Developmental toxicity within the central cholinergic nervous system

Neurons that use acetylcholine in the developing brain make up an extremely important network that helps guide other systems during critical time periods of cell proliferation and differentiation. This important function and the variety of molecular targets for developmental neurotoxicants makes the central cholinergic system vulnerable to neurodevelopmental abnormalities that can result in functional deficits later in life. The alteration of brain development by toxicants, such as anticholinesterase pesticides, lead (Pb), nicotine, and others is supported by many studies that demonstrate concomitant changes in a variety of cholinergic targets, which provide clues to potential underlying mechanisms for their neurodevelopmental toxicity. This chapter discusses the role of the cholinergic system in brain development, special vulnerabilities related to brain region and developmental time periods, and human, animal, and mechanistic data on the neurodevelopmental toxicity of pesticides and other environmental chemicals

Zinc deficiency affects the STAT1/3 signaling pathways in part through redox-mediated mechanisms.

Zinc deficiency affects the development of the central nervous system (CNS) through mechanisms only partially understood. We previously showed that zinc deficiency causes CNS oxidative stress, damaging microtubules and impairing protein nuclear shuttling. STAT1 and STAT3 transcription factors, which require nuclear import for their functions, play major roles in CNS development. Thus, we investigated whether zinc deficiency disrupts STAT1 and STAT3 signaling pathways in the developing fetal CNS, characterizing the involvement of oxidative stress and the cytoskeleton in the adverse effects. Maternal (gestation day 0-19) marginal zinc deficiency (MZD) reduced STAT1 and STAT3 tyrosine phosphorylation and their nuclear translocation in the embryonic day 19 (E19) rat brain. Similar effects were observed in zinc depleted IMR-32 neuroblastoma cells, with an associated decrease in STAT1- and STAT3-dependent gene transactivation. Zinc deficiency caused oxidative stress (increased 4-hydroxynonenal-protein adducts) in E19 brain and IMR-32 cells, which was prevented in cells by supplementation with 0.5mM α-lipoic acid (LA). In zinc depleted IMR-32 cells, the low tyrosine phosphorylation of STAT1, but not that of STAT3, recovered upon incubation with LA. STAT1 and STAT3 nuclear transports were also restored by LA. Accordingly, chemical disruption of the cytoskeleton partially reduced STAT1 and STAT3 nuclear levels. In summary, the redox-dependent tyrosine phosphorylation, and oxidant-mediated disruption of the cytoskeleton are involved in the deleterious effects of zinc deficit on STAT1 and STAT3 activation and nuclear translocation. Therefore, disruption of the STAT1 and STAT3 signaling pathways may in part explain the deleterious effects of maternal MZD on fetal brain development

Nutritional marginal zinc deficiency disrupts placental 11β-hydroxysteroid dehydrogenase type 2 modulation

This paper investigated if marginal zinc nutrition during gestation could affect fetal exposure to glucocorticoids as a consequence of a deregulation of placental 11βHSD2 expression. Placenta 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) plays a central role as a barrier protecting the fetus from the deleterious effects of excess maternal glucocorticoids. Rats were fed control (25 μg zinc per g diet) or marginal (10 μg zinc per g diet, MZD) zinc diets from day 0 through day 19 (GD19) of gestation. At GD19, corticosterone concentration in plasma, placenta, and amniotic fluid was similar in both groups. However, protein and mRNA levels of placenta 11βHSD2 were significantly higher (25% and 58%, respectively) in MZD dams than in controls. The main signaling cascades modulating 11βHSD2 expression were assessed. In MZD placentas the activation of ERK1/2 and of the downstream transcription factor Egr-1 was low, while p38 phosphorylation and SP-1-DNA binding were low compared to the controls. These results point to a central role of ERK1/Egr-1 in the regulation of 11βHSD2 expression under the conditions of limited zinc availability. In summary, results show that an increase in placenta 11βHSD2 expression occurs as a consequence of gestational marginal zinc nutrition. This seems to be due to a low tissue zinc-associated deregulation of ERK1/2 rather than to exposure to high maternal glucocorticoid exposure. The deleterious effects on brain development caused by diet-induced marginal zinc deficiency in rats do not seem to be due to fetal exposure to excess glucocorticoids.Fil: Huang, Y. L.. University of California at Davis; Estados UnidosFil: Supasai, S.. University of California at Davis; Estados UnidosFil: Kucera, H.. University of California at Davis; Estados UnidosFil: Gaikwad, N. W.. University of California at Davis; Estados UnidosFil: Adamo, Ana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas ; ArgentinaFil: Mathieu, Patricia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas ; ArgentinaFil: Oteiza, Patricia Isabel. University of California at Davis; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin