PMID- 9380000
OWN - NLM
STAT- MEDLINE
DCOM- 19971110
LR  - 20190920
IS  - 0892-0362 (Print)
IS  - 0892-0362 (Linking)
VI  - 19
IP  - 5
DP  - 1997 Sep-Oct
TI  - Gestational retinoic acid exposure: a sensitive period for effects on neonatal 
      mortality and cerebellar development.
PG  - 335-46
AB  - This is the first in a series of studies investigating the developmental 
      stage-specific neurobehavioral effects of all-trans retinoic acid (RA) exposure. 
      Because high doses of this compound are known to be lethal to the developing 
      organism, we first conducted a dose-response study to identify RA doses that 
      produce low enough levels of gestational/postnatal mortality to make a behavioral 
      analysis possible in survivors. Secondarily, at doses found to produce sufficient 
      survivors on PND 28, effects on body and regional brain weights were examined. 
      Finally, at these doses, effects on somatic malformations were evaluated. Four 
      separate exposure periods were analyzed: gestational days (GD) 8 through 10, 11 
      through 13, 14 through 16, or postnatal days (PND) 3 through 5. In the postnatal 
      exposure period rat pups were injected (s.c.) with three consecutive daily doses 
      of 0, 5, 10, or 20 mg/kg RA on PND 3 through 5. This postnatal exposure had no 
      detectable effect on survival, body or brain weight. In contrast, there was a 
      marked sensitivity to RA in the GD 11-13 group. Many pups from dams given 10 
      mg/kg RA PO on GD 11-13 were found dead in the cage on the day of birth, and all 
      surviving pups died within 4 days of birth. Examination of milkbands revealed no 
      evidence of effective suckling in these short-term survivors. The same 10 mg/kg 
      dose at GD 8-10 or GD 14-16 produced much lower mortality and pups appeared to 
      suckle normally. To produce adequate PND 28 survival in the GD 11-13 group, it 
      was necessary to reduce dosage to 2.5 mg/kg daily. Even this lower exposure 
      produced effects on PND 28 body and brain weight, significantly lowering weights 
      of body (84% of control), whole brain (94%), and cerebellum (90%). Cerebellar 
      weight was also depressed as percent of whole brain weight, suggesting an effect 
      focused specifically on this region. RA at 10 or 12.5 mg/kg over GD 14-16 also 
      reduced cerebellar weight (92% and 91% of control, respectively). Thus, exposure 
      on GD 14-16 had effects similar to those seen at GD 11-13, but only at 
      considerably higher doses. In contrast, exposure to RA on GD 8-10 did not affect 
      whole body or brain weight, and of eight brain regions examined, only brain stem 
      weight was reduced (91% of control). The GD 8-10 exposure also differed 
      substantially from later exposures in that it was the only treatment to produce 
      substantial malformations, including exencephaly, eye and skeletal defects. We 
      conclude that gestational exposure to RA produces lethality and regional brain 
      stunting that is dose and developmental stage specific, with a pronounced 
      sensitive period on GD 11-13. In contrast, the GD 8-10 period is most sensitive 
      for production of malformations, albeit at somewhat higher doses.
FAU - Holson, R R
AU  - Holson RR
AD  - Division of Reproductive and Developmental Toxicology, National Center for 
      Toxicological Research, Jefferson, AR 72079, USA.
FAU - Gazzara, R A
AU  - Gazzara RA
FAU - Ferguson, S A
AU  - Ferguson SA
FAU - Ali, S F
AU  - Ali SF
FAU - Laborde, J B
AU  - Laborde JB
FAU - Adams, J
AU  - Adams J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Neurotoxicol Teratol
JT  - Neurotoxicology and teratology
JID - 8709538
RN  - 5688UTC01R (Tretinoin)
SB  - IM
MH  - Abnormalities, Drug-Induced/pathology
MH  - Animals
MH  - Animals, Newborn/*physiology
MH  - Birth Weight/drug effects
MH  - Cerebellum/drug effects/*growth & development
MH  - Eating/drug effects
MH  - Female
MH  - Gestational Age
MH  - Organ Size/drug effects
MH  - Pregnancy
MH  - Rats
MH  - Tretinoin/*toxicity
MH  - Weight Gain/drug effects
EDAT- 1997/10/06 00:00
MHDA- 1997/10/06 00:01
CRDT- 1997/10/06 00:00
PHST- 1997/10/06 00:00 [pubmed]
PHST- 1997/10/06 00:01 [medline]
PHST- 1997/10/06 00:00 [entrez]
AID - S0892-0362(97)00039-1 [pii]
AID - 10.1016/s0892-0362(97)00039-1 [doi]
PST - ppublish
SO  - Neurotoxicol Teratol. 1997 Sep-Oct;19(5):335-46. doi: 
      10.1016/s0892-0362(97)00039-1.