Early chronic intermittent maternal hyperoxygenation impairs cortical development by inhibition of pax6-positive apical progenitor cell proliferation

Abstract

Maternal hyperoxygenation is a feasible, noninvasive method to treat fetal diseases, such as heart hypoplasia, but effects of maternal hyperoxygenation on the developing brain remain poorly understood. Previous studies showed that short-term maternal hyperoxygenation during midneurogenic phase (E14–E16) but not in earlier development (E10–E12) increases oxygen tension and enhances neurogenesis in the developing mouse cortex. We investigated effects of early chronic maternal hyperoxygenation (CMH) as a potential clinical treatment. Pregnant C57BL/6J mice were housed in a chamber at 75% atmospheric oxygen and the brains of E16 fetuses were analyzed using immunohistochemistry. The mitosis marker phH3 showed a significant reduction of proliferation in the dorsolateral cortices of CMH-treated E16 fetuses. Numbers of Tbr2-positive intermediate progenitor cells were unaffected whereas numbers of Pax6-positive apical progenitor cells were significantly reduced in CMH-treated mice. This resulted in altered cortical plate development with fewer Satb2-positive upper layer neurons but more Tbr1-positive neurons corresponding to the deeper layer 6. Thus, maternal hyperoxygenation affects the developing cortex depending on timing and length of applied oxygen. Early CMH causes a severe reduction of neuroprogenitor proliferation likely affecting cortical development. Further studies are needed to investigate the mechanisms underlying these findings and to assess the clinical and neurodevelopmental outcomes of the pups.