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Leakey JEA, Allaben WT, Dunnick JK, et al. NTP Genetically Modified Model Report on the Toxicology and Carcinogenicity Studies of 3’-Azido-3’-Deoxythymidine (CASRN 30516-87-1) in Genetically Modified C3B6.129F1-Trp53tm1Brd N12 Haploinsufficient Mice (In Utero and Postnatal Gavage Study): NTP GMM 14 [Internet]. Research Triangle Park (NC): National Toxicology Program; 2013 Oct.
NTP Genetically Modified Model Report on the Toxicology and Carcinogenicity Studies of 3’-Azido-3’-Deoxythymidine (CASRN 30516-87-1) in Genetically Modified C3B6.129F1-Trp53tm1Brd N12 Haploinsufficient Mice (In Utero and Postnatal Gavage Study): NTP GMM 14 [Internet].
Show detailsMethods and Results
Plug-positive dams were provisionally assigned to dose groups on gestational day (GD) 0 and monitored for body weight gain from GD 1 to GD 10 to determine whether they were pregnant. Non-pregnant dams were returned to the breeding pool. Dosing of pregnant dams began on GD 12. More dams were assigned to the 0/0/0 (0/0) mg/kg groups and 240/120/240 (240/40) mg/kg groups because more pups were required to populate the 45-week stop-study and the 30-week continuous dosing study, which only used these doses. Litters of more than six live pups were culled to six pups (three male and three female where possible) on postnatal day (PND) 1 prior to the first postnatal dose.
Litter success and pup survival were high across all dose groups with pup losses due mainly to gavage errors rather than dose effects (Table H1). There was no significant treatment-related effect on maternal body weight during gestation (Figure H1). Although the dams in the 80 mg/kg group exhibited higher mean body weight values, this was due to heavier dams being assigned to this dose group. The body weight curves for the treated pups between PND 1 and PND 10 for the litters used for the 30- and 45-week continuous dosing studies and from PND 1 though PND 8 for the 45-week stop-study litters are given in Figures H2 and H3 respectively. These growth curves are presented separately from the main growth curves for the heterozygous F1 p53+/− mice because during this period the daily pup weights were derived from the total weight of each litter divided by the number of surviving pups in the litter and not all pups were loaded onto the studies. Therefore, there is not a natural continuation between these growth curves and the main growth curves, which are derived from the individual mice that were loaded onto the studies. There was no significant dose effect on neonatal body weight gain in the litters used for the continuous dosing studies (Figure H2), but neonatal stop-study mice administered 240/40 mg/kg did exhibit a slower weight gain than the corresponding pups in the 0/0 mg/kg group (Figure H3).
Table H1Litter Parameters and Pup Survival for Mouse Pups in the In Utero/Postnatal Gavage Studies of AZT
| 0/0/0 (0/0) mg/kga | 80/40/80 mg/kg | 160/80/160 mg/kg | 240/120/240 (240/40) mg/kga | |
|---|---|---|---|---|
| Total dams pregnant | 50 | 22 | 19 | 53 |
| Dams which did not litter | 4 | 4 | 3 | 3 |
| Total litters | 46 | 18 | 16 | 50 |
| Total pups born | 314 | 141 | 105 | 351 |
| Average born per litter | 6.8 | 7.8 | 6.6 | 7.0 |
| Number of males bornb | 152 (48.4) | 69 (48.9) | 56 (53.3) | 174 (49.6) |
| Sex ratioc | 1:0.97 | 1:1.01 | 1:0.88 | 1:0.94 |
| Pups born dead (%) | 14 (4.5) | 2 (1.4) | 0 (0) | 13 (3.7) |
| % Survival PND 1 – PND 10d | 92.8 | 98.1 | 97.8 | 95.3 |
| % Survival PND 11 – PND 28d | 96.8 | 91.1 | 98.9 | 93.8 |
- a
Litters dosed to provide stop-study pups are included in the litter and pup birth data but are excluded from the pup survival estimates. Postnatal survival for stop-study pups was 98.6% and 96.5% between PND 1 and PND 10 for the 0/0 mg/kg and 240/40 mg/kg groups, respectively, and 98.6% and 100% between PND 11 and PND 28 for the 0/0 mg/kg and 240/40 mg/kg groups, respectively.
- b
Excludes pups born dead, percent of total live pups given in parentheses
- c
Male:female
- d
Excludes pups culled on PND 1 and stop-study litters
Figure H1Growth Curves for Pregnant Dams Administered AZT by Gavage in the In Utero/Postnatal Studies of AZT
Figure H2Growth Curves for Mice Administered AZT by Gavage in the 30- and 45-Week In Utero/Postnatal Studies of AZT
Figure H3Growth Curves for Mice Administered AZT by Gavage in the 45-Week In Utero/Postnatal Stop-Study of AZT
- LITTER SUCCESS AND SURVIVAL - NTP Genetically Modified Model Report on the Toxic...LITTER SUCCESS AND SURVIVAL - NTP Genetically Modified Model Report on the Toxicology and Carcinogenicity Studies of 3’-Azido-3’-Deoxythymidine (CASRN 30516-87-1) in Genetically Modified C3B6.129F1-Trp53tm1Brd N12 Haploinsufficient Mice (In Utero and Postnatal Gavage Study)
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