Bypassing the Brain Barriers: Serum microRNAs Reflective of Developmental Neurotoxicity Induced by Thyroid Disruption

This is an invited webinar presentation; no abstract will be released or published. A previously cleared abstract for this work can be found below. 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.  

Impact/Purpose

Evaluating the health effects of endocrine disrupting chemicals is a high priority area of research at US EPA. Some endocrine disrupting chemicals specifically act upon the thyroid system; as thyroid hormones (TH) are critical for brain development, this class of xenobiotics is of especial concern for children’s health. Many types of chemicals have been shown to interrupt thyroid signaling in animal models, including but limited to, perfluoroalkyl substances, some pesticides, and flame retardants. A challenge when determining the risk of thyroid disrupting chemicals is how precisely the developing brain may or may not be affected by a certain exposure. This uncertainty stems from multiple issues; first, current animal testing paradigms (US EPA and OECD) use insufficiently sensitive methods to evaluate adverse outcomes of the brain, and in vitro testing for thyroid is isolated to molecular imitating events only (ie: thyroid peroxidase inhibition, deiodinase inhibition, etc). Therefore, with both in vitro and in vivo testing strategies, there is a disconnect between the assay’s endpoints and neurodevelopmental phenotypes. In this study we tested whether serum microRNAs may be used as a rapid, non-invasive biomarker of developmental neurotoxicity.

Citation

OShaughnessy, K. Bypassing the Brain Barriers: Serum microRNAs Reflective of Developmental Neurotoxicity Induced by Thyroid Disruption. Healthy Environment and Endocrine Disruptor Strategies (HEEDS) Endocrine Disruptor Showcase (Webinar), NA-Virtual, NC, November 09, 2021.