Biology subjects

Boyd, S. L.

Publications and source records attributed to Boyd, S. L..

3 recordsLinked to original sources

bioRxiv2025

Development of a network formation assay for developmental neurotoxicity hazard screening using 3D human iPSC derived BrainSpheres

Exposure of the developing brain to environmental neurotoxicants can result in permanent alterations in structure and/or function. To investigate the effects of chemical exposures on neurodevelopment, the human induced-pluripotent stem cell (iPSC)-derived neural BrainSphere model has been utilized due to its ability to form mature neuronal populations and exhibit spontaneous electrical activity. To model network formation for developmental neurotoxicity screening, developing BrainSpheres were plated on high-density microelectrode arrays (hdMEA) three weeks after beginning differentiation. Starting two days post-plating, BrainSpheres were treated three times per week with compounds known to disrupt in vitro network formation (i.e. assay positive controls; loperamide, dieldrin and deltamethrin), or with an assay negative control, glyphosate, expected to have no effect. For 29 days, BrainSphere activity was recorded to measure neural network activity, general activity, and features of action potential propagation. Concentration-dependent disruption in neural network formation was observed for positive controls at concentrations below cytotoxicity. Dieldrin, deltamethrin, and loperamide exposure disrupted several features of general activity, neural network formation, and action potential propagation. BrainSpheres on hdMEAs detected chemically induced perturbations in neural network formation and may represent a valuable complex in vitro model useful for developmental neurotoxicity screening.

neuroscience↗

bioRxiv2024

Developmental origins of Parkinson's disease risk: perinatal exposure to the organochlorine pesticide dieldrin leads to sex-specific DNA modifications in critical neurodevelopmental pathways in the mouse midbrain

Epidemiological studies show that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinsons disease (PD). Animal studies support a link between developmental dieldrin exposure and increased neuronal susceptibility in the -synuclein preformed fibril (-syn PFF) and MPTP models in adult male C57BL/6 mice. In a previous study, we showed that developmental dieldrin exposure was associated with sex-specific changes in DNA modifications within genes related to dopaminergic neuron development and maintenance at 12 weeks of age. Here, we used capture hybridization-sequencing with custom baits to interrogate DNA modifications across the entire genetic loci of the previously identified genes at multiple time points - birth, 6 weeks, 12 weeks, and 36 weeks old. We identified largely sex-specific dieldrin-induced changes in DNA modifications at each time point that annotated to pathways important for neurodevelopment, potentially related to critical steps in early neurodevelopment, dopaminergic neuron differentiation, synaptogenesis, synaptic plasticity, and glial-neuron interactions. Despite large numbers of age-specific DNA modifications, longitudinal analysis identified a small number of DMCs with dieldrin-induced deflection of epigenetic aging. The sex-specificity of these results adds to evidence that sex-specific responses to PD-related exposures may underly sex-specific differences in disease. Overall, these data support the idea that developmental dieldrin exposure leads to changes in epigenetic patterns that persist after the exposure period and disrupt critical neurodevelopmental pathways, thereby impacting risk of late life diseases, including PD.

neuroscience↗

bioRxiv2023

Developmental exposure to the Parkinson's disease-associated organochlorine pesticide dieldrin alters dopamine neurotransmission in α-synuclein pre-formed fibril (PFF)-injected mice

Parkinsons disease (PD) is the most common movement disorder and one of the fastest-growing neurological diseases worldwide. This increase outpaces the rate of aging and is most rapid in recently industrialized areas, suggesting the role of environmental factors. Consistent with this, epidemiological studies show an association between exposure to persistent organic pollutants and an increased risk of PD. When combined with post-mortem analysis and mechanistic studies, a role for specific compounds, including the organochlorine pesticide dieldrin, emerges. In mouse models, developmental dieldrin exposure causes male-specific exacerbation of neuronal susceptibility to MPTP and synucleinopathy. Specifically, our novel two-hit model combining developmental dieldrin exposure with the -synuclein (-syn) pre-formed fibril (PFF) model showed a male-specific exacerbation of PFF-induced increases in striatal dopamine (DA) turnover and motor deficits on the challenging beam 6 months post-PFF injection in male offspring developmentally exposed to dieldrin. Here, we hypothesized that alterations in DA handling contribute to the observed changes and assessed vesicular monoamine transporter 2 (VMAT2) function and DA release in this dieldrin/PFF two-hit model. Female C57BL/6 mice were exposed to 0.3 mg/kg dieldrin or vehicle every 3 days, starting at 8 weeks of age by feeding and continuing throughout breeding, gestation, and lactation. Male offspring from independent litters underwent unilateral, intrastriatal injections of -syn PFFs via stereotaxic surgery at 12 weeks of age and DA handling was assessed 4 months post-PFF injection via vesicular 3H-DA uptake assay and fast-scan cyclic voltammetry (FSCV). We observed no dieldrin-associated change in VMAT2 activity, but a dieldrin-induced increase in DA release in striatal slices in PFF-injected animals. These results suggest that developmental dieldrin exposure alters the dopaminergic response to synucleinopathy-triggered toxicity and supports our hypothesis that alterations in DA handling may underly the observed exacerbation of PFF-induced deficits in motor behavior and DA turnover. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=67 SRC="FIGDIR/small/545967v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@d679deorg.highwire.dtl.DTLVardef@db0d70org.highwire.dtl.DTLVardef@14f368dorg.highwire.dtl.DTLVardef@1868894_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