Metal Homeostasis and Exposure in Distinct Phenotypic Subtypes of Insulin Resistance among Children with Obesity.

BACKGROUND: Trace elements and heavy metals have proven pivotal roles in childhood obesity and insulin resistance. However, growing evidence suggests that insulin resistance could encompass distinct phenotypic subtypes. METHODS: Herein, we performed a comprehensive metallomics characterization of plasma samples from children and adolescents with obesity and concomitant insulin resistance, who were stratified as early (N = 17, 11.4 ± 2.4 years), middle (N = 16, 11.8 ± 1.9 years), and late (N = 33, 11.7 ± 2.0 years) responders according to the insulin secretion profile in response to an oral glucose tolerance test. To this end, we employed a high-throughput method aimed at determining the biodistribution of various essential and toxic elements by analyzing total metal contents, metal-containing proteins, and labile metal species. RESULTS: Compared with the early responders, participants with delayed glucose-induced hyperinsulinemia showed a worsened insulin resistance (HOMA-IR, 4.5 vs. 3.8) and lipid profile (total cholesterol, 160 vs. 144 mg/dL; LDL-cholesterol, 99 vs. 82 mg/dL), which in turn was accompanied by sharpened disturbances in the levels of plasmatic proteins containing chromium (4.8 vs. 5.1 µg/L), cobalt (0.79 vs. 1.2 µg/L), lead (0.021 vs. 0.025 µg/L), and arsenic (0.077 vs. 0.17 µg/L). A correlation analysis demonstrated a close inter-relationship among these multielemental perturbations and the characteristic metabolic complications occurring in childhood obesity, namely impaired insulin-mediated metabolism of carbohydrates and lipids. CONCLUSIONS: These findings highlight the crucial involvement that altered metal homeostasis and exposure may have in regulating insulin signaling, glucose metabolism, and dyslipidemia in childhood obesity.

Trace elements as potential modulators of puberty-induced amelioration of oxidative stress and inflammation in childhood obesity.

Although puberty is known to influence obesity progression, the molecular mechanisms underlying the role of sexual maturation in obesity-related complications remains largely unexplored. Here, we delve into the impact of puberty on the most relevant pathogenic hallmarks of obesity, namely oxidative stress and inflammation, and their association with trace element blood status. To this end, we studied a well-characterized observational cohort comprising prepubertal (N = 46) and pubertal (N = 48) children with obesity. From all participants, plasma and erythrocyte samples were collected and subjected to metallomics analysis and determination of classical biomarkers of oxidative stress and inflammation. Besides the expected raise of sexual hormones, pubertal children displayed better inflammatory and oxidative control, as reflected by lower levels of C-reactive protein and oxidative damage markers, as well as improved antioxidant defense. This was in turn accompanied by a healthier multielemental profile, with increased levels of essential elements involved in the antioxidant system and metabolic control (metalloproteins containing zinc, molybdenum, selenium, and manganese) and decreased content of potentially deleterious species (total copper, labile free iron). Therefore, our findings suggest that children with obesity have an exacerbated inflammatory and oxidative damage at early ages, which could be ameliorated during pubertal development by the action of trace element-mediated buffering mechanisms.

Sexually dimorphic metal alterations in childhood obesity are modulated by a complex interplay between inflammation, insulin, and sex hormones.

Although growing evidence points to a pivotal role of perturbed metal homeostasis in childhood obesity, sexual dimorphisms in this association have rarely been investigated. In this study, we applied multi-elemental analysis to plasma and erythrocyte samples from an observational cohort comprising children with obesity, with and without insulin resistance, and healthy control children. Furthermore, a wide number of variables related to carbohydrate and lipid metabolism, inflammation, and sex hormones were also determined. Children with obesity, regardless of sex and insulin resistance status, showed increased plasma copper-to-zinc ratios. More interestingly, obesity-related erythroid alterations were found to be sex-dependent, with increased contents of iron, zinc, and copper being exclusively detected among female subjects. Our findings suggest that a sexually dimorphic hormonal dysregulation in response to a pathological cascade involving inflammatory processes and hyperinsulinemia could be the main trigger of this female-specific intracellular sequestration of trace elements. Therefore, the present study highlights the relevance of genotypic sex as a susceptibility factor influencing the pathogenic events behind childhood obesity, thereby opening the door to develop sex-personalized approaches in the context of precision medicine.

