Gestational zinc deficiency affects the regulation of transcription factors AP-1, NF-κB and NFAT in fetal brain

Abstract

Transcription factors AP-1, NF- κB and NFAT are central to brain development by regulating the expression of genes that modulate cell proliferation, differentiation, apoptosis, and synaptic plasticity. This work investigated the consequences of feeding zinc deficient and marginal zinc diets to rat dams during gestation on the modulation of AP-1, NF- κB and NFAT in fetal brain. Sprague-Dawley rats were fed from gestation day 0 a control diet ad libitum (25 μg zinc/g diet, C), a zinc deficient diet ad libitum (0.5 μg zinc/g diet, ZD), the control diet in the amounts eaten by the ZD rats (restrict fed, RF), or a diet containing a marginal zinc concentration ad libitum (10 μg zinc/g diet, MZD) until gestation day 19. AP-1-DNA binding was higher (50-190%) in nuclear fraction isolated from ZD, RF and MZD fetal brains compared to controls. In MZD fetal brain high levels of activation of the upstream mitogen-activated protein kinases JNK and p38 and low levels of ERK phosphorylation were observed. Total levels of NF- κB and NFAT activation were higher or similar in the ZD and MZD groups than in controls, respectively. However, NF- κB- and NFAT-DNA binding in nuclear fractions was markedly lower in ZD and MZD fetal brain than in controls (50-80%). The latter could be related to zinc deficiency-associated alterations of the cytoskeleton which is required for NF- κB and NFAT nuclear transport. In summary, suboptimal zinc nutrition during gestation could cause long term effects on brain function, partially through a deregulation of transcription factors AP-1, NF- κB and NFAT.

Gestational marginal zinc deficiency impaired fetal neural progenitor cell proliferation by disrupting the ERK1/2 signaling pathway

“…As previously described [14], marginal zinc nutrition throughout gestation did not affect dam food intake and body weight or fetal body and brain weight (Table 1). Phosphorylated and total ERK1/2 were measured with quantitative immunoblots of total cell lysates from the E19 cerebral cortex.…”

“…Gestational marginal zinc deficiency decreased NPC proliferation and impaired ERK1/2 phosphorylation in the ventricular zone of the fetal rat brain during a critical period for cortical neurogenesis At E19 maternal plasma zinc was 35% lower in the MZD group than in controls (Table 1), which reflects a state of marginal zinc deficiency in rats [14]. As previously described [14], marginal zinc nutrition throughout gestation did not affect dam food intake and body weight or fetal body and brain weight (Table 1).…”

“…Extraction of total cellular protein from fetal brains was done as previously described [14]. For extraction of total protein from cell cultures, cells in 30-mm dishes were washed in cold phosphate-buffered saline (PBS) and scraped in 50 μl lysis buffer, and total cell extracts were prepared as previously described [15].…”

“…Marginal zinc deficiency decreases the levels of phosphorylated ERK1/2 in the fetal rat brain at E19 [14]. In cell culture, zinc deficiency decreases ERK1/2 phosphorylation in human IMR-32 neuroblastoma cells and in rat embryonic cortical neuron (RCN) cultures [15,16].…”

Zinc and the ERK Kinases in the Developing Brain

“…Severe zinc deficiency can be deleterious for the conceptus, but also marginal dietary zinc levels during gestation can lead to major changes in signaling cascades that are central to brain development (Aimo et al 2010b). Besides a low dietary zinc intake or poor food zinc availability (Briefel et al 2000; Walsh et al 1994), other conditions during pregnancy, including diabetes, maternal infections, chemotherapy, stress, and toxin exposure (e.g., arsenic, ethanol, or herbicides) can reduce fetal zinc availability (Coyle et al 2009; Taubeneck et al 1995; Taubeneck et al 1994).…”