Psychoactive pharmaceuticals at environmental concentrations induce in vitro gene expression associated with neurological disorders.

ABSTRACT

BACKGROUND: A number of researchers have speculated that neurological disorders are mostly due to the interaction of common susceptibility genes with environmental, epigenetic and stochastic factors. Genetic factors such as mutations, insertions, deletions and copy number variations (CNVs) are responsible for only a small subset of cases, suggesting unknown environmental contaminants play a role in triggering neurological disorders like idiopathic autism. Psychoactive pharmaceuticals have been considered as potential environmental contaminants as they are detected in the drinking water at very low concentrations. Preliminary studies in our laboratory identified gene sets associated with neuronal systems and human neurological disorders that were significantly enriched after treating fish brains with psychoactive pharmaceuticals at environmental concentrations. These gene expression inductions were associated with changes in fish behavior. Here, we tested the hypothesis that similar treatments would alter in vitro gene expression associated with neurological disorders (including autism) in human neuronal cells. We differentiated and treated human SK-N-SH neuroblastoma cells with a mixture (fluoxetine, carbamazepine and venlafaxine) and valproate (used as a positive control to induce autism-associated profiles), followed by transcriptome analysis with RNA-Seq approach. RESULTS: We found that psychoactive pharmaceuticals and valproate significantly altered neuronal gene sets associated with human neurological disorders (including autism-associated sets). Moreover, we observed that altered expression profiles in human cells were similar to gene expression profiles previously identified in fish brains. CONCLUSIONS: Psychoactive pharmaceuticals at environmental concentrations altered in vitro gene expression profiles of neuronal growth, development and regulation. These expression patterns were associated with potential neurological disorders including autism, suggested psychoactive pharmaceuticals at environmental concentrations might mimic, aggravate, or induce neurological disorders.