Folic acid attenuates maternal sertraline-induced hepatic injury in rat offspring

Abstract

Sertraline, a selective serotonin reuptake inhibitor, is commonly prescribed during pregnancy. While its adverse effects on pregnant mothers are documented, its impact on fetal organ development, particularly the liver, is less understood. Folic acid is a standard prenatal supplement, possessing antioxidant, anti-inflammatory, and anti-apoptotic effects. This study aimed to investigate the effects of maternal exposure to sertraline during pregnancy alone, as well as during both pregnancy and lactation, on the offspring liver and to investigate the potential role of concurrent folic acid supplementation. Pregnant Sprague-Dawley albino rats were divided into four groups: Control, Folic acid-supplemented, Sertraline-treated, and Sertraline + folic acid-treated. Treatments were administered to dams by oral gavage once daily during pregnancy alone, as well as during both pregnancy and lactation. Male offspring were sacrificed at birth (0-Day) and 14 days postpartum (14-Day). Offspring livers were processed for histopathological (H&E and Masson trichrome staining), immunohistochemical evaluation of cleaved Caspase-3 expression, and morphometric analysis. Offspring from sertraline-treated dams (Sertraline 0-Day, prenatal exposure only) exhibited marked hepatocellular vacuolation, vascular congestion, and inflammatory infiltration in portal areas. In the sertraline 14-Day group (combined prenatal and lactational exposure), partial structural recovery was observed; however, liver damage persisted but was less severe, showing diffuse vacuolation. Strong cleaved Caspase-3 immunoreactivity was observed in the sertraline-treated group, indicating increased apoptosis. Conversely, offspring from the Sertraline+ folic acid groups (0-Day and 14-Day) showed apparently normal hepatic architecture at both time points, with minimal histopathological changes and significantly weaker cleaved Caspase-3 expression, comparable to that of the control and folic acid groups. Maternal sertraline exposure during pregnancy, with or without continuation into early lactation, induces significant structural damage and increases apoptosis in the offspring's liver. Concurrent maternal folic acid supplementation effectively mitigates these effects at both time points, although the extent of protection may vary depending on the exposure window (prenatal vs. combined prenatal and lactational exposure). These findings suggest a potential modulatory benefit of folic acid supplementation in mitigating sertraline-induced hepatic alterations in offspring.