Maternal exposure to environmental levels of carbamazepine induces mild growth retardation in mouse embryos

Abstract

As chemical pollution is constantly increasing, the impact on the environment and public health must be investigated. This study focuses on the anticonvulsant drug carbamazepine (CBZ), which is ubiquitously present in the environment. Due to its physicochemical properties and stability during wastewater treatment, CBZ is detected in reclaimed wastewater, surface water and groundwater. In water-scarce regions heavily relying on treated wastewater for crop irrigation, CBZ is detected in arable land, produce and even in humans consuming crops irrigated with recealimed wastewater. Aalthough environmental levels of CBZ are very low, risks associated with unintentional exposure to CBZ are essential to be revealed. In perinatal medicine, CBZ is a teratogen; its prescription to pregnant women increases the risk for fetal malformations. This raises the concern of whether environmental exposure to CBZ may also impact embryogenesis. Studies in zebrafish and chick embryos or in cell culture have indicated negative outcomes upon exposure to low CBZ levels. Yet, these systems do not recapitulate the manner by which human fetuses are exposed to pharmaceuticals via maternal uptake. Here, we employed the mouse model to determine whether maternal exposure to environmental-relevant doses of CBZ will impact embryonic development. No effects on fertility, number of gestation sacs, gross embryonic malformations or fetal survival were detected. Yet, embryos were growth-delayed compared to controls (p=0.0011), as manifested in lower embryonic stage and somite number, earlier morphological features and reduction in mitotically-active cells. This study provides the first evidence for the effect of environmental concentration of CBZ on the developmental kinetics of maternally-exposed mammalian embryos. While the developmental delay was relatively modest, its consistency in high number of biological replicates, together with the known implication of developmental delay on post-natal health, calls for further in-depth risk analyses to reveal the effects of pharmaceuticals released to the environment on public health.