Grantee Research Project Results
Final Report: Improved Reproductive Risk Assessment by Elucidation of Comparative Metabolism
EPA Grant Number: R827685E02Title: Improved Reproductive Risk Assessment by Elucidation of Comparative Metabolism
Investigators: Gandy, Jay
Institution: University of Arkansas for Medical Sciences
EPA Project Officer: Chung, Serena
Project Period: August 1, 1999 through July 31, 2001
RFA: EPSCoR (Experimental Program to Stimulate Competitive Research) (1999) RFA Text | Recipients Lists
Research Category: EPSCoR (The Experimental Program to Stimulate Competitive Research)
Objective:
The objective of this research project was to develop in vitro systems expressing isoforms of rodent drug metabolizing enzymes that are expressed in reproductive tissues and compare them with corresponding human isoforms, which currently are available commercially. Knowledge of species-comparative differences in the metabolism of drugs and endocrine disrupting chemicals will allow animal study data to provide a better assessment of human risk.
Summary/Accomplishments (Outputs/Outcomes):
The project focused on the cellular localization and the constitutive cytochrome P450 (CYP) isoforms that may play a role in 7-ethoxyresorufin or 7-benzyloxyresorufin-O-dealkylase (EROD or BROD) activities in rat testes. In the absence of Leydig cells, neither EROD nor BROD activities were detectable in the testes, whereas enriched Leydig cells had a four- to fivefold increase in activities when compared to whole testes. Hepatic EROD and BROD activities in rodents have been associated with CYP1A1 and CYP1A2, but these isoforms were not immunochemically detectable in testicular microsomes. In contrast, significant levels of CYP1B1 immunoreactive protein were detected. Thus, CYP1B1 mRNA was isolated from rat testes and expressed in human lymphoblastoid cells. The CYP1B1 recombinant cells expressed both BROD and EROD activities, with the relative expression (approximately threefold more BROD than EROD) being similar to that observed in testicular microsomes isolated from young sexually mature rats. Recombinant cells expressing CYP2A1 were obtained commercially and found to express EROD, but not BROD activity. Testes from older rats expressed significant levels of CYP2A1 in addition to CYP1B1, and also expressed more EROD activity relative to BROD.
Conclusions:
CYP2A1 and CYP1B1 were found to be the major CYP isoforms expressed in sexually mature Sprague Dawley rat testes, and they appear to be responsible for the testicular alkoxyresorufin-O-dealkylase activities that reside primarily in Leydig cells. Knowledge of which CYP isoforms are expressed in testes from animal strains used in reproductive toxicology testing, in comparison to those expressed in human testes, is important for the evaluation of human risk from developmental toxicants, particularly those requiring metabolic activation.
Journal Articles on this Report : 1 Displayed | Download in RIS Format
| Other project views: | All 1 publications | 1 publications in selected types | All 1 journal articles |
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Seng JE, Gandy J, Ansari R, Leakey JEA. Cellular distribution of selective age dependent testicular cytochrome P450-dependent alkoxyresorufin-O-dealkylases in Sprague-Dawley rats. Archives of Biochemistry and Biophysics. |
R827685E02 (Final) |
not available |
Supplemental Keywords:
species comparison, endocrine disruptors, reproductive tissue, reproductive risk assessment, reproduction, metabolism, Experimental Program to Stimulate Competitive Research, EPSCoR, Science and Engineering Environmental Research, SEER., Health, RFA, Scientific Discipline, PHYSICAL ASPECTS, Geographic Area, ENVIRONMENTAL MANAGEMENT, Health Risk Assessment, Physical Processes, Risk Assessments, State, Environmental Chemistry, Endocrine Disruptors - Human Health, endocrine disruptors, Endocrine Disruptors - Environmental Exposure & Risk, Risk Assessment, insulin resistance, human exposure, exposure, assessment technology, human reproductive health, Arkansas, endocrine disrupting chemicals, isoforms, comparative metabolism, reproductive risk management, metabolizing enzymes, human health risk, exposure assessmentRelevant Websites:
http://www.uams.edu/aces/ Exit
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.