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.
Highlights
Multiple studies have identified a strong genetic component to the manifestation of neurodevelopmental disorders such as autism spectrum disorders (ASD) [1,2,3] that can account only for a subset of diagnosed cases
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
We chose as collection day embryonic day 10 (E10) to preempt the formation of the bloodbrain barrier (BBB), which in mice starts at ~E12 [22]
Summary
Multiple studies have identified a strong genetic component to the manifestation of neurodevelopmental disorders such as autism spectrum disorders (ASD) [1,2,3] that can account only for a subset of diagnosed cases. The presence of individual low risk contributing susceptibility genes, or common variants [3] are not sufficient causal agents without the interaction with other environmental, epigenetic, or stochastic factors to cause ASD [4,5,6]. These findings suggest that likely a majority of cases results from the presence of unknown environmental triggers in genetically susceptible individuals [1, 5,6,7]. Among PPCPs, our laboratory has been studying psychoactive pharmaceuticals (including fluoxetine, venlafaxine and carbamazepine) as potential neurological disorder-relevant contaminants that have been detected in the drinking water [8, 9]
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