# Presentation: 095291

## 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

**a thyroid hormone-synthesis inhibitor**
**decreases T3 and T4; increases TSH**
**weight reduction**
**thyroid weight and pathology**

## Study Design

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- F0: Exposure

- F0: Necropsy

- F0:

- Cohabi

- tation

- F0: Gestation

- F1: Pup Obs

- F1:

- PND 16

- Select.

- F0: Lactation

- F1: Testicular

- Descent

- F1: Vaginal

- Opening

- F1: Preputial

- Separation

- F1: Exposure

- F1:

- Cohabi

- tation

- F1: Gestation

- F2: Pup Obs

- F0:

- Vag.

- Cytol.

- F1:

- PND 21

- Sep.

- F1: AGD

- F1: Pinna

- detachment

- and eye

- opening

- F1: Ret.

- Nipples

- F1: PND

- 21

- necrop.

- F1: Lactation

- F2:

- AGD

- F2: Pinna

- detachment

- and eye

- opening

- F2: Ret.

- Nipples

- F2: PND

- 16

- Select.

- F2: PND

- 21

- Necrop.

- F1:

- Vag

- Cytol.

## F0 Body Weight

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- 540

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- Study Weeks

- Grams

- Group 1M - 0.0000% M

- Group 2M - 0.0001% M

- Group 3M - 0.0004% M

- Group 4M - 0.0015% M

- Group 1F - 0.0000% F

- Group 2F - 0.0001% F

- Group 3F - 0.0004% F

- Group 4F - 0.0015% F

**F****0**** Body Weight**

## F0 Food Consumption

## F0 Water Consumption

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- Study Week

- Gram

- Group 1M

- Group 2M

- Group 3M

- Group 4M

- Group 1F

- Group 2F

- Group 3F

- Group 4F

**F****0**** Water Consumption**

## 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**

## F1 and F2 AGD and AGD/Pup Weight Ratio

|  | F1 |  |  |  | F2 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Dose Groups | F AGD
mm | F AGD/ gWt | M AGD
mm | M AGD / gWt | F 
AGD
mm | F AGD/ gWt | M AGD
mm | M AGD / 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* | 0.37 |
| 0.0004 | 1.15 | 0.18 | 2.59 | 0.38 | 1.22 | 0.19 | 2.52* | 0.37* |
| 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

## F1 Thyroid Hormone Levels

## 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 | 10/10 |
| F0 F
 | 0/10 | 0/10 | 1/10 | 10/10 |
| F1 M
 | 0/10 | 0/10 | 1/10 | - |
| F1 F
 | 0/10 | 0/10 | 0/10 | - |
| Degeneration of germinal epithelium |  |  |  |  |
| F0
 | 0/10 | 3/10 | 3/10 | 2/10 |
| F1 
 | 0/10 | 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%**

## Slide 17