Evaluation of a Tier I Screening Battery for Detecting Endocrine-Active Compounds (EACs) Using the Positive Controls Testosterone, Coumestrol, Progesterone, and RU486

After previously examining 12 compounds with known endocrine activities, we have evaluated 4 additional compounds in a Tier I screening battery for detecting endocrine-active compounds: a weak estrogen receptor agonist, an androgen receptor agonist, a progesterone receptor agonist, and a PR antagonist

J. C. O'Connor


Scholarcy highlights

  • Changes of the testis
  • Mean final body weights and relative liver weights were not affected by TEST, COUM, PROG, or RU486 administration at the dosages tested
  • In the dietary restriction experiment using the in vivo female battery, the only endpoint affected by dietary restriction levels that resulted in final body-weight decrements up to 80% of ad libitum control was uterine progesterone receptor concentrations
  • These changes may not always be statistically significant. The absence of this characteristic pattern of changes suggests that the evaluated compound is not a thyroid toxicant, even if statistically significant hormonal changes are observed. Using this integrated Tier I screening battery consisting of a 5-day ovariectomized female battery, a 15-day intact male battery, and an in vitro yeast transactivation system, all 4 test compounds were identified as endocrine-active compounds and produced distinct fingerprints of activity
  • These responses coupled with the YTS data demonstrating primary binding to the progesterone receptor would allow one to distinguish RU486 as a progesterone antagonist
  • Relative accessory sex gland weight, and the individual component weights of the ASG were unaffected by dietary restriction at levels that resulted in a final body weight decrement of up to a 26% when compared to the ad libitum control
  • Parts of the Tier I screening battery have been used to identify several other compounds with potential endocrine-modulating activity, including methoxychlor, bisphenol A, linuron, atrazine and cyanazine, a placebo pellet with estrogenic activity, and 3 proprietary compounds. Based on this validation exercise, a distinct “fingerprint” for each of these endocrine activities was observed against which compounds with unknown activities can be compared. This validation exercise is consistent with the ICCVAM process and we believe illustrates the rigor that the EPA endocrine validation team should apply to any test before it is implemented as an endocrine screen

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