Bypassing the Brain Barriers: Identification of Serum microRNAs Reflective of Developmental Neurotoxicity#
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Evaluating the neurodevelopmental effects of thyroid disrupting chemicals like flame retardants, perfluorinated compounds, and pesticides is challenging. While current regulatory tests attempt to determine if these chemicals may affect the developing brain, existing strategies are expensive, time consuming, and lack sensitivity. Previously we characterized that transient developmental thyroid hormone (TH) insufficiency alters cell adhesion and cell survival at the ventricular epithelium in newborn rats. As this progenitor cell population functions as one of the protective brain barriers (cerebrospinal fluid-brain barrier), we hypothesized that these abnormalities may permit “leaking” of small molecules from the brain tissue and back into the circulation. These small molecules could then be identified in blood samples, serving as a direct readout of abnormal neurodevelopment. To address this hypothesis pregnant rats were treated with a low dose of propylthiouracil (3 ppm) via the drinking water to induce TH insufficiency, and dams were permitted to give birth. This treatment reduced THs in both the serum and brain of neonates relative to controls. Next, we performed small RNA sequencing (RNA-Seq) of sera and brain tissue in neonates to identify small, non-coding RNAs that may reflect the observed cell abnormalities at the ventricle. Of the differentially expressed RNAs identified, seven microRNAs were upregulated in the serum of hypothyroid pups. Interestingly, these serum microRNAs have been linked to neuronal apoptosis and endothelial dysfunction in the brain, directly paralleling our identified cellular abnormalities in the tissue. These data show that serum microRNAs may be a novel tool to detect and monitor developmental neurotoxicity by a rapid, non-invasive method in regulatory studies. Additionally, as the microRNAs identified are conserved in humans, we are considering the utility of these biomarkers to monitor the health effects of TDCs in children. This work does not reflect US EPA policy.