Behavioral effects of low-dose gestational day 11-13 retinoic acid exposure.
In a comparison article we report that maternal PO exposure to 2.5 mg/kg all-trans retinoic acid (RA) daily for 3 consecutive days over gestational days (GD) 11-13 produces a 10% reduction in weight of cerebellum at 4 weeks of age, not accompanied by other malformations. Here we report the results of a preliminary behavioral analysis of offspring exposed gestationally to RA as above. Exposed dams were allowed to deliver normally, and litters were culled to eight pups (4 +/- 1 of each sex) at birth. Both male and female offspring were tested prior to weaning on GD 21. Thereafter females were killed on postnatal day (PND) 28 for verification of RA effects on regional brain weight, and all subsequent behavioral testing was conducted on males. Preweaning tests were restricted to negative geotaxis (PND 8-9) and open field activity (PND 22). Postweaning tests included open field activity (PND 43), auditory startle response (three times, on PNDs 22, 43, and 84), 2-week activity in residential running wheels (PNDs 62-76), complex maze performance for 5 consecutive days (PND 83-87), emergence latency (PND 106), and assessment of the behavioral response to an amphetamine challenge (PND 107). Males were then killed on PND 108 for verification of RA effects on regional brain weights. In this study, RA reduced weight of cerebellum but not striatum. Cerebellar weight was 92% of control values in PND 28 females, and this weight difference had diminished to 95% of control weight by PND 108 in males. There were no treatment effects on negative geotaxis, activity in a small open field, auditory startle amplitude, or latency to enter an illuminated alley from a dark chamber. Maze learning occurred at levels equal to or slightly better than controls. Running wheel activity was enhanced by RA exposure, whereas activity in response to an amphetamine challenge was reduced by such exposure. We conclude that RA doses low enough to produce mild weight reductions in cerebellum, without attendant malformations, can alter behavior. The precise nature of these alterations remains to be elucidated, but the findings reported here suggest that effects may be more pronounced on activity than on learning.
Holson
R R
RR
Division of Reproductive and Developmental Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
Gazzara
R A
RA
Ferguson
S A
SA
Adams
J
J
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000254:growth & development; D005260:Female; D005865:Gestational Age; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D004856:Postural Balance / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D011919:Rats, Inbred Strains; D013216:Reflex, Startle / Q000187:drug effects; D014212:Tretinoin / Q000633:toxicity*; D014828:Vocalization, Animal / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
D014212:Tretinoin