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BACKGROUND: Few epidemiologic studies have focused on the specific source of ambient air pollution and adverse health effects in early life. Here, we investigated whether air pollutants from different emission sources were associated with decreased birth anthropometry parameters and increased DNA adduct formation in mother-child pairs residing in the Mexico City Metropolitan Area (MCMA). METHODS: This cross-sectional study included 190 pregnant women recruited during their last trimester of pregnancy from two hospitals at MCMA, and a Modeling Emissions Inventory (MEI) to calculate exposure to ambient air pollutants from different emissions sources (area, point, mobile, and natural) for two geographical buffers 250 and 750 m radii around the participants households. RESULTS: Contaminants were positively correlated with umbilical cord blood (UCB) adducts, but not with maternal blood (MB) adducts. PM10 emissions (area and point sources, overall emissions), PM2.5 (point sources), volatile organic compounds (VOC), total organic compounds (TOC) from point sources were positively correlated with UCB adducts. Air pollutants emitted from natural sources were correlated with a decrease in MB and UCB adducts. PM10 and PM2.5 were correlated (p < 0.05) with a decrease in birth weight (BW), birth length (BL) and gestational age at term (GA). In multivariate analyses adjusted for potential confounders, PM10 was associated with an increase in UCB adducts. PM10 and PM2.5 from overall emissions were associated with a decrease in BW, BL and GA at term. IMPACT: Results suggested higher susceptibility of newborns compared to mothers to damage related to ambient air pollution. PMs are associated with birth anthropometry parameters and DNA damage in adjusted models, highlighting the need for more strict regulation of PM emissions.

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The transsulfuration pathway (TSP) is a metabolic pathway involving sulfur transfer from homocysteine to cysteine. Transsulfuration pathway leads to many sulfur metabolites, principally glutathione, H2S, taurine, and cysteine. Key enzymes of the TSP, such as cystathionine ß-synthase and cystathionine γ-lyase, are essential regulators at multiple levels in this pathway. TSP metabolites are implicated in many physiological processes in the central nervous system and other tissues. TSP is important in controlling sulfur balance and optimal cellular functions such as glutathione synthesis. Alterations in the TSP and related pathways (transmethylation and remethylation) are altered in several neurodegenerative diseases, including Parkinson's disease, suggesting their participation in the pathophysiology and progression of these diseases. In Parkinson's disease many cellular processes are comprised mainly those that regulate redox homeostasis, inflammation, reticulum endoplasmic stress, mitochondrial function, oxidative stress, and sulfur content metabolites of TSP are involved in these damage processes. Current research on the transsulfuration pathway in Parkinson's disease has primarily focused on the synthesis and function of certain metabolites, particularly glutathione. However, our understanding of the regulation of other metabolites of the transsulfuration pathway, as well as their relationships with other metabolites, and their synthesis regulation in Parkinson´s disease remain limited. Thus, this paper highlights the importance of studying the molecular dynamics in different metabolites and enzymes that affect the transsulfuration in Parkinson's disease.

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Organisms have metabolic pathways responsible for eliminating endogenous and exogenous toxicants. Generally, we associate the liver par excellence as the organ in charge of detoxifying the body; however, this process occurs in all tissues, including the brain. Due to the presence of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), the Central Nervous System (CNS) is considered a partially isolated organ, but similar to other organs, the CNS possess xenobiotic transporters and metabolic pathways associated with the elimination of xenobiotic agents. In this review, we describe the different systems related to the detoxification of xenobiotics in the CNS, providing examples in which their association with neurodegenerative processes is suspected. The CNS detoxifying systems include carrier-mediated, active efflux and receptor-mediated transport, and detoxifying systems that include phase I and phase II enzymes, as well as those enzymes in charge of neutralizing compounds such as electrophilic agents, reactive oxygen species (ROS), and free radicals, which are products of the bioactivation of xenobiotics. Moreover, we discuss the differential expression of these systems in different regions of the CNS, showing the different detoxifying needs and the composition of each region in terms of the cell type, neurotransmitter content, and the accumulation of xenobiotics and/or reactive compounds.

