Contact information
Department of Biochemistry and Molecular Biology
Michigan State University
East Lansing, MI 48824-1319
fertuckk@msu.edu

Education
B.Sc. Environmental Toxicology, University of Toronto, Canada., 1998
Ph.D. Biochemistry and Environmental Toxicology, April 2003.

Research Project

Estrogenicity of Environmentally-Relevant PAHs

I began my studies at MSU by characterizing 20 representative members of the polycyclic aromatic hydrocarbon (PAH) group of compounds for estrogenic behavior. PAHs are released continually into the environment through combustion processes, including industrial activities and motor vehicle usage, and exposure to humans and wildlife can occur through inhaled air particulates, river and lake sediments, and in charred foods. I was able to show during my undergraduate thesis project that several PAHs possess strong teratogenic activity. At the beginning of my graduate program at MSU we then decided to study instead the potential estrogen receptor-interacting effects of these compounds, due to their evident steroid-like structure. I was able to confirm that several of these compounds possess a significant ability to produce in vitro estrogenic responses.

Further studies focused on benzo[a]pyrene, the PAH found to show the strongest estrogenic response. In a recently published paper we reported that although the metabolites responsible for estrogen receptor interactions in vitro could be identified, no estrogen-like response could be detected in a mouse model system (using the estrogen-inducible endpoints of uterine weight and uterine expression of the lactoferrin gene). In fact, even dosing the mice directly with the active metabolites produced no detectable estrogenic response. While there are several possible interpretations of these findings (which include insufficient dose or very rapid excretion), we chose to explore one other very provocative hypothesis, which can be stated as follows: benzo[a]pyrene mimics the transcriptional effects of endogenous estrogen in a subset of estrogen-responsive tissues, while acting as an antiestrogen or non-estrogen in other tissues. In other words, it is possible that some pollutant compounds may interfere with estrogen signaling only in certain organs, and therefore the examination of only uterine responses, which is common in the industrial screening of compounds for estrogenic effect, may be misleading and liable to result in some false negatives. Support for this idea comes from the relatively recent concept of selective estrogen receptor modulators (SERMs), a class of drugs that have been designed to exhibit tissue-specific estrogenic effects for use in the treatment of postmenopausal symptoms.

My project now involves the use of oligonucleotide and cDNA microarrays to monitor the expression of several thousand genes in estrogen-responsive tissues of mice treated with benzo[a]pyrene or other suspected estrogenic endocrine disruptors, with the aim of developing an assay that can be used to rapidly identify estrogenic compounds and reveal specific mechanisms of action. We are in the process of creating a custom microarray containing genes that have been selected because of their known or suspected regulation by estrogen. A test printing of this array is currently being evaluated, and then tissues from a preliminary estrogen time course study (uterus, mammary gland, bone, and liver) will next be analyzed. In the meantime similar experiments have been performed using commercial Affymetrix GeneChips. These experiments have allowed rapid generation of preliminary data, as well as empirical identification of additional estrogen-responsive genes. The custom microarrays will next be used to characterize the responses to suspected estrogen mimics, including PAHs and other pollutants that are of interest based on our in vitro studies. Gene expression profiles for selected genes will be confirmed using traditional methods (e.g. RT-PCR). Overall, we anticipate that this assay will greatly increase the amount of information gained from each animal used in endocrine disruptor research, while simultaneously providing a means to more accurately evaluate chemicals for potential to interfere with vital estrogen signaling pathways.