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J Bishop1, L Nehrebeckyj2,Y Wang2, J Quance3, J Kariya4, and G Wolfe2

Two-Generation Reproduction Toxicity of Propylthiouracil When Administered to Sprague-Dawley Rats in the Drinking Water. J Bishop1, L Nehrebeckyj2,Y Wang2, J Quance3, J Kariya4, and G Wolfe2.

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J Bishop1, L Nehrebeckyj2,Y Wang2, J Quance3, J Kariya4, and G Wolfe2

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  1. Two-Generation Reproduction Toxicity of Propylthiouracil When Administered to Sprague-Dawley Rats in the Drinking Water. J Bishop1, L Nehrebeckyj2,Y Wang2, J Quance3, J Kariya4, and G Wolfe2 1NIEHS/NTP, RTP, NC2TherImmune Research Corporation, Gaithersburg, MD;3PAI, Frederick, MD;4USEPA, Washington DC;

  2. H2 C H N S H3C C H2 NH O Propylthiouracil • a thyroid hormone-synthesis inhibitor • decreases T3 and T4; increases TSH • weight reduction • thyroid weight and pathology

  3. Study Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 F0: Exposure F0: Necropsy F0: F0: Cohabi Vag. tation Cytol. F0: Gestation F0: Lactation F1: Exposure F1: F1: Pup Obs F1: Cohabi Vag F1: AGD tation Cytol. F1: Pinna F1: Gestation detachment F1: Lactation and eye opening F2: Pup Obs F1: Ret. F2: Nipples AGD F1: Testicular F2: Pinna Descent detachment and eye F1: Vaginal opening Opening F2: Ret. F1: F1: Preputial Nipples PND 16 Separation Select. F2: PND F1: 16 PND 21 Select. Sep. F2: PND F1: PND 21 21 Necrop. necrop.

  4. F0 Body Weight 540 520 Group 1M - 0.0000% M 500 Group 2M - 0.0001% M 480 Group 3M - 0.0004% M Group 4M - 0.0015% M 460 Group 1F - 0.0000% F 440 Group 2F - 0.0001% F 420 Group 3F - 0.0004% F Group 4F - 0.0015% F 400 380 Grams 360 340 320 300 280 260 240 220 200 180 1 2 3 4 5 6 7 8 9 10 Study Weeks

  5. F0 Food Consumption

  6. F0 Water Consumption 38 37 36 35 34 33 32 31 30 Gram 29 Group 1M Group 2M 28 Group 3M Group 4M Group 1F Group 2F 27 Group 3F Group 4F 26 25 24 23 22 21 20 1 2 3 4 5 6 7 8 Study Week

  7. 4.9* 10.3* F1 Pups/litter Dose Group 0.000 0.0001 0.0004 0.0015 % W/V Male 6.2 5.6 5.4 5.5 Female 8.6 7.0 7.6 4.9* Combined 14.8 12.6 13.8 10.3* * p < 0.001

  8. 2.51* 2.52* 0.37* F1 and F2 AGD and AGD/Pup Weight Ratio * p < 0.05 Dunnett’s

  9. F1 and F2 Sexual Developmental Parameters

  10. 7.2* 0.5* 21.6* 22.1* F0 Thyroid Hormone Levels

  11. 0.9* 1.4* 9.1* 13.9* F1 Thyroid Hormone Levels

  12. F0 and F1 Organ Weight Changes

  13. F0 Thyroid Weight

  14. F1 Thyroid Weight

  15. 10/10 7/10 1/10 10/10 1/10 3/10 3/10 2/10 1/10 1/10 F0 and F1 Histopathological Changes

  16. Summary • PTU at 0.0015% in drinking water is a reproductive toxicant based upon reduction in F1 litter size • Thyroid hormones (T4 and TSH) were altered at both 0.0004% and 0.0015% PTU • Thyroid hyperplasia and degeneration of testicular germinal epithelium were noted at all dose levels • Degeneration of the testicular germinal epithelium was the only observable effects of PTU at 0.0001%

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