Citation:

OShaughnessy, Katherine. Bypassing the Brain Barriers: Identification of Serum microRNAs Reflective of Developmental Neurotoxicity. Teratology Society, San Diego, CA, June 23 - 27, 2019.

Impact/Purpose:

Developmental neurotoxicity is difficult to assess in vitro and current in vivo guideline studies are largely insensitive to thyroid disrupting chemicals. Serum biomarkers for developmental neurotoxicity would be very useful in guideline animal studies and have potential for extrapolation to human populations for identification and monitoring purposes. Thyroid hormone disruption impairs brain barriers - vasculature and ventricular barriers. microRNAs are small non coding molecules that can potentially leak out from brain and be detected in serum. These data reveal a number of microRNAs in serum of hypothyroid rat pups. These could serve as biomarkers of neurodevelopmental insult.

Description:

Evaluating the potential 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 severely 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 across the barrier from the brain and back into the circulation. These small molecules could then be identified in blood, serving as direct readouts of abnormal neurodevelopment. To address this hypothesis pregnant rats were treated with a low dose of propylthiouracil (3 ppm) to induce TH insufficiency and dams were permitted to give birth. This xenobiotic 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. These serum microRNAs are associated with neuronal apoptosis and endothelial dysfunction in patients. 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, these biomarkers may find direct application for identification of potential neurodevelopmental insults in children exposed to TDCs . This work does not reflect US EPA policy.

Record Details: