Sergio Montes

Intellectual Function in Mexican Children Living in a Mining Area and Environmentally Exposed to Manganese

Background Excessive exposure to manganese (Mn), an essential trace element, has been shown to be neurotoxic, especially when inhaled. Few studies have examined potential effects of Mn on cognitive functions of environmentally exposed children. Objective This study was intended to estimate environmental exposure to Mn resulting from mining and processing and to explore its association with intellectual function of school-age children. Methods Children between 7 and 11 years of age from the Molango mining district in central Mexico (n = 79) and communities with similar socioeconomic conditions that were outside the mining district (n = 93) participated in the cross-sectional evaluation. The revised version of the Wechsler Intelligence Scale for Children adapted for the Mexican population was applied. Concentrations of Mn in blood (MnB) and hair (MnH) were used as biomarkers of exposure. Results Exposed children had significantly higher median values for MnH (12.6 μg/g) and MnB (9.5 μg/L) than did nonexposed children (0.6 μg/g and 8.0 μg/L, respectively). MnH was inversely associated with Verbal IQ [β = −0.29; 95% confidence interval (CI), −0.51 to −0.08], Performance IQ (β = −0.08; 95% CI, −0.32 to 0.16), and Total Scale IQ (β = −0.20; 95% CI, −0.42 to 0.02). MnB was inversely but nonsignificantly associated with Total and Verbal IQ score. Age and sex significantly modified associations of MnH, with the strongest inverse associations in young girls and little evidence of associations in boys at any age. Associations with MnB did not appear to be modified by sex but appeared to be limited to younger study participants. Conclusions The findings from this study suggest that airborne Mn environmental exposure is inversely associated with intellectual function in young school-age children.

The transition metals copper and iron in neurodegenerative diseases

Neurodegenerative diseases constitute a worldwide health problem. Metals like iron and copper are essential for life, but they are also involved in several neurodegenerative mechanisms such as protein aggregation, free radical generation and oxidative stress. The role of Fe and Cu, their pathogenic mechanisms and possible therapeutic relevance are discussed regarding four of the most common neurodegenerative diseases, Alzheimers, Parkinsons and Huntingtons diseases as well as amyotrophic lateral sclerosis. Metal-mediated oxidation by Fenton chemistry is a common feature for all those disorders and takes part of a self-amplifying damaging mechanism, leading to neurodegeneration. The interaction between metals and proteins in the nervous system seems to be a crucial factor for the development or absence of neurodegeneration. The present review also deals with the therapeutic strategies tested, mainly using metal chelating drugs. Metal accumulation within the nervous system observed in those diseases could be the result of compensatory mechanisms to improve metal availability for physiological processes.

Free Copper, Ferroxidase and SOD1 Activities, Lipid Peroxidation and NO x Content in the CSF. A Different Marker Profile in Four Neurodegenerative Diseases

The understanding of oxidative damage in different neurodegenerative diseases could enhance therapeutic strategies. Our objective was to quantify lipoperoxidation and other oxidative products as well as the activity of antioxidant enzymes and cofactors in cerebrospinal fluid (CSF) samples. We recorded data from all new patients with a diagnosis of either one of the four most frequent neurodegenerative diseases: Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD) and lateral amyotrophic sclerosis (ALS). The sum of nitrites and nitrates as end products of nitric oxide (NO) were increased in the four degenerative diseases and fluorescent lipoperoxidation products in three (excepting ALS). A decreased Cu/Zn-dependent superoxide dismutase (SOD) activity characterized the four diseases. A significantly decreased ferroxidase activity was found in PD, HD and AD, agreeing with findings of iron deposition in these entities, while free copper was found to be increased in CSF and appeared to be a good biomarker of PD.

Possible Mechanisms of Neurodegeneration in Schizophrenia

Brain morphological alterations in schizophrenic patients have led to the neurodevelopmental hypothesis of schizophrenia. On the other hand, a progressive neurodegenerative process has also been suggested and some follow-up studies have shown progressive morphological changes in schizophrenic patients. Several neurotransmitter systems have been suggested to be involved in this disorder and some of them could lead to neuronal death under certain conditions. This review discusses some of the biochemical pathways that could lead to neurodegeneration in schizophrenia showing that neuronal death may have a role in the etiology or natural course of this disorder.

Manganese accumulation in the CNS and associated pathologies.

Manganese (Mn) is an essential metal for life. It is a key constituent of clue enzymes in the central nervous system, contributing to antioxidant defenses, energetic metabolism, ammonia detoxification, among other important functions. Until now, Mn transport mechanisms are partially understood; however, it is known that it shares some mechanisms of transport with iron. CNS is susceptible to Mn toxicity because it possesses mechanisms that allow Mn entry and favor its accumulation. Cases of occupational Mn exposure have been extensively reported in the literature; however, there are other ways of exposure, such as long-term parental nutrition and liver failure. Manganism and hepatic encephalopathy are the most common pathologies associated with the effects of Mn exposure. Both pathologies are associated with motor and psychiatric disturbances, related in turn to mechanisms of damage such as oxidative stress and neurotransmitters alterations, the dopaminergic system being one of the most affected. Although manganism and Parkinson’s disease share some characteristics, they differ in many aspects that are discussed here. The mechanisms for Mn transport and its participation in manganism and hepatic encephalopathy are also considered in this review. It is necessary to find an effective therapeutic strategy to decrease Mn levels in exposed individuals and to treat Mn long term effects. In the case of patients with chronic liver failure it would be worthwhile to test a low-Mn diet in order to ameliorate symptoms of hepatic encephalopathy possibly related to Mn accumulation.

