Maternal Administration of Aripiprazole Impedes the Appendicular Skeletal Growth of Rat Fetuses: A Teratological and Histomorphometrical Assessment

Abstract

Background/Objectives: A third-generation atypical antipsychotic drug, aripiprazole, is known to cross the placental barrier and pose negative consequences on placental growth and the normal development of the fetus. Although a few studies demonstrated these debilitating effects of aripiprazole, its skeletal effects remain unexplored. Therefore, this study was undertaken to evaluate the impact of prenatal aripiprazole exposure, administered at three different dose levels, on the ossification of the appendicular skeleton in 20-day-old rat fetuses. Methods: Forty pregnant Sprague–Dawley rats (n = 40) were assigned to four groups: control and three aripiprazole-treated groups receiving 3 mg/kg (LDA), 6 mg/kg (HDA), and 12 mg/kg (DHDA) daily from gestational days 6–19. Fetuses were delivered on gestation day 20, weighed, and processed for skeletal evaluation using Alizarin Red S staining. Ossification patterns of metacarpals, metatarsals, hip bones, long bones of the forelimb and hindlimbs from a total of 151 fetuses were analyzed and categorized as complete, delayed, or absent. Results: Aripiprazole exposure induced a dose-dependent reduction in the number of completely ossified skeletal bony centers (p < 0.01) with a highly significant reduction in the length of ossified portions of the long bones (p < 0.001). Histomorphometric analysis of Von Kossa-stained fetal femur sections revealed a significant decrease in the thickness of ossified cortical and trabecular bone with a statistically significant reduction in the length of hypertrophied chondrocytes of the growth plate cartilage in the aripiprazole-treated groups (p < 0.05). Conclusions: Prenatal exposure to aripiprazole leads to dose-dependent skeletal growth restriction and delayed ossification of the appendicular skeleton in rat fetuses. Future investigations should focus on the molecular mechanisms and consequences related to the prenatal impact of aripiprazole.