Gestational all-trans retinoic acid treatment in the rat: neurofunctional changes and cerebellar phenotype.
Neurofunctional effects produced by gestational all-trans retinoic acid (all-trans RA) treatment were investigated in the offspring of Sprague-Dawley rats. Reproduction data, onset of reflexive behavior, locomotor activity, motor coordination and motor learning were examined. Moreover, possible changes in size and morphology of the cerebellum were evaluated. The results show that all-trans RA treatment (2.5 mg/kg, by gavage) on gestational days (GD) 11-13 significantly increased postnatal mortality and decreased pup weight gain. Moreover, all-trans RA-treated rats showed a significant delay in eyes opening, hair growth as well as in the maturation of righting reflex, cliff aversion and pole grasping. All-trans RA treatment significantly impaired the ambulatory activity in adult rats without altering the number of rearings. All-trans RA-treated rats subjected to the rotarod/accelerod task showed significant impairment in both motor coordination and motor learning ability. The morphological analysis revealed a significant reduction in the cerebellar size and impairment in foliation profile, at PND 3 with subsequent recovery at PNDs 8 and 40. The evidence that functional alterations increase with age and persist in adulthood whereas the morphological changes decline with age, strongly supports the view that, besides the cerebellum morphology, the organization of the cerebellar circuitry, and in particular of cortico-cerebellar connections, are also affected by all-trans RA treatment.
Coluccia
Addolorata
A
Department of Pharmacology and Human Physiology, Medical School, University of Bari, Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy.
Belfiore
Domenico
D
Bizzoca
Antonella
A
Borracci
Pietro
P
Trerotoli
Paolo
P
Gennarini
Gianfranco
G
Carratù
Maria Rosaria
MR
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D002531:Cerebellum / Q000002:abnormalities* / Q000187:drug effects* / Q000473:pathology; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology; D005260:Female; D007859:Learning Disabilities / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D019957:Motor Skills Disorders / Q000139:chemically induced / Q000503:physiopathology; D009421:Nervous System Malformations / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D009434:Neural Pathways / Q000002:abnormalities / Q000187:drug effects / Q000503:physiopathology; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D012727:Sex Characteristics; D013237:Stereoisomerism; D013723:Teratogens / Q000633:toxicity*; D013995:Time; D014212:Tretinoin / Q000633:toxicity*
D000970:Antineoplastic Agents; D013723:Teratogens; D014212:Tretinoin