Aripiprazole‑induced alterations in axial skeletal ossification following in utero exposure in rats

Aripiprazole, a third-generation atypical antipsychotic drug, crosses the placental barrier, yet its developmental skeletal effects remain unexplored. This study aimed to evaluate impact of prenatal aripiprazole exposure, administered at three different doses, on the ossification of axial skeleton in 20-day old rat fetuses. Forty pregnant Sprague-Dawley rats were assigned to four groups: control and three aripiprazole treated-groups receiving 3 mg/kg (low dose aripiprazole), 6 mg/kg (high dose aripiprazole), and 12 mg/kg (double high dose aripiprazole [DHDA]) daily from gestational days 6-19. Fetuses were delivered on gestation day 20, weighed, and processed for skeletal evaluation using Alizarin Red staining. Ossification of craniofacial bones, hyoid bone, vertebral centra and arches, sternum, and ribs were assessed and categorized as complete, delayed, or absent. A total of 151 fetuses were analyzed. Aripiprazole exposure induced a dose dependent reduction in fetal weight and in the number of completely ossified skeletal centers. Craniofacial bones, particularly parietal, interparietal, supraoccipital, and presphenoid, were the most affected. Significant impairments were observed in vertebral centra and arches across cervical, thoracic, lumbar, sacral, and coccygeal regions, with the DHDA group exhibiting the greatest deficits. Sternebrae ossification showed marked reduction, whereas rib ossification remained unaffected. A strong positive correlation was found between fetal weight and total number of complete ossification centers across all groups. Prenatal exposure to aripiprazole leads to dose dependent fetal growth restriction and delayed ossification of axial skeleton in rat fetuses. Future investigations should focus on the molecular mechanisms and consequences related to prenatal impacts of aripiprazole.