Angeline Andrew PhD

June 2002

Young investigator enjoys disciplinary border crossing

Angeline Andrew has always been interested in science and biology. On choosing a field to pursue, she says, “It was the environmental aspects of toxicology that attracted me.” And while she may enjoy toxicology, interdisciplinary work is her strong point, making her a collaborator extraordinaire. Working at Dartmouth Medical School between Margaret Karagas’s lab in the department of Epidemiology and Biostatistics and Joshua Hamilton’s lab in the department of Pharmacology and Toxicology, this post-doctoral research associate is forming a bridge between two very different areas of research. Angeline’s work combines epidemiology, which studies health and disease trends in populations of people, with toxicology, which looks at the way toxins affect the human body. And Angeline’s research has real world implications that are easy enough to appreciate: one of her several current projects is working to find the mechanism by which arsenic causes cancer, through the Center for Environmental Health Science’s Toxic Metals Research Program. Researchers believe that arsenic can be at least partially responsible for causing some cases of bladder, lung, and skin cancers. The precise way that this occurs is far from being completely understood.

Angeline was the principal investigator a study published in the International Journal of Cancer, April 10, 2003, that suggests that arsenic that enters the body’s tissue, for example through drinking water, plays a role in disabling the natural DNA repair mechanisms. These exist to help prevent damaged and mutated DNA from replicating and causing cancer. If this hypothesis is true, then arsenic can be considered what is called a co-carcinogen—a substance that is not directly carcinogenic, but helps a carcinogen to become harmful — in this case, by keeping the DNA mutations caused by a carcinogen from being fixed before it's too late.

There are many types of gene repair mechanisms. Angeline is looking at one called nucleotide excision repair, one of the most common repair mechanisms that the body uses. When a segment of DNA has been damaged, enzyme complexes find the error, cut it out of the DNA strand, and let other enzymes replace the correct sequence by copying the opposite strand of the two-stranded DNA molecule. Many spontaneous mutations occur even in a healthy system; mutations also occur through exposure to UV light and other environmental factors. Thus, DNA repair systems are constantly at work to prevent mistakes in the DNA.

So how does Angeline study DNA repair? She analyzes blood samples from human subjects enrolled in Dr. Margaret Karagas’s case-control study of bladder cancer in New Hampshire. Using advanced DNA technology, Angeline measures the changes of gene expression for genes encoding for DNA repair in the blood samples. Arsenic can have a direct effect on the DNA, not by causing mutation, but by causing it to express different genes than normal. This could mean that the DNA no longer expresses genes that make enzymes that repair DNA. By studying the changes in gene expression, Angeline is hoping to figure out what is causing DNA repair to be limited. Currently, she is looking only at nucleotide excision repair, but there are many more types of DNA repair mechanisms that also need to be examined. Eventually she and the researchers she works with hope to come up with a mechanism for arsenic-induced bladder cancer that can also be applied to other cancers that may have arsenic as a co-carcinogen.

Her interdisciplinary experience has been an asset for other projects. Angeline was one of the co-principal investigators for undergraduate researcher Joel Wickre’s [http://www.dartmouth.edu/~toxmetal/NWPU2002.shtml] epidemiological study of drinking water contamination in Siuna, Nicaragua. During her undergraduate career at Tufts, Angeline spent two years in Nicaragua, teaching at the American Nicaragua School where children of diplomats can learn in English in their home country. This experience gave her qualifications to help with not only the science, but also the logistical aspects of Joel’s trip. Joel will work with Angeline and several other Dartmouth researchers to analyze his data.

Angeline explains the benefits of using real-life samples from people who may be affected by arsenic in their groundwater. This method is often much more accurate because it is testing hypotheses using natural conditions rather than what Angeline called, “artifacts of cell culture work” from rats and chickens. Not only can cell cultures, or cell masses grown from a piece of tissue in a lab, soon lose the characteristics of the cells they started out as, but rats and chickens are not the same as humans. Thus by testing people’s blood, the researchers are one step closer to finding out how arsenic induced cancer is caused than if they began with laboratory animals. And that could be vitally important to people who are exposed to arsenic daily through the water they drink.

Bethany Fleishman
CEHS intern

Publications during training:

Andrew AS, Barchowsky A. Nickel induced plasminogen activator inhibitor-1 (PAI-1) expression inhibits the fibrinolytic activity of human airway epithelial cells. Toxicol Appl Pharmacol 168:50-57, 2000.

Andrew AS, Klei L, Barchowsky A. Nickel requires hypoxia-inducible factor-1{alpha}, not redox signaling, to induce plasminogen activator inhibitor-1. Am J Physiol 281:L607, 2001.

Andrew AS, Klei L, Barchowsky A. AP-1-dependent induction of plasminogen activator inhibitor-1 by nickel does not require reactive oxygen. Am J Physiol 281:L616, 2001

Andrew AS, Soucy N, Klei L, and Barchowsky A. Nickel induces interleukin-8 via AP-1 and mitogen activated protein kinases. Journal of Biological Chemistry 277(27): 24225-31, 2002.

Jacobs A, Nichols C, Andrew AS, Marek D, Wood S, Sinclair S, Wrighton S, Kostrubsky V, Sinclair J. Effect of arsenite on induction of CYP1A, CYP2B and CYP3A in primary cultures of rat hepatocytes. Toxicol Appl Pharmacol 157:51-59, 1999.

Awards and presentations during training:

1998 - Graduate Research Fellowship, National Institute of Diabetes & Digestive & Kidney Diseases

1999 - First Prize, Northeast Society of Toxicology Best Graduate Student Poster Award

2000 - Third Annual Karen Wetterhahn Award, Sponsored by the National Institute of Environmental Health Sciences

2000 - Outstanding Scientific Presentation Award Sponsored by the Oxygen Society

2000 - Environmental Carcinogenesis Conference Poster Award, Sponsored by the Vermont Cancer Center

2000 - Travel Award - 2000 Conference on Hazardous Waste Research. Sponsored by the National Institute of Environmental Health Sciences

2000 - Graduate Research Fellowship, NIEHS/EPA

2002 - Cancer Prevention Research Fellowship, Sponsored by the Cancer Research Foundation of America and the American Society of Preventive Oncology

2002 - Post-doctoral Research Award, Sponsored by the Society of Toxicology Metals Specialty Section.

Post-doctoral mentors: Margaret R. Karagas, PhD, Joshua W. Hamilton, PhD

Post-doctoral thesis: Arsenic, DNA repair, and the molecular epidemiology of bladder cancer

Research focus: Angeline focused on studying the mechanisms by which arsenic acts as a co-carcinogen in several types of cancer including bladder cancer. Combining epidemiology with toxicology, she is looking at how arsenic disables DNA repair mechanisms, leading to cancer.

Publications during fellowship:

Andrew AS, Karagas MR, Hamilton JW. Decreased DNA repair gene expression among individuals exposed to arsenic in United States drinking water. Int J Cancer 104 (3):263-268, 2003.

Andrew AS, Warren AJ, Barchowsky A, Temple KA, Klei L, Soucy NV, O’Hara KA, Hamilton JW. Genomic and proteomic profiling responses to heavy metals in human lung cells. EHP Toxicogenomics 111(6):825-838, 2003.

Awards during fellowship:

2002 - Cancer Prevention Research Fellowship sponsored by American Society of Preventive Oncology (ASPO) and the Cancer Research Foundation of America (CRFA) and funded by CRFA.

Current position: Assistant Professor of Community and Family Medicine, Dartmouth Medical School