pathology and an BA in Clinical Medicine from Norman Bethune Medical College of Jilin University in China.

Research Interests
Dr. Fang’s research is focused on the circadian clock mechanisms underlying chemical and abnormal lighting induced disease processes, especially mammary tumorigenesis. Of particular interest is how endogenous differences (e.g., genetic make-up and microbiome) influence the response to environmental factors, including genotoxic stress and abnormal lighting. A major emphasis of her work is analysis of circadian rhythm of mammary epithelial clock upon exposure to carcinogen or jet-lag (mimic shift work), with or without treatment of preventive dietary agents. We use chemical-induced mammary tumorigenesis rat models and in vitro circadian reporter cell models to elucidate how the epigenetic regulation of mammary epithelial clock involves in mammary tumorigenesis and its prevention. Well-known transgenic mouse model for mammary tumorigenesis and progression is also used to demonstrate the promoting effect of circadian disruption by chronic jet-lag on mammary tumorigenesis and lung metastasis. Based on preclinical study results, we also perform clinical translational studies on the development of biomarkers and intervention strategies to mitigate the adverse effects of circadian disruption in night shift workers. In addition, Dr. Fang also study epigenetic mechanism, including DNA methylation and histone modification, underlying the development of environmental diseases.

Research Highlights

As a postdoctoral fellow, Dr. Fang demonstrated that DNA hypermethylation of key tumor suppressor genes and DNA repair genes are frequently happened early events during esophageal squamous carcinogenesis, indicating that they can be used as early molecular targets in chemoprevention and chemotherapy. Dr. Fang is the first to demonstrate the epigenetic chemopreventive effects of dietary polyphenols and isoflavones. Recently, she has demonstrated that exposure to a carcinogen significantly disrupts circadian expression of genes involved in DNA damage response/repair (DDRR) and mammary cell growth/differentiation during the early stages of carcinogen-induced rat mammary tumorigenesis. Dr. Fang also revealed that chemopreventive dietary methylselenocysteine restored the rhythmic expression of those genes by resetting mammary circadian clock through enhancement of NAD+-dependent SIRT1 deacetylase activity in carcinogen-treated mammary epithelial cells, leading to inhibition of mammary tumorigenesis. These findings provide the first evidence for the role of circadian rhythm on chemoprevention. Moreover, Dr. Fang demonstrated that uncoupling of DDRR from circadian control by environmental stresses and endogenous factors increases susceptibility to mammary carcinogenesis. In addition, she has successfully established and validated in vitro bioluminescence assay to determine mammary epithelial circadian rhythm.

Select Publications
X Chen,N Li,S Wang,J Hong,M Fang,J Yousselfson,P Yang,RA Newman,RA Lubet,CS Yang (2002) "Aberrant arachidonic acid metabolism in esophageal adenocarcinogenesis, and the effects of sulindac, nordihydroguaiaretic acid, and alpha-difluoromethylornithine on tumorigenesis in a rat surgical model.", Carcinogenesis 23(5) 2095-2102 http://www.ncbi.nlm.nih.gov/pubmed/?term=12507933&report=abstract

Y Wang,MZ Fang,J Liao,GY Yang,Y Nie,Y Song,C So,X Xu,LD Wang,CS Yang (2003) "Hypermethylation-associated inactivation of retinoic acid receptor beta in human esophageal squamous cell carcinoma.", Clinical cancer research : an official journal of the American Association for Cancer Research 9(5) 5257-5263 http://www.ncbi.nlm.nih.gov/pubmed/?term=14614007&report=abstract

MZ Fang,Y Wang,N Ai,Z Hou,Y Sun,H Lu,W Welsh,CS Yang (2003) "Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines.", Cancer research 63(5) 7563-7570 http://www.ncbi.nlm.nih.gov/pubmed/?term=14633667&report=abstract