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Exposure to toxic metals and metalloids is an important cause of preventable diseases worldwide. Inorganic arsenic (iAs) affects several organs and tissues, causing neurobehavioral alterations in the central nervous system (CNS) that might lead to neurodegeneration. In this work, we wanted to explore the time- and dose-related changes on glutathione (GSH) levels in several regions of the CNS, such as the cortex, striatum, hippocampus, and cerebellum, to identify the initial cellular changes associated to GSH depletion due to iAs exposure. Mice received a single intraperitoneal injection containing 5 or 14 mg/kg sodium arsenite. Animals were killed at 2, 6, and 24 h. Significant depletion of GSH levels was observed in the cortex at 2 and 6 h, while on the striatum, hippocampus, or cerebellum regions, no significant changes were observed. GSH depletion in the cortex was associated with the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa B (NFκB) pathways, which led to the upregulation of xCT, excitatory amino acid carrier 1 (EAAC1), glutamate/aspartate transporter (GLAST), and glial glutamate transporter 1 (GLT-1), and the activation of the transsulfuration pathways, which led to the overproduction of H2S in the cortex and increased levels of GSH in the cortex and cerebellum at 24 h. In the cortex, the N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B were also altered at 24 h. These early effects were not homogeneous among different brain regions and indicate early neurotoxic alterations in the cortex and cerebellum.

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Glutathione (GSH) is the most abundant intracellular antioxidant. GSH depletion leads to oxidative stress and neuronal damage in the central nervous system (CNS). In mice, the acute systemic inhibition of GSH synthesis by L-buthionine-S-R-sulfoximine (BSO) triggers a protective response and a subsequent increase in the CNS GSH content. This response might be modulated by a peripheral increment of circulating nerve growth factor (NGF). NGF is an important activator of antioxidant pathways mediated by tropomyosin-related kinase receptor A (TrkA). Here, we report that peripheral administration of BSO increased plasma NGF levels. Additionally, BSO increased NGF levels and activated the NGF/TrkA/Akt pathway in striatal neurons. Moreover, the response in the striatum included an increased transcription of nrf2, gclm, lat1, eaac1, and xct, all of which are involved in antioxidant responses, and L-cys/L-cys2 and glutamate transporters. Using antibody against NGF confirmed that peripheral NGF activated the NGF/TrkA/Akt/Nrf2 pathway in the striatum and subsequently increased the transcription of gclm, nrf2, lat1, eaac1, and xct. These results provide evidence that the reduction of peripheral GSH pools increases peripheral NGF circulation that orchestrates a neuroprotective response in the CNS, at least in the striatum, through the NGF/TrkA/Akt/Nrf2 pathway.

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Mexico City's Metropolitan Area (MCMA) includes Mexico City and 60 municipalities of the neighbor states. Inhabitants are exposed to emissions from over five million vehicles and stationary sources of air pollutants such as particulate matter (PM) and ozone. MCMA PM contains elemental carbon and organic carbon (OC). OCs include polycyclic aromatic hydrocarbons (PAHs), many of which induce mutagenic and carcinogenic DNA adducts. Gestational exposure to air pollution has been associated with increased risk of intrauterine growth restriction, preterm birth or low birth weight risk, and PAH-DNA adducts. These effects also depend on the presence of risk alleles. We investigated the presence of bulky PAH-DNA adducts, plasma 8-iso-PGF2α (8-iso-prostaglandin F2α ) and risk allele variants in neonates cord blood and their non-smoking mothers' leucocytes from families that were living in a highly polluted area during 2014-2015. The presence of adducts was significantly associated with both PM2.5 and PM10 levels, mainly during the last trimester of gestation in both neonates and mothers, while the last month of pregnancy was significant for the association between ozone levels and maternal plasma 8-iso-PGF2α . Fetal CYP1B1*3 risk allele was associated with increased adduct levels in neonates while the presence of the maternal allele significantly reduced the levels of fetal adducts. Maternal NQO1*2 was associated with lower maternal levels of adducts. Our findings suggest the need to reduce actual PM limits in MCMA. We did not observe a clear association between PM and/or adduct levels and neonate weight, length, body mass index, Apgar or Capurro score. Environ. Mol. Mutagen. 60:428-442, 2019. © 2019 Wiley Periodicals, Inc.

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Studies associate particulate matter (PM) exposure with pulmonary, cardiovascular, and neurologic diseases. Elevated levels of coarse (PM10) and fine (PM2.5) PM have been reported in the Mexico City metropolitan area during the last two decades. There is limited information if these conditions affect newborns. We associated maternal exposure to PM reported by the monitoring stations considering the place of residence of each participant with the presence of genotoxic damage (cytome analysis) in maternal and umbilical cord blood (UCB) lymphocytes. Eighty-four healthy women in their last quarter of pregnancy met the inclusion criteria. Each volunteer exposure was estimated according to the average PM2.5 and PM10 levels during the last month of gestation. The micronuclei (MN) frequencies in UCB lymphocyte cultures ranged between 0 and 9. They also showed lower cell proliferation indexes than their mothers. There was a strong correlation between the maternal and the UCB MN frequency (ρ = 0.3767, P = 0.0002). Multiple regression analysis including PM10 and PM2.5 levels, maternal age, and occupation, showed a significant and positive association between UCB MN frequency and PM2.5. A statistically significant increase in the MN frequency in both maternal and UCB lymphocytes was observed in samples obtained during the dry season (higher PM levels) as compared with the MN frequency in blood samples obtained during the rainy season (lower PM levels). These results suggest that PM, mainly PM2.5 , can cross the placenta causing DNA damage in fetal cells which may increase the potential for diseases during childhood or adult life. Environ. Mol. Mutagen. 60:421-427, 2019. © 2019 Wiley Periodicals, Inc.

