In Utero Bisphenol A Exposure Induces Abnormal Neuronal Migration in the Cerebral Cortex of Mice

Wenting Ling,Ken-Ichiro Kubo,Toshihiro Endo,Chiharu Tohyama,Masaki Kakeyama,Kazunori Nakajima

doi:10.3389/fendo.2016.00007

Abstract

Bisphenol A (BPA) has been known to have endocrine-disrupting activity to induce reproductive and behavioral abnormalities in offspring of laboratory animal species. However, morphological basis of this abnormality during brain development is largely unknown. Cerebral cortex plays a crucial role in higher brain function, and its precisely laminated structure is formed by neuronal migration. In the present study, transfecting a plasmid (pCAG-mCherry) by in utero electroporation (IUE), we visualized developing neurons and investigated the possible effects of in utero BPA exposure on neuronal migration. Pregnant mice were exposed to BPA by osmotic pump at estimated daily doses of 0, 40 (BPA-40), or 400 (BPA-400) μg/kg from embryonic day 14.5 (E14.5) to E18.5. IUE was performed at E14.5 and neuronal migration was analyzed at E18.5. Compared with the control group, neuronal migration in the cortical plate was significantly decreased in the BPA-40 group; however, there was no significant difference in the BPA-400 group. Among several neuronal migration-related genes and cortical layer-specific genes, TrkB in the BPA-400 group was found significantly upregulated. In conclusion, in utero exposure to low BPA dose was found to disrupt neuronal migration in the cerebral cortex in a dose-specific manner.

Highlights

Bisphenol A (BPA, 4,4′-dihydroxy-2,2-diphenylpropane) is a monomer used worldwide for manufacturing plastics, such as polycarbonates and epoxy resins
To investigate whether in utero BPA exposure affects neuronal migration, in utero electroporation (IUE) was performed at E14.5 to introduce a fluorescent protein expression vector into neural progenitor cells, and the distribution of mCherry-positive neurons was analyzed at E18.5 in the three groups (Control, BPA-40, and BPA400) (Figure 1A)
At E18.5, mCherry-positive cells were found in ventricular zone (VZ), subventricular zone (SVZ), intermediate zone (IZ), and cortical plate (CP) (Figures 1B,C)

Summary

Introduction

Bisphenol A (BPA, 4,4′-dihydroxy-2,2-diphenylpropane) is a monomer used worldwide for manufacturing plastics, such as polycarbonates and epoxy resins. Humans are widely exposed to BPA via leaching from plastic bottles, sealants for canned food, and other environmental sources. Low. BPA Disrupts Murine Neuronal Migration doses of BPA exposure during the perinatal period can result in numerous effects on health, ranging from reversible physiological responses to more long-term adverse effects. BPA has been suggested to have adverse effects on neuronal development in human infants [4]. Animal studies have shown that offspring born to dams exposed to low doses of BPA during gestation and the early postnatal period had abnormal brain morphologies [5,6,7,8,9]. The mechanisms by which maternal BPA exposure affects embryonic brain development are still largely unknown

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