Y Su,X Chen,M Klein,M Fang,S Wang,CS Yang,RK Goyal (2004) "Phenotype of columnar-lined esophagus in rats with esophagogastroduodenal anastomosis: similarity to human Barrett's esophagus.", Laboratory investigation; a journal of technical methods and pathology 84(5) 753-765 http://www.ncbi.nlm.nih.gov/pubmed/?term=15094711&report=abstract

MZ Fang,C Liu,Y Song,GY Yang,Y Nie,J Liao,X Zhao,Y Shimada,LD Wang,CS Yang (2004) "Over-expression of gastrin-releasing peptide in human esophageal squamous cell carcinomas.", Carcinogenesis 25(5) 865-871 http://www.ncbi.nlm.nih.gov/pubmed/?term=14764456&report=abstract

MZ Fang,Z Jin,Y Wang,J Liao,GY Yang,LD Wang,CS Yang (2005) "Promoter hypermethylation and inactivation of O(6)-methylguanine-DNA methyltransferase in esophageal squamous cell carcinomas and its reactivation in cell lines.", International journal of oncology 26(5) 615-622 http://www.ncbi.nlm.nih.gov/pubmed/?term=15703815&report=abstract

N Li,S Sood,S Wang,M Fang,P Wang,Z Sun,CS Yang,X Chen (2005) "Overexpression of 5-lipoxygenase and cyclooxygenase 2 in hamster and human oral cancer and chemopreventive effects of zileuton and celecoxib.", Clinical cancer research : an official journal of the American Association for Cancer Research 11(5) 2089-2096 http://www.ncbi.nlm.nih.gov/pubmed/?term=15756036&report=abstract

MZ Fang,D Chen,Y Sun,Z Jin,JK Christman,CS Yang (2005) "Reversal of hypermethylation and reactivation of p16INK4a, RARbeta, and MGMT genes by genistein and other isoflavones from soy.", Clinical cancer research : an official journal of the American Association for Cancer Research 11(5) 7033-7041 http://www.ncbi.nlm.nih.gov/pubmed/?term=16203797&report=abstract

M Fang,D Chen,CS Yang (2007) "Dietary polyphenols may affect DNA methylation.", The Journal of nutrition 137(5) 223S-228S http://www.ncbi.nlm.nih.gov/pubmed/?term=17182830&report=abstract

X Ren,X Zhang,AS Kim,AM Mikheev,M Fang,RC Sullivan,RE Bumgarner,H Zarbl (2008) "Comparative genomics of susceptibility to mammary carcinogenesis among inbred rat strains: role of reduced prolactin signaling in resistance of the Copenhagen strain.", Carcinogenesis 29(5) 177-185 http://www.ncbi.nlm.nih.gov/pubmed/?term=17916903&report=abstract

CS Yang,M Fang,JD Lambert,P Yan,TH Huang (2008) "Reversal of hypermethylation and reactivation of genes by dietary polyphenolic compounds.", Nutrition reviews 66(5) S18-20 http://www.ncbi.nlm.nih.gov/pubmed/?term=18673481&report=abstract

MZ Fang,X Zhang,H Zarbl (2010) "Methylselenocysteine resets the rhythmic expression of circadian and growth-regulatory genes disrupted by nitrosomethylurea in vivo.", Cancer prevention research (Philadelphia, Pa.) 3(5) 640-652 http://www.ncbi.nlm.nih.gov/pubmed/?term=20424134&report=abstract

X Ren,JC Graham,L Jing,AM Mikheev,Y Gao,JP Lew,H Xie,AS Kim,X Shang,C Friedman,G Vail,MZ Fang,Y Bromberg,H Zarbl (2013) "Mapping of Mcs30, a new mammary carcinoma susceptibility quantitative trait locus (QTL30) on rat chromosome 12: identification of fry as a candidate Mcs gene.", PloS one 8(5) e70930- http://www.ncbi.nlm.nih.gov/pubmed/?term=24023717&report=abstract

FR Silva,L Zanatta,RC Pedrosa,MZ Fang (2013) "Steroids and related compounds: basic and clinical aspects.", BioMed research international 2013(5) - http://www.ncbi.nlm.nih.gov/pubmed/?term=23484145&report=abstract

