Prenatal Octamethylcyclotetrasiloxane Exposure Impaired Proliferation of Neuronal Progenitor, Leading to Motor, Cognition, Social and Behavioral Functions.

Eui-Man Jung,Dinh Nam Tran,Eui-Bae Jeung,Seon-Mi Park

doi:10.3390/ijms222312949

Abstract

Cyclic siloxane octamethylcyclotetrasiloxane (D4) has raised concerns as an endocrine-disrupting chemical (EDC). D4 is widely used in detergent products, cosmetics, and personal care products. Recently, robust toxicological data for D4 has been reported, but the adverse effects of D4 on brain development are unknown. Here, pregnant mice on gestational day 9.5 were treated daily with D4 to postnatal day 28, and the offspring mice were studied. The prenatal D4-treated mice exhibited cognitive dysfunction, limited memory, and motor learning defect. Moreover, prenatal D4 exposure reduced the proliferation of neuronal progenitors in the offspring mouse brain. Next, the mechanisms through which D4 regulated the cell cycle were investigated. Aberrant gene expression, such as cyclin-dependent kinases CDK6 and cyclin-dependent kinase inhibitor p27, were found in the prenatal D4-treated mice. Furthermore, the estrogen receptors ERa and ERb were increased in the brain of prenatal D4-treated mice. Overall, these findings suggest that D4 exerts estrogen activity that affects the cell cycle progression of neuronal progenitor cells during neurodevelopment, which may be associated with cognitive deficits in offspring.

Highlights

The effects of environmental pollutants on the brain are raising concern because the brain is sensitive to toxic chemicals and physical stimuli, during development
Sox1 is the earliest known marker for committed neural precursors in the proliferating neuroepithelium, and Sox1-green fluorescence protein (GFP) expression is likely to identify an earlier subset of neural precursors
The Sox1-GFP reporter system is highly useful for the identification, isolation, and characterization of neural stem and progenitor cells [19]

Summary

Introduction

The effects of environmental pollutants on the brain are raising concern because the brain is sensitive to toxic chemicals and physical stimuli, during development. The expansion of neural progenitor reservoirs and their differentiation to generate specific neuronal subtypes are important events under the control of several extrinsic and intrinsic factors. The regulation of neural progenitor cell (NPC) proliferation and survival is essential to ensure proper brain development. Neural development is fundamentally linked to the cell cycle [1]. The failure of cell cycle regulation and the survival of NPCs might be the root causes of several neurodevelopmental disorders [2,3]. The dysregulation of cell cycle progression lies at the heart of many neurodegenerative disorders, such as Alzheimer’s

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