The peripubertal male rat assay as an alternative to the Hershberger castrated male rat assay for the detection of anti-androgens, oestrogens and metabolic modulators.
A range of chemicals with various levels of activity as actual or potential endocrine disrupters have been evaluated for activity in the peripubertal male rat assay. The chemicals studied included anti-androgens (vinclozolin), cyproterone acetate, flutamide, 2, 2-bis(4-chlorophenyl)-1,1-dichloroethylene (DDE), metabolic modulators (anastrazole, finasteride, ketoconazole) and oestrogens (butyl benzyl phthalate (BBP), methoxychlor, bisphenol A (BPA), diethylstilboestrol (DES)), the suspected anti-androgen dibutyl phthalate (DBP) and the non-oestrogen fenitrothion. Dosing extended over postnatal days (pnd) 22-35, 36-50, 36-55 and 22-35, with recovery to pnd 55 or 22-55. The endpoints studied were changes in the weights of testes, epididymides, seminal vesicles and prostate. Changes in body weight and the weights of the liver and kidney were also monitored. In some experiments changes in the day of prepuce separation (PPS) were also determined. Only BBP and BPA were inactive in all the assays conducted. Changes in the weight of reproductive tissues provided a sensitive indicator of activity for the remaining chemicals with the exception of DDE, for which higher dose levels could have been used. However, none of the curtailed periods of exposure were able to detect all of the agents. Diethyl stilboestrol, and to a lesser extent DBP and DDE, delayed PPS when exposure occurred over the period pnd 22-55. A complex dependence of the day of PPS on the period of exposure and the body weight of the test animals was observed, and caution is recommended when assessing this endpoint in the presence of reductions in body weight. It is concluded that reproductive tissue weight changes in the peripubertal male have shown sensitivity to a range of biochemical modulators, oestrogens and anti-androgens, and that as such the assay warrants further evaluation. Measurement of delays in PPS may be of value in cases of large delays, but delays of 1-2 days will be difficult to interpret with confidence. The present results are discussed within the context of the sexually mature male rat assay described by O'Connor and the castrated male rat assay described by Hershberger, both of which are the subject of current international study. It is concluded that a decision on the usefulness of the peripubertal male rat assay must await the generation of further data on each of these three assays. There is an urgent need for international agreement on a list of reference endocrine disrupters and their active dose levels, with which to validate individual endocrine disruption assays and batteries of assays.
Ashby
J
J
AstraZeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK. John.Ashby@CTL.AstraZeneca.com
Lefevre
P A
PA
D000077384:Anastrozole; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000032:analysis / Q000494:pharmacology*; D000818:Animals; D001681:Biological Assay; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004968:Estrogens, Non-Steroidal / Q000008:administration & dosage / Q000032:analysis / Q000494:pharmacology*; D005278:Fenitrothion / Q000494:pharmacology; D018120:Finasteride / Q000494:pharmacology; D005837:Genitalia, Male / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D011627:Puberty / Q000502:physiology; D051381:Rats; D012741:Sexual Maturation / Q000187:drug effects*; D014230:Triazoles / Q000494:pharmacology
D000726:Androgen Antagonists; D004968:Estrogens, Non-Steroidal; D009570:Nitriles; D014230:Triazoles; D000077384:Anastrozole; D018120:Finasteride; D007654:Ketoconazole; D005278:Fenitrothion