|Kathleen F. Arcaro
Associate Professor of Veterinary and Animal Sciences, University of Massachusetts
Ph.D.: Rutgers University
One of the goals of environmental toxicologists is to understand the relationship between exposure to toxicants and disease. The research in my laboratory focuses on a heterogeneous group of environmental pollutants referred to as “endocrine disruptors”. Endocrine disruptors may mimic, block, or alter the metabolism of endogenous hormones and have been implicated in the decline of amphibian populations and the etiology of some cancers. Many pesticides, herbicides, industrial pollutants, pharmaceuticals, and household products are potential endocrine disruptors.
The research in my laboratory is aimed at understanding the human health effects of exposure to complex mixtures of environmental pollutants with emphasis on estrogenic and antiestrogenic pollutants. There presently are three major funded projects in the lab: 1) breast milk as a marker of exposure, effect and breast cancer risk, 2) signaling pathways in estrogen receptor-negative breast cancer and, 3) bioassays for detection of endocrine disruptors in water ways.
Breast Milk and Breast Milk Cells: Biomarkers of Exposure, Effect and Genetic Susceptibility to Breast Cancer Breast milk is an ideal human fluid for studying the relationship between exposure to pollutants and breast cancer risk because it contains lipophilic compounds implicated in the etiology of breast cancer and exfoliated breast epithelial cells. We have ongoing studies in which we are analyzing the relationship between pollutants in milk and levels of DNA damage, changes in gene expression and promoter hypermethylation in the exfoliated breast epithelial cells.
Signaling Pathways in Estrogen Receptor-Negative Breast Cancer Estrogen receptor tumor status is an important clinical characteristic of breast cancer, which correlates with patients’ prognosis, response to hormone therapy, and overall survival. Tamoxifen, a landmark drug that acts as an anti-estrogen in the therapy of hormone-dependent breast cancers, reduces disease recurrence in patients with estrogen receptor-positive tumors, but is ineffective against estrogen receptor-negative tumors. Additionally, some tumors do not respond to tamoxifen treatment despite estrogen receptor-positive status, and some tumors that initially respond to tamoxifen eventually acquire tamoxifen-resistance resulting in a more aggressive tumor with poorer prognosis. Using a recently derived, tamoxifen-selected, estrogen receptor-negative breast cancer cell line, we have identified several genes that are differentially regulated in breast cancer. One gene, mitogen-inducible gene 2 (MIG2) is the subject of a recent publication.
Gene Expression in the Freshwater Japanese Medaka (Oryzias latipes): A Sensitive Biomarker for Exposure to Endocrine Disrupting Compounds The Japanese medaka is a small freshwater, temperate zone, fish that breeds readily in the laboratory and can tolerate local waters year round making it ideal for toxicological studies both in the laboratory and in the field. We are using medaka to develop and optimize sensitive, reliable, and inexpensive assays for detecting endocrine disrupting compounds in water ways. Many pollutants in water quickly concentrate in fish and can be measured by the changes in gene expression that they produce. Using real time reverse-transcriptase PCR we have found that exposing male medaka to concentrations as low as one picomolar of 17 b-estradiol for as little as 48 hours results in a significant increase in the estrogen-responsive gene, Vitellogenin. By examining the mRNA levels of Vitellogenin, and other estrogen-responsive genes in male medaka we can determine if they have been exposed to any estrogens in the water. Likewise, examination of mRNA levels of androgen- or dioxin-like-responsive genes can alert us to the presence of the pollutants in the water. Thus, medaka can serve as sentinels for the detection of endocrine disrupting compounds in water.
Representative recent publications:
Gozgit J.M., Pentecost P.T., Marconi S.A., Otis C.N., Wu C., and Arcaro K.F. 2006, Use of an Aggressive MCF-7 Cell Line Variant, TMX2-28, to Study Cell Invasion in Breast Cancer: Altered Expression of MIG2 in Human Breast Carcinomas May Play a Role in Cancer Cell Invasion. Molecular Cancer Research, 4(12):905-913.
Gozgit J.M., Nestor K.M., Fasco M.J., Pentecost B.T. and Arcaro K.F. 2004, Polycyclic aromatic hydrocarbons induce estrogen receptor-mediated luciferase, but do not upregulate estrogen responsive genes in MCF-7 cells. Toxicology and Applied Pharmacology 196:58-67.
Ssempebwa J.C., Carpenter D.C., Yilmaz B., DeCaprio, A.P., O’Hehir, D.J. and Arcaro K.F. 2004, Waste crankcase oil: an environmental contaminant with potential to modulate estrogenic responses. J Toxicology and Environmental Health 67:1081-1094.
Carpenter, D.O., Arcaro, K.F., Spink, D.C. 2002, Understanding the human health effects of chemical mixtures. Environmental Health Perspectives, 110(S1): 25-42.
Arcaro, K.F., Gierthy, J.F. and Mackerer, C.R. 2001, Antiestrogenicity of clarified slurry oil and two crude oils in a human breast-cancer cell assay. Journal of Toxicology and Environmental Health, Part A 62:101-107.