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Pubertal assays ( ♀ and ♂)

Pubertal assays ( ♀ and ♂). Summary of study designs for Single-dose Multi-dose Multi-chemical array. Pubertal single-dose study. Pubertal single-dose: general design. Gavage 6 rats/chemical/block/strain 2 blocks per sex

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Pubertal assays ( ♀ and ♂)

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  1. Pubertal assays (♀ and ♂) Summary of study designs for Single-dose Multi-dose Multi-chemical array

  2. Pubertalsingle-dosestudy

  3. Pubertal single-dose:general design • Gavage • 6 rats/chemical/block/strain • 2 blocks per sex • 6 chemicals per sex, with different means of affecting endocrine system • Single (high) dose per chemical • 2 strains of rat (LE and SD)

  4. Ethinyl estradiol (potent estrogen) 0.005 Tamoxifen(blocks ER; partial antagonist/agonist) 10 Propylthiouracil(inhibits T3/T4 formation) 240 Pimozide(increases prolactin secretion) 30 Methoxychlor(weak estrogen) 100 Ketoconazole(inhibits steroidogenesis) 100 Female pubertal single-dose:chemicals and doses(mg/kg/day)

  5. Flutamide (potent anti-androgen) 50 Methyl testosterone(potent androgen) 80 Propylthiouracil(inhibits T3/T4 formation) 240 Pimozide(increases prolactin secretion) 30 Dibutylphthalate(weak anti-androgen) 1000 Ketoconazole(inhibits steroidogenesis) 100 Male pubertal single-dose:chemicals and doses(mg/kg/day)

  6. Pubertalmulti-dosestudy

  7. Pubertal multi-dose:general design • Gavage • 15 SD rats per dose • Weak estrogen (♀) or anti-androgen (♂) at 3 doses • Positive and negative controls(2 doses of positive control to investigate putative influence of bodyweight changes)

  8. Males Vehicle control Vinclozolin 10 30 100 Flutamide 25 50 Females Vehicle control Methoxychlor 12.5 25 50 Ethinyl estradiol 0.0025 0.0050 Pubertal multi-dose:chemicals and doses(mg/kg/day)

  9. Pubertal multi-dose:endpoints (female) • Daily body weight, clinical observations • Age at vaginal opening(pinhole, thread, complete) • Estrous cyclicity • Weights: uterus and cervix (wet & dry), ovaries, thyroid/parathyroids; liver, kidney, pituitary, adrenals • Histopathology of ovaries, uterus, thyroid; gross lesions

  10. Pubertal multi-dose:endpoints (male) • Daily body weight, clinical observations • Age at preputial separation(onset, thread, complete) • Weights: testes, epididymides, prostate (DL/V separately), seminal vesicles/coagulating glands, levator ani/bulbocavernosus, thyroid/parathyroids; liver, kidney, pituitary, adrenals • Histopathology of testis, epididymis, thyroid

  11. Pubertal multi-chemical arraystudy

  12. Pubertal multi-chemical array:general design • Gavage • 15 SD rats per dose • 10 chemicals with different means of affecting endocrine system • 2 doses per chemical • Vehicle control for each of 2 “components” per sex

  13. Pubertalmulti-chemical array study(females)

  14. Vehicle control Fenarimol(inhibits aromatase) 50 250 Octylphenol(weak estrogen) 200 400 Bisphenol A(weak estrogen) 100 400 Ketoconazole(inhibits steroidogenesis) 50 100 Female pubertal array:chemicals and doses(mg/kg/day) Component 1 Component 2 • Vehicle control • Atrazine(affects hypothalamus) • 75 • 150 • Propylthiouracil(inhibits T3/T4 formation) • 2 • 25 • Fadrozole(inhibits aromatase) • 0.3 • 3.0

  15. Female pubertal array:endpoints • Daily body weight, clinical observations • T4 and TSH levels • Age at vaginal opening(pinhole, thread, complete) • Estrous cyclicity • Weights: uterus (wet & dry), ovaries, thyroid • Histopathology of ovaries, uterus, thyroid(vagina if warranted) • Liver, kidney, pituitary, adrenal weights if warranted

  16. Pubertalmulti-chemical array study(males)

  17. Male pubertal array:chemicals and doses(mg/kg/day) Component 1 Component 2 • Vehicle control • Atrazine(affects hypothalamus) • 75 • 150 • Propylthiouracil(inhibits T3/T4 formation) • 2 • 25 • Procymidone(anti-androgen) • 50 • 100 • Vehicle control • Linuron (anti-androgen +/prenatal, -/adult) • 50 • 100 • p,p’-DDE(anti-androgen) • 50 • 100 • Ketoconozole(inhibits steroidogenesis) • 50 • 100

  18. Male pubertal array:endpoints • Daily body weight, clinical observations • T4 and TSH levels • Age at preputial separation(onset, thread, complete) • Weights: testes, epididymides, prostate (whole and DL/V), seminal vesicles/coagulating glands, levator ani/bulbocavernosus, thyroid • Histopathology of testis, epididymis, thyroid • Liver, kidney, pituitary, adrenal weights if warranted

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