##c Effects Of Feoptoxic Effects Of Maternal Ethanol ( E )...

Fetotoxic effects of maternal ethanol (E) intake are well documented in animals and humans. Central among the responses to E exposure are developmental deficits affecting multiple brain regions, including the cerebellum, hippocampus, olfactory bulbs, and cerebral cortex [1-4]. In vivo, moderate, clinically relevant E can generate enhanced apoptotic loss of neurons in the developing brain [4-11]. E is a prooxidant and fetal cells are highly sensitive to E/ oxidative stress (OS) [5, 12-14]. Thus, redox imbalance is a mechanism underlying E-induced neuron apoptosis in developing brain [5, 12-14]. E produces an enhanced apoptotic death in a subpopulation of cells with the lowest GSH content and normalizing this redox imbalance by stabilizing†¦show more content†¦However, during intense stress challenge, dangerous level of ROS accumulates shifting the redox balance that cannot be reversible leading to detrimental effect and cause organismal damage (B). A/the central regulator of GSH homeostasis, hence redox balance mitigation of neuron apoptotic death [5], is the master transcription factor, nuclear factor E2-related factor 2 (Nrf2). Nrf2 regulated genes include glutamate-cysteine ligase (GCL) (rate limiting enzyme in GSH synthesis), glutathione reductase (generation of reduced/active GSH), and multiple components of the gamma glutamyl cycle by which the GSH synthesis substrate, Cys is supplied to neurons in addition to dietary source(s) [20, 25]. Previous study in our laboratory addressed Nrf2/ARE (Antioxidant Response Element)-mediated neuroprotection which should prevent neuron death by maintaining GSH homeostasis [7]. E does up-regulate Nrf2 and the knockout of Nrf2 illustrated that this increase in Nrf2 confers a certain degree of neuroprotection [7]. However, somehow E prevents Nrf2 from providing complete protection and a population of fetal neurons still succumbs unless we artificially increase Nrf2 beyond its innate capaci ty [7]. A potential explanation for this incomplete protection resides in kinetics of the GSH synthesis path. GSH, a tripeptide is synthesized in a two-step enzymatic reaction [26, 27] with GCL ultimately regulated by availability of Cys