Toxicological Sciences, Vol 51, 44-53, Copyright © 1999 by Society of Toxicology
JC O'Connor, SR Frame, LG Davis and JC Cook
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.
ARTICLES
Detection of the environmental antiandrogen p,p-DDE in CD and long- evans rats using a tier I screening battery and a Hershberger assay
DuPont Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware 19714, USA. john.c.oconnor@usa.dupont.com
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