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

• Published in: Biochemical and biophysical research communications 2016-05, Vol.474 (2), p.291-295
• Main Authors: Kaushik, Gaurav, Huber, David P., Aho, Ken, Finney, Bruce, Bearden, Shawn, Zarbalis, Konstantinos S., Thomas, Michael A.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ABUNDANCE; Animals; Anticonvulsants - pharmacokinetics; Anticonvulsants - toxicity; Autism spectrum disorders (ASD); BRAIN; Brain - embryology; Brain - metabolism; Carbamazepine - pharmacokinetics; Carbamazepine - toxicity; CONCENTRATION RATIO; DAMS; DEUTERIUM; DIFFUSION BARRIERS; DRINKING WATER; DRUGS; EMBRYOS; Environmental concentrations; FATHEAD MINNOW; Female; FETUSES; Fluoxetine - pharmacokinetics; Fluoxetine - toxicity; GENES; IN VITRO; INFANTS; Intestinal Absorption - physiology; ISOTOPE RATIO; ISOTOPE SEPARATION; LIVER; Liver - embryology; Liver - metabolism; Male; MASS SPECTROSCOPY; Maternal Exposure; Maternal-Fetal Exchange - physiology; MICE; Mice, Inbred C57BL; MOTHS; Placenta - metabolism; PREGNANCY; PROTEINS; Psychoactive pharmaceuticals; Psychotropic Drugs - pharmacokinetics; Psychotropic Drugs - toxicity; PYRAZOLINES; SPECTRA; Venlafaxine Hydrochloride - pharmacokinetics; Venlafaxine Hydrochloride - toxicity; Water Pollutants, Chemical - pharmacokinetics; Water Pollutants, Chemical - toxicity
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.04.088

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.