US EPA

Methoxychlor and Environmental "Estrogen" Receptors in ER-Minus Mice

EPA Grant Number: R825295
Title: Methoxychlor and Environmental "Estrogen" Receptors in ER-Minus Mice
Investigators: Lubahn, Dennis B. , Welshons, Wade V.
Institution: University of Missouri - Columbia
EPA Project Officer: Deener, Kacee
Project Period: February 10, 1997 through February 9, 1999
Project Amount: $190,000
RFA: Endocrine Disruptors (1996) RFA Text |  Recipients Lists
Research Category: Endocrine Disruptors , Economics and Decision Sciences , Health , Safer Chemicals

Description:

The long term goals of our research program are to find novel functions for both estrogens and estrogen response proteins, and then to identify the molecular mechanisms mediating these functions. This research will lead to a better understanding of the developmental, physiological, and biochemical roles of estrogens, and additionally will add to our general understanding of how estrogenic chemicals in the environment can impinge upon human and wildlife health. To pursue these research goals, we "knocked out" the estrogen receptor (ER) gene in mice via homologous recombination and asked the following question: Would an ER-minus mouse, which lacked the classic full length ER protein, respond to any known estrogen, estrogen metabolite, or exogenous (natural or synthetic) estrogen analog? If ER-minus mice did respond, then we would know that at least one estrogen response protein other than ER exists. The working hypothesis was that several non-ER response proteins exist and that in transgenic ER-minus mice we would see a response to some estrogens, such as the environmental estrogen, methoxychlor. We have found in ER-minus mice a uterine lactoferrin mRNA response to methoxychlor, but not to estradiol. We propose that the putative methoxychlor receptor will elicit additional responses distinct from estradiol and the classic ER protein. We now hypothesize that: A) methoxychlor works, at least in part, through its own unique non-classical, estrogen response (NCER) protein; and B) a NCER "receptor" can be readily characterized in the ER-minus mouse background. Using this mouse model system we propose to characterize the putative methoxychlor receptor. Specifically, we propose to clone the putative methoxychlor receptor. Isolation of the putative methoxychlor receptor is critically important in understanding the molecular mechanism of action of methoxychlor, an important environmental endocrine disruptor.

Publications and Presentations:

Publications have been submitted on this project: View all 5 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 2 journal articles for this project

Supplemental Keywords:

RFA, Health, Scientific Discipline, Environmental Chemistry, Health Risk Assessment, Endocrine Disruptors - Environmental Exposure & Risk, endocrine disruptors, Risk Assessments, Children's Health, Molecular Biology/Genetics, Biology, Endocrine Disruptors - Human Health, adverse outcomes, wildlife, molecular mechanisms, endocrine disrupting chemicals, Methoxychlor, receptor bindings, animal models, human exposure, mice, estrogen response, biochemistry, biological effects

Progress and Final Reports:

1998 Progress Report
Final Report