Maternal exposure to carbamazepine at environmental concentrations can cross intestinal and placental barriers

Abstract

Psychoactive pharmaceuticals have been found as teratogens at clinical dosage during pregnancy. These pharmaceuticals have also been detected in minute (ppb) concentrations in drinking water in the US, and are environmental contaminants that may be complicit in triggering neurological disorders in genetically susceptible individuals. Previous studies have determined that psychoactive pharmaceuticals (fluoxetine, venlafaxine and carbamazepine) at environmentally relevant concentrations enriched sets of genes regulating development and function of the nervous system in fathead minnows. Altered gene sets were also associated with potential neurological disorders, including autism spectrum disorders (ASD). Subsequent in vitro studies indicated that psychoactive pharmaceuticals altered ASD-associated synaptic protein expression and gene expression in human neuronal cells. However, it is unknown if environmentally relevant concentrations of these pharmaceuticals are able to cross biological barriers from mother to fetus, thus potentially posing risks to nervous system development. The main objective of this study was to test whether psychoactive pharmaceuticals (fluoxetine, venlafaxine, and carbamazepine) administered through the drinking water at environmental concentrations to pregnant mice could reach the brain of the developing embryo by crossing intestinal and placental barriers. We addressed this question by adding 2H-isotope labeled pharmaceuticals to the drinking water of female mice for 20 days (10 pre-and 10 post-conception days), and quantifying 2H-isotope enrichment signals in the dam liver and brain of developing embryos using isotope ratio mass spectrometry. Significant levels of 2H enrichment was detected in the brain of embryos and livers of carbamazepine-treated mice but not in those of control dams, or for fluoxetine or venlafaxine application. These results provide the first evidence that carbamazepine in drinking water and at typical environmental concentrations is transmitted from mother to embryo. Our results, combined with previous evidence that carbamazepine may be associated with ASD in infants, warrant the closer examination of psychoactive pharmaceuticals in drinking water and their potential association with neurodevelopmental disorders.

Detection of drugs in paired maternal and umbilical cord blood samples

“…While based only on one mother/umbilical cord pair, this observation might be misleading. Regarding carbamazepine, it has recently been shown that even carbamazepine in drinking water and at typical environmental concentrations is transmitted from mother to embryo [35]. In the underlying case, date and dose of carbamazepine intake were not known, but based on the findings published by Kaushik and colleagues [35] a higher transfer ratio can probably be expected.…”

“…Regarding carbamazepine, it has recently been shown that even carbamazepine in drinking water and at typical environmental concentrations is transmitted from mother to embryo [35]. In the underlying case, date and dose of carbamazepine intake were not known, but based on the findings published by Kaushik and colleagues [35] a higher transfer ratio can probably be expected. Children exposed to carbamazepine in utero were shown to have an increased risk of having a major malformation like oro-facial malformations and neural tube malformations [19].…”

Understanding the Clotting Cascade, Regulators, and Clinical Modulators of Coagulation

“…IIIa on the activated platelets [57]. The genes encoding for Bβ (FGB), Aα (FGA) and γ (FGG) are located on chromosome 4 from centromere to telomere [58]. Fibrinogen is primarily synthesized in liver [59].…”

“…Chronic smoking and chronic alcoholism effect coagulation system by altering the liver functions. Environmental factors like hypoxia, drugs like aspirin, oral contraceptive pills, dietary problems like vitamin K deficiency affect the blood coagulation [12,[56][57][58][59][60][61].…”

Biodegradation of carbamazepine using fungi and bacteria

“…Carbamazepine was detected in embryo of pregnant mice when the mother was exposed to ntal concentration of carbamazepine through drinking water [4]. Exposure of Jenynsiamultidentata caused irregular cortisol activity and aggressive .…”