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Toxicol Sci. 1999 Sep;51(1):44-53.

Detection of the environmental antiandrogen p,p-DDE in CD and long-evans rats using a tier I screening battery and a Hershberger assay.

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  • 1DuPont Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware 19714, USA. john.c.oconnor@usa.dupont.com

Abstract

In this report, p,p'-DDE, a weak androgen receptor (AR) antagonist, has been examined in a Tier I screening battery designed to detect endocrine-active compounds (EACs). The screening battery that was used to examine p,p'-DDE was an abbreviated version of a proposed Tier I screening battery (Cook et al., 1997, Regul. ToxicoL Pharmacol. 26, 60-68) that consisted of a 15-day intact male in vivo battery and an in vitro yeast transactivation system (YTS). In addition, strain sensitivity differences were evaluated using male Crl:CDIGS BR (CD) and Long-Evans (LE) rats. Finally, p,p'-DDE was examined in a Hershberger assay designed to detect AR agonists. In the in vivo male battery using CD rats, responses to p,p'-DDE included organ weight changes (increased relative liver weight and decreased absolute epididymis weight) and hormonal alterations (increased serum estradiol [E2] levels and decreased serum FSH and T4 levels). Responses to p,p'-DDE in LE rats included organ weight changes (increased relative liver weight, absolute epididymis weight, relative accessory sex gland [ASG] unit weight, as well as the individual component weights of the ASG [prostate and seminal vesicles]), and hormonal alterations (increased serum testosterone [T], E2, dihydrotestosterone [DHT], thyroid-stimulating hormone [TSH], and decreased T4 levels). These data demonstrate that there are considerable strain-sensitivity differences to p,p'-DDE exposure. The described in vivo male battery using CD rats did not identify p,p'-DDE as an EAC. In contrast, the in vivo male battery using LE rats identified p,p'-DDE as a EAC. Evaluation of the data for the LE rats demonstrate that p,p'-DDE appears to be acting as an AR antagonist whose primary effects are more potent centrally than peripherally. In the YTS for the AR, p,p'-DDE had an EC50 value of 3.5 x 10(-4) M; however, in the AR YTS competition assay, p,p'-DDE did not inhibit DHT binding to the AR. p,p'-DDE was inactive in the YTS containing the estrogen receptor or progesterone receptor at the concentrations evaluated. In the Hershberger assay, p,p'-DDE administration caused antiandrogen-like effects characterized by attenuation of the testosterone propionate-induced increases in reproductive-organ weights. In summary, these data suggest that strain selection will affect the ability to detect certain weak EACs. However, a Tier I screening battery consisting of both in vivo and in vitro endpoints would reduce the chance that weak-acting compounds such as p,p'-DDE would not be identified as potential EACs.

PMID:
10496676
[PubMed - indexed for MEDLINE]
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