Biology subjects

McCarthy, D. M.

Publications and source records attributed to McCarthy, D. M..

3 recordsLinked to original sources

bioRxiv2025

Nicotine in E-Cigarette Aerosol Reduces GABA Neuron Migration via the α7 Nicotinic Acetylcholine Receptor

Prenatal nicotine exposure is linked to adverse neurodevelopmental outcomes, yet e-cigarette use during pregnancy continues to rise due to aggressive marketing efforts and misconceptions of safety. We investigated the effect of prenatal e-cigarette aerosol exposure on the migration of GABA neurons, a developmental process critical for the establishment of cerebral cortical circuitry. Pregnant mice were exposed to nicotine-containing aerosol (e-cigarette), nicotine-free aerosol (e-liquid) or room air (control) daily beginning 2 weeks before conception and continuing until gestational day 14. E-cigarette, but not e-liquid, aerosol significantly reduced GABA neuron density in the dorsal cerebral wall at rostral forebrain level and within the marginal zone, reflecting region-specific vulnerabilities. In vitro explant cultures revealed that nicotine dose-dependently reduced neuronal migration, and this effect was mimicked by a selective 7 nicotinic acetylcholine receptor (nAChR) agonist. Blocking the 7 nAChR using a selective antagonist attenuated the effects of nicotine on neuronal migration. These findings reveal a previously unrecognized vulnerability of GABA neuron migration to e-cigarette aerosol and identify 7 nAChR activation as a mechanism for nicotine-induced impairment of GABA neuron migration. Moreover, the findings highlight the need for translational efforts to update clinical guidance and public policy regarding e-cigarette use during pregnancy.

neuroscience↗

bioRxiv2024

Metabolic engineering improves transduction efficiency and downstream vector isolation by altering the lipid composition of extracellular vesicle-enclosed AAV.

Adeno-associated viruses (AAV) are promising vectors for gene therapy due to their efficacy in vivo. However, there is room for improvement to address key limitations such as the pre-existing immunity to AAV in patients, high-dose toxicity, and relatively low efficiency for some cell types. This study introduces a metabolic engineering approach, using knockout of the enzyme phosphatidylserine synthase 1 (PTDSS1) to increase the abundance of extracellular vesicle-enclosed AAV (EV-AAV) relative to free AAV in the supernatant of producer cells, simplifying downstream purification processes. The lipid-engineered HEK293T-{Delta}PTDSS1 cell line achieved a 42.7-fold enrichment of EV-AAV9 compared to free AAV9 in the supernatant. The rational genetic strategy also led to a 300-fold decrease of free AAV in supernatant compared to wild-type HEK293T. The membrane-engineered EV-AAV9 (mEV-AAV9) showed unique envelope composition alterations, including cholesterol enrichment and improved transduction efficiency in human AC16 cardiomyocytes by 1.5-fold compared to conventional EV-AAV9 and by 11-fold compared to non-enveloped AAV9. Robust in-vivo transduction four weeks after intraparenchymal administration of mEV-AAV9 was observed in the murine brain. This study shows promise in the potential of lipid metabolic engineering strategies to improve the efficiency and process development of enveloped gene delivery vectors.

bioengineering↗

bioRxiv2023

Learning and memory deficits produced by aspartame are heritable via the paternal lineage

Environmental exposures produce heritable traits that can linger in the population for one or two generations. Millions of individuals consume substances such as artificial sweeteners daily that are declared safe by regulatory agencies without evaluation of their potential heritable effects. We show that consumption of aspartame, an FDA-approved artificial sweetener, daily for up to 16-weeks at doses equivalent to only 7-15% of the FDA recommended maximum daily intake value (equivalent to 2-4 small, 8 oz diet soda drinks per day) produces significant spatial learning and memory deficits in mice. Moreover, the cognitive deficits are transmitted to male and female descendants along the paternal lineage suggesting that aspartames adverse cognitive effects are heritable, and that they are more pervasive than current estimates, which consider effects in the directly exposed individuals only. Traditionally, deleterious environmental exposures of pregnant and nursing women are viewed as risk factors for the health of future generations. Environmental exposures of men are not considered to pose similar risks. Our findings suggest that environmental exposures of men can produce adverse impact on mental health of future generations and demonstrate the need for considering heritable effects via the paternal lineage as part of the regulatory evaluations of artificial sweeteners.

neuroscience↗