Two Generation Reproduction Toxicity of Propylthiouracil When

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Two Generation Reproduction Toxicity of Propylthiouracil When Powered By Docstoc
					   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, NC 2TherImmune Research Corporation,

   Gaithersburg, MD;3PAI, Frederick, MD;4USEPA, Washington DC;
         Propylthiouracil
                   H2   H
       H 3C        C    N        S
              C
              H2
                            NH

                        O
 a thyroid hormone-synthesis inhibitor
 decreases T3 and T4; increases TSH
 weight reduction
 thyroid weight and pathology
                                               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:
                                   Vag.     Cohabi
                                   Cytol.   tation

                                            F0: Gestation
                                                        F0: Lactation             F1: Exposure
                                                        F1: Pup Obs                                F1:                             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
                                                                           F1: Vaginal                         and eye
                                                                           Opening                             opening
                                                                  F1:        F1: Preputial                          F2: Ret.
                                                                  PND 16     Separation                             Nipples
                                                                  Select.                                              F2: PND
                                                                      F1:                                              16
                                                                      PND 21                                           Select.
                                                                      Sep.
                                                                                                                         F2: PND
                                                                      F1: PND                                            21
                                                                      21                                                 Necrop.
                                                                      necrop.
                             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
Grams




        380
        360
        340
        320
        300
        280
        260
        240
        220
        200
        180
              1       2            3     4    5       6    7   8   9   10
                                             Study Weeks
F0 Food Consumption
                F0 Water Consumption
       38
       37
       36
       35
       34
       33
       32
       31
Gram




       30
       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
              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*
                                           4.9*

Combined       14.8     12.6     13.8    10.3*
                                          10.3*

* p < 0.001
            F1 and F2 AGD and
           AGD/Pup Weight Ratio
                         F1                                      F2
Dose       F        F          M      M          F         F           M      M
Groups    AGD     AGD/        AGD   AGD /       AGD       AGD/        AGD   AGD /
          mm       gWt        mm     gWt        mm        gWt         mm     gWt

0.0000   1.14    0.18     2.58      0.39    1.20      0.19        2.72      0.40


0.0001   1.14    0.18     2.58      0.38    1.20      0.19       2.51*
                                                                  2.51*     0.37


0.0004   1.15    0.18     2.59      0.38    1.22      0.19       2.52* 0.37*
                                                                        0.37*
                                                                  2.52*


0.0015   1.12    0.18     2.61      0.40    -         -           -         -

* p < 0.05 Dunnett’s
        F1 and F2 Sexual
   Developmental Parameters
Dose Groups      0.0000% 0.0001%   0.0004% 0.0015%

F1 Eye Opening   15.7    15.6      16.2    17.6*

F1 Day of PPS    42.7    43.3      49.7*   -

F1 Day of VO     32.4    32.9      33.8*   -

F2 Eye Opening   16.3    16.1      16.9    -
F0 Thyroid Hormone Levels




                       7.2*
               0.5*   21.6*   22.1*
F1 Thyroid Hormone Levels




           0.9*   1.4*   9.1* 13.9*
F0 and F1 Organ Weight Changes
                                       F0 Generation                            F1 Generation
                        0.0001%    0.0004%                  0.0015%        0.0001%       0.0004%
 Body Weight                                           M             F
 Abs Thyroid                 F   M         F        M             F              M        F
 Rel Thyroid                      M         F        M             F   M         M        F
 Abs Adrenals                                                         F
 Abs Brain                                                            F
 Abs Kidney                                                           F
 Abs Liver                                                            F
 Abs Ovaries                                                          F
 Abs Spleen                                                           F
 Rel Brain                                             M
 Rel Pituitary                    M                   M
 Rel Right Testis                                      M
 Rel Seminal Vesicles                                  M
 Rel Adrenals                                                         F
F0 Thyroid Weight
F1 Thyroid Weight
       F0 and F1 Histopathological
                Changes
Dose Group          0.0000%           0.0001%   0.0004%   0.0015%
Thyroid Follicular Hyperplasia

F0 M                   0/10            0/10      7/10
                                                7/10       10/10
                                                          10/10
F0 F                   0/10            0/10      1/10      10/10
                                                1/10      10/10
F1 M                   0/10            0/10      1/10
                                                 1/10        -

F1 F                   0/10            0/10      0/10        -

Degeneration of germinal epithelium

F0                     0/10           3/10
                                       3/10      3/10
                                                 3/10      2/10
                                                           2/10

F1                     0/10            1/10
                                       1/10      1/10
                                                 1/10        -
                  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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