Striatal manganese accumulation induces changes in dopamine metabolism in the cirrhotic rat

Manganese (Mn) is an essential metal that, in excess, causes an extrapyramidal syndrome consisting in tremor, rigidity and akinesia. Recently, Mn was found to accumulate in brains of cirrhotic patients who also present motor abnormalities. Manganese alters dopaminergic transmission promoting an increase in the turnover of dopamine (DA). In this study, we studied the changes in dopamine and its main metabolite homovanillic acid (HVA) to evaluate DA turnover following administration of manganese to bile-duct obstructed rats. Some groups of rats were treated with manganese chloride in two concentrations: 0.5 and 1 mg/ml of Mn2+ in their drinking water. Four weeks after surgery and treatment with manganese, striatal Mn, DA and HVA were assessed. Marked increases (P<0.05) of striatal manganese content were observed in cirrhotic rats treated and untreated with manganese, these augments were dependent on the Mn concentration in water. Striatal contents of DA in cirrhotic rats diminished by 30% (P<0.05), administration of 0.5 mg/ml of manganese in drinking water to these rats returned dopamine to the basal level and 1 mg/ml of manganese increased dopamine content by 27%. The relationship of Mn content and DA turnover (HVA:DA) in the same animal showed a positive and statically significant correlation (P<0.05), with differences in slope for sham (b1=0.1528) and cirrhotic rats (b1=0.0174). These results suggest that manganese brain accumulation observed in liver failure could be a key element to understand dopamine metabolism in cirrhotic condition of humans.

Low concentration of nitrite and nitrate in the cerebrospinal fluid from schizophrenic patients: a pilot study

Some evidence suggests a dysfunctional nitric oxide (NO) system in the brain of schizophrenic subjects. We measured the concentrations of the stable metabolites of NO, nitrite, and nitrate in the cerebrospinal fluid (CSF) from schizophrenic and control patients with other neurological disorders and found lowered levels in the schizophrenic group as compared with the control group. This finding supports the hypothesis of a NO system reduction in the brain of schizophrenic subjects.

Effect of environmental manganese exposure on verbal learning and memory in Mexican children

Manganese (Mn) is an essential metal, but in excess it becomes neurotoxic. Childrens developing nervous system may be especially vulnerable to the neurotoxic effects of overexposure to this metal. The aim of this study was to assess the effect of Mn exposure on verbal memory and learning in 7- to 11-year-old children. We tested 79 children living in the Molango Mn-mining district and 95 children from a non-exposed community in the same State of Mexico. The Childrens Auditory Verbal Learning Test (CAVLT) was administered. Blood and hair samples were obtained to determine Mn concentrations using atomic absorption spectrophotometry. CAVLT performance was compared between the two groups and multilevel regression models were constructed to estimate the association between biomarkers of Mn exposure and the CAVLT scores. The exposed group presented higher hair and blood Mn (p<0.001) than the non-exposed group (median 12.6 vs. 0.6μg/g, 9.5vs. 8.0μg/L respectively), as well as lower scores (p<0.001) for all the CAVLT subscales. Hair Mn was inversely associated with most CAVLT subscales, mainly those evaluating long-term memory and learning (β=-0.47, 95% CI -0.84, -0.09). Blood Mn levels showed a negative but non-significant association with the CAVLT scores. These results suggest that Mn exposure has a negative effect on childrens memory and learning abilities.

Modulation of neurotransmitter systems by dehydroepiandrosterone and dehydroepiandrosterone sulfate: Mechanism of action and relevance to psychiatric disorders

Dehydroepiandrosterone (DHEA) is synthesized in the brain and several studies have shown that this steroid is a modulator of synaptic transmission. The effect of DHEA, and its sulfate ester DHEAS, on glutamate and GABA neurotransmission has been extensively studied but some effects on other neurotransmitter systems, such as dopamine, serotonin and nitric oxide, have also been reported. This review summarizes studies showing the effect of DHEA and DHEAS on neurotransmitter systems at different levels (metabolism, release, reuptake, receptor activation), as well as the activation of voltage-gated ion channels and calcium homeostasis, showing the variety of effects that these steroids exert on those systems, allowing the discussion of its mechanisms of action and its relevance to psychiatric disorders.

Environmental exposure to manganese and motor function of children in Mexico.

OBJECTIVES Occupational manganese (Mn) exposure has been associated with motor deficits in adult workers, but data on the potential effects of environmental exposure to Mn on the developing motor function for a children population is scarce. The aim of this study was to evaluate the association between exposure to Mn and motor function of school aged children. METHODS We conducted a cross-sectional study selecting 195 children (100 exposed and 95 unexposed) between 7 and 11 years old. The following tests were used to evaluate the motor function: Grooved pegboard, finger tapping, and Santa Ana test. Mn exposure was assessed by blood (MnB) and hair concentrations (MnH). We constructed linear regression models to evaluate the association between exposure to Mn and the different test scores adjusting for age, sex, maternal education, hemoglobin and blood lead. RESULTS The median concentration of MnH and MnB was significantly higher in exposed (12.6 μg/g and 9.5 μg/L) compared to unexposed children (0.6 μg/g and 8.0 μg/L). The exposed children on average performed the grooved pegboard test faster, but made more errors, although these results did not reach statistical significance with neither one of the Mn exposure biomarkers. MnB showed an inverse association on the execution of the finger tapping test (average in 5 trials β -0.4, p=0.02), but no association was observed with MnH. CONCLUSIONS A subtle negative association of Mn exposure on motor speed and coordination was shown. In adults, the main effect of environmental Mn exposure has been associated with motor skills, but these results suggest that such alterations are not the main effect on children.