Role of apoptosis in mediating diclofenac-induced teratogenesis

Abstract

Diclofenac (DCF) is among the most commonly used nonsteroidal anti-inflammatory drugs worldwide for the treatment of various conditions in postpubertal women. However, very limited information is available regarding its safety during pregnancy and teratogenecity. The present study was designed to elucidate the effects of DCF on the developing rat embryos during the major organogenesis period and investigate the critical role of apoptosis in bringing about these congenital anomalies. Embryos were exposed in vitro to various concentrations of DCF, that is, 0, 3.75, 7.5 and 15 µg/ml for 24 h, respectively, and examined for the growth and differentiation at the end of the culture period for the presence of any specific malformations. Growth and developmental parameters such as weight of embryos, crown-rump length and number of somites were found to be lower in the embryos exposed to high concentrations of DCF (7.5 and 15.0 μg/ml) when compared with the untreated control. However, no significant difference in growth parameters was found between embryos exposed to 3.75 µg/ml and the control group. In parallel to this, flow cytometric analysis and DNA quantitation of cultured rat embryos were performed to verify the involvement of apoptosis in mediating DCF-induced teratogenesis. A concentration-dependent increase in apoptosis in embryos suggests a possible engagement of apoptosis in the role of DCF as a teratogenic agent. A detailed analysis of the actual effect of DCF on cellular apoptotic machinery necessitates further evaluation.

Controlled and tuneable drug release from electrospun fibers and a non-invasive approach for cytotoxicity testing

“…Drug-induced oxidative stress can primarily recruit rescue pathways, but, if sustained, the stress can cause mitochondrial injury 65,66 . Thus, the cells are usually not able anymore to repair the damage, and apoptotic or necrotic events mainly occur 67–69 .…”

Comparative study of diclofenac-induced embryotoxicity and teratogenesis in Xenopus laevis and Lithobates catesbeianus, using the frog embryo teratogenesis assay: Xenopus (FETAX)

“…Diverse studies using other NSAIDs also found significant growth inhibition (Chae et al, 2015;Fort et al, 1992;Veldhoen et al, 2014). While Singh et al (2015) found that exposure to DCF in a rat embryo culture reduced overall growth and developmental parameters such as embryo weight, head-to-tail length and number of somites in vitro in a concentration-dependent pattern, and that the mechanism of teratogenicity of DCF may be oxidative stress induction leading to an abrupt increase in apoptosis, while the uncontrolled pattern of this cell death process results in diverse malformations whose severity depends on pharmaceutical concentration. Previous studies have reported DCF induction of oxidative stress and genotoxicity in aquatic organisms Fig.…”