H Zhu,H Zhang,F Jin,M Fang,M Huang,CS Yang,T Chen,L Fu,Z Pan (2014) "Elevated Orai1 expression mediates tumor-promoting intracellular Ca2+ oscillations in human esophageal squamous cell carcinoma.", Oncotarget 5(5) 3455-3471 http://www.ncbi.nlm.nih.gov/pubmed/?term=24797725&report=abstract

M Fang,P Ohman-Strickland,K McNeil,JP Lew,B Crabtree,H Kipen,H Zarbl (2015) "Sleep interruption associated with house staff work schedules alters circadian gene expression", Sleep Medicine 16(5) 1388-1394 https://doi.org/10.1016/j.sleep.2015.06.011

M Fang,WR Guo,Y Park,HG Kang,H Zarbl (2015) "Enhancement of NAD?-dependent SIRT1 deacetylase activity by methylselenocysteine resets the circadian clock in carcinogen-treated mammary epithelial cells.", Oncotarget 6(5) 42879-42891 http://www.ncbi.nlm.nih.gov/pubmed/?term=26544624&report=abstract

VR Sunil,KN Vayas,M Fang,H Zarbl,C Massa,AJ Gow,JA Cervelli,H Kipen,RJ Laumbach,PJ Lioy,JD Laskin,DL Laskin (2017) "World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung.", Experimental and molecular pathology 102(5) 50-58 http://www.ncbi.nlm.nih.gov/pubmed/?term=27986442&report=abstract

M Fang,PA Ohman Strickland,HG Kang,H Zarbl (2017) "Uncoupling genotoxic stress responses from circadian control increases susceptibility to mammary carcinogenesis.", Oncotarget 8(5) 32752-32768 http://www.ncbi.nlm.nih.gov/pubmed/?term=28427145&report=abstract

M Fang,HG Kang,Y Park,B Estrella,H Zarbl (2017) "In Vitro Bioluminescence Assay to Characterize Circadian Rhythm in Mammary Epithelial Cells.", Journal of visualized experiments : JoVE 0(5) - http://www.ncbi.nlm.nih.gov/pubmed/?term=28994762&report=abstract

Scholarly Activities
Ad Hoc Reviewer in Scientific Report, Oncotarget, Carcinogenesis, Cancer Prev Res, Toxicology Science, Int J Cancer, Toxicology Letter, Chemotherapy,

Regular Member, Society of Research on Biological Rhythm (SRBR)

Associate Editor, Fundamental Toxicological Sciences Full Member, Society of Toxicology (SOT) and American College of Toxicology (ACT)

Active Member, American Association for Cancer Research (AACR)

Guest Editor, BioMed Research International, Special Issue “Steroids and Related Compounds: Basic and Clinical Aspects.”

Awards
Distinguished Chinese Toxicologist Lectureship Award - AACT (2018) - This Award is to honor an established toxicologist of Chinese ethnic origin who is deemed to have contributed significantly to the science of toxicology and is exemplary in his/her professional life.

EOHSI Faculty Development Program Travel Award - EOHSI (2011) - EOHSI awards faculty the Faculty Development Program Travel Award to assist in research travel costs.

Annual Bibliography of Significant Advances in Dietary Supplements Research by ODS/NIH - ODS/NIH (2004) - From 1999 to 2007, ODS produced the Annual Bibliography of Significant Advances in Dietary Supplement Research.

Gallo Award - Annual Retreat on Cancer Research in New Jersey (2003) - he Gallo Awards recognize the scientific contribution of researchers at the Annual Retreat of Cancer Research in New Jersey.

The New Jersey Cancer Research Award for Scientific Excellence - New Jersey Cancer Research (2002) - The New Jersey Cancer Research Award for Scientific Excellence given to the best research abstracts.

Young investigator Award - Asian Society of Toxicology (2000) - The Young Investigator Award is presented to the applicant who submits the best research proposal.