Fig. 9

Schematic diagram shows the effect of ethanol, antioxidant disruption on microglia phenotype, and the underlying mechanism in the developing fetal brain. Maternal ethanol consumption acts as an oxidant in the fetal brain by activating the generation of ROS. Also, suboptimal conditions of cellular GSH further aggravates ethanol-induced oxidative stress, ROS accumulation, and Nrf-2 activation. ROS in turn triggers redox-sensitive NF-κB activation by phosphorylation of NF-κB p65 on its two serine residues. Activated NF-κB then induces the production of inflammatory cytokines (IL-1β, IL-6, TNF-α, IFN-γ), chemokines (CCL3, CCL4, CCL7, CCL9) in the fetal brain. Inflammatory milieu drives the microglia cells to a classically activated (M1) phenotype which displays spherical morphology in vivo. Enhanced expression of these inflammatory cytokines, chemokines, iNOS and free radical are key to cytotoxicity and tissue injury. In contrast, optimal or enhanced GSH content in the fetal brain inhibits the damaging mechanism that accompanies maternal ethanol consumption. In addition, it predominantly drives M2 phenotypic changes which exhibit an elongated bipolar morphology with robust expression of (ARG-1, IL-10, TGF-β), the absence (or very low levels) of pro-inflammatory cytokines, and ROS response generally associated with tissue injury. Therefore, poor nutritional status or antioxidant reserves pertaining to maternal-fetal environment amplifies effects of environmental stressors such as ethanol