Maternal exposure to carbamazepine at environmental concentrations can cross intestinal and placental barriers.
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 (2)H-isotope labeled pharmaceuticals to the drinking water of female mice for 20 days (10 pre-and 10 post-conception days), and quantifying (2)H-isotope enrichment signals in the dam liver and brain of developing embryos using isotope ratio mass spectrometry. Significant levels of (2)H 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.
Department of Biological Sciences, Idaho State University, Stop 8007, 921 S 8th Ave, Pocatello, ID 83209-8007, USA; Department of Medical Pathology and Laboratory Medicine, University of California at Davis, Davis, CA 95817, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Northern California, 2425 Stockton Boulevard, Sacramento, CA 95817, USA. Electronic address: kausgaur@isu.edu.
Gaurav
G
Kaushik
Department of Biological Sciences, Idaho State University, Stop 8007, 921 S 8th Ave, Pocatello, ID 83209-8007, USA. Electronic address: hubedavi@isu.edu.
David P
DP
Huber
Department of Biological Sciences, Idaho State University, Stop 8007, 921 S 8th Ave, Pocatello, ID 83209-8007, USA. Electronic address: ahoken@isu.edu.
Ken
K
Aho
Department of Biological Sciences, Idaho State University, Stop 8007, 921 S 8th Ave, Pocatello, ID 83209-8007, USA. Electronic address: finney@isu.edu.
Bruce
B
Finney
Department of Biological Sciences, Idaho State University, Stop 8007, 921 S 8th Ave, Pocatello, ID 83209-8007, USA. Electronic address: bearshaw@isu.edu.
Shawn
S
Bearden
Department of Medical Pathology and Laboratory Medicine, University of California at Davis, Davis, CA 95817, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Northern California, 2425 Stockton Boulevard, Sacramento, CA 95817, USA. Electronic address: kzarbalis@ucdavis.edu.
Konstantinos S
KS
Zarbalis
Department of Biological Sciences, Idaho State University, Stop 8007, 921 S 8th Ave, Pocatello, ID 83209-8007, USA. Electronic address: mthomas@isu.edu.
Michael A
MA
Thomas
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000633:toxicity; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002220:Carbamazepine / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D005473:Fluoxetine / Q000493:pharmacokinetics / Q000633:toxicity; D007408:Intestinal Absorption / Q000502:physiology*; D008099:Liver / Q000196:embryology / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011619:Psychotropic Drugs / Q000493:pharmacokinetics / Q000633:toxicity; D000069470:Venlafaxine Hydrochloride / Q000493:pharmacokinetics / Q000633:toxicity; D014874:Water Pollutants, Chemical / Q000493:pharmacokinetics* / Q000633:toxicity
D000927:Anticonvulsants; D011619:Psychotropic Drugs; D014874:Water Pollutants, Chemical; D005473:Fluoxetine; D002220:Carbamazepine; D000069470:Venlafaxine Hydrochloride
Autism spectrum disorders (ASD); Drinking water; Environmental concentrations; Psychoactive pharmaceuticals