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Accumulating evidence indicates that homeostatic plasticity mechanisms dynamically adjust synaptic strength to promote stability that is crucial for memory storage. Our previous studies have shown that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of long-term potentiation (LTP) in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) in vivo. We have also reported that induction of LTP in the Bla-IC pathway modifies the CTA extinction. Memoryextinction involves the formation of a new associativememorythat inhibits a previously conditioned association. The aim of the present study was to analyze the effect of CTA extinction on the ability to induce subsequent LTP in the Bla-IC projection in vivo. Thus, 48 h after CTA extinction animals received high frequency stimulation in order to induce IC-LTP. Our results show that extinction training allows the induction but not the maintenance of IC-LTP. In addition, with the purpose of exploring part of the mechanisms involved in this process and since a body of evidence suggests that protein phosphatase calcineurin (CaN) is involved in the extinction of some behavioral tasks, we analyzed the participation of this phosphatase. The present results show that extinction training increases the CaN expression in the IC, as well as that the inhibition of this phosphatase reverts the effects of the CTA-extinction on the IC-LTP. These findings reveal that CTA extinction promotes a homeostatic regulation of subsequent IC synaptic plasticity maintenance through increases in CaN levels.

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Early life exposure to environmental pollutants and toxic chemicals has been linked to learning and behavioral alterations in children. iAs exposure is associated with different types neurological disorders such as memory and learning impairment. iAs is methylated in the brain by the arsenic III-methyltransferase in a process that requires glutathione (GSH). The xCT-antiporter cell membrane transporter participates in the influx of cystine for GSH synthesis in exchange for glutamate in a 1:1 ratio. In CD-1 mice gestationally exposed to 20 ppm of sodium arsenite in drinking water, we have previously observed up-regulation of xCT in the male mouse hippocampus which caused glutamatergic synapse alterations affecting learning and memory processes. Here, we used the same gestational iAs exposure model to investigate whether the up-regulation of xCT and down-regulation of GLT-1 transporters were associated with higher levels of extracellular glutamate and changes in the expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor, responsible for excitatory fast synaptic transmission. The induction of LTP in the perforant-dentate gyrus pathway (PP-DG) of the hippocampus was also studied, as well as learning and memory formation using the water maze test. Changes in GSH levels were also tested in the hippocampus of animals exposed to iAs. Results showed increased GSH synthesis (p < 0.05), associated with significantly higher extracellular glutamate levels in iAs exposed mice. Exposure was also significantly associated with AMPA subunits down-regulation, deficient LTP induction, and lower excitability of the PP-DG pathway. In addition, animals showed deficient learning and memory in the Morris Water Maze test.

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BACKGROUND: Mexico is included in the list of countries with concurrent arsenic and fluoride contamination in drinking water. Most of the studies have been carried out in the adult population and very few in the child population. Urinary arsenic and urinary fluoride levels have been accepted as good biomarkers of exposure dose. The Biomonitoring Equivalents (BE) values are useful tools for health assessment using human biomonitoring data in relation to the exposure guidance values, but BE information for children is limited. METHODS: We conducted a systematic review of the reported levels of arsenic and fluoride in drinking water, urinary quantification of speciated arsenic (inorganic arsenic and its methylated metabolites), and urinary fluoride levels in child populations. For BE values, urinary arsenic and fluoride concentrations reported in Mexican child populations were revised discussing the influence of factors such as diet, use of dental products, sex, and metabolism. RESULTS: Approximately 0.5 and 6 million Mexican children up to 14 years of age drink water with arsenic levels over 10 µg/L and fluoride over 1.5 mg/L, respectively. Moreover, 40% of localities with arsenic levels higher than 10 µg/L also present concurrent fluoride exposure higher than 1.5 mgF/L. BE values based in urinary arsenic of 15 µg/L and urinary fluoride of 1.2 mg/L for the environmentally exposed child population are suggested. CONCLUSIONS: An actual risk map of Mexican children exposed to high levels of arsenic, fluoride, and both arsenic and fluoride in drinking water was generated. Mexican normativity for maximum contaminant level for arsenic and fluoride in drinking water should be adjusted and enforced to preserve health. BE should be used in child populations to investigate exposure.

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