Characterization of the Plasmatic and Erythroid Multielemental Biodistribution in Childhood Obesity Using a High-Throughput Method for Size Fractionation of Metal Species.

In this chapter, we describe a metallomics method based on protein precipitation under non-denaturing conditions and further analysis by inductively coupled plasma mass spectrometry for high-throughput metal speciation in plasma and erythrocyte samples. This methodology enables to study the total multielemental profile of these biological matrices, as well as to quantify the metal fractions conforming the metallometabolome and the metalloproteome. Furthermore, the analytical coverage comprises several essential and toxic metal elements, namely aluminum, arsenic, cadmium, cobalt, chromium, copper, iron, lithium, manganese, molybdenum, nickel, lead, selenium, vanadium, and zinc. Altogether, the metallomics method here proposed represents an excellent approach to comprehensively characterize the metal biodistribution in human peripheral blood, which would enable to decipher the role of metal homeostasis in health and disease, and particularly in childhood obesity.

Altered Metal Homeostasis Associates with Inflammation, Oxidative Stress, Impaired Glucose Metabolism, and Dyslipidemia in the Crosstalk between Childhood Obesity and Insulin Resistance.

Metals are redox-active substances that participate in central biological processes and may be involved in a multitude of pathogenic events. However, considering the inconsistencies reported in the literature, further research is crucial to disentangle the role of metal homeostasis in childhood obesity and comorbidities using well-characterized cohorts and state-of-the-art analytical methods. To this end, we studied an observational population comprising children with obesity and insulin resistance, children with obesity without insulin resistance, and healthy control children. A multi-elemental approach based on the size-fractionation of metal species was applied to quantify the total content of various essential and toxic elements in plasma and erythrocyte samples, and to simultaneously investigate the metal fractions conforming the metalloproteome and the labile metal pool. The most important disturbances in childhood obesity were found to be related to elevated circulating copper levels, decreased content of plasmatic proteins containing chromium, cobalt, iron, manganese, molybdenum, selenium, and zinc, as well as the sequestration of copper, iron, and selenium within erythrocytes. Interestingly, these metal disturbances were normally exacerbated among children with concomitant insulin resistance, and in turn were associated to other characteristic pathogenic events, such as inflammation, oxidative stress, abnormal glucose metabolism, and dyslipidemia. Therefore, this study represents one-step further towards a better understanding of the involvement of metals in the crosstalk between childhood obesity and insulin resistance.

Impact of the SARS-CoV-2 lockdown measures in Southern Spain on PM10 trace element and gaseous pollutant concentrations.

Trace element concentrations within PM10, gaseous pollutants (NO2 and SO2), and PM10 levels were studied during the Covid-19 lockdown at a regional level in Southern Spain (Andalusia). Pollutant concentrations were compared considering different mobility periods (pre-lockdown, lockdown, and relaxation) in 2020 and previous years (2013-2016). An acute decrease in NO2 levels (<50%) was observed as a consequence of traffic diminution during the confinement period. Moreover, a lower reduction in PM10 levels and a non-clear pattern for SO2 levels were observed. During the lockdown period, PM10 elements released from traffic emissions (Sn and Sb) showed the highest concentration diminution in the study area. Regarding the primary industrial sites, there were no significant differences in V, Ni, La, and Cr concentration reduction during 2020 associated with industrial activity (stainless steel and oil refinery) in Algeciras Bay. Similarly, concentrations of Zn showed the same behaviour at Cordoba, indicating that the Zn-smelter activity was not affected by the lockdown. Nevertheless, stronger reductions of Cu, Zn, and As in Huelva during the confinement period indicated a decrease in the nearby Cu-smelter emissions. Brick factories in Bailen were also influenced by the confinement measures, as corroborated by the marked decrease in concentrations of Ni, V, Cu, and Zn during the lockdown compared to that from previous years. This work has shown the baseline concentrations of trace elements of PM10, which is of great value to air quality managers in order to minimise pollution levels by applying the confinement of the population, affecting both traffic and industrial anthropogenic activities.

Exploring the association between circulating trace elements, metabolic risk factors, and the adherence to a Mediterranean diet among children and adolescents with obesity.

Diet is one of the most important modifiable lifestyle factors for preventing and treating obesity. In this respect, the Mediterranean diet (MD) has proven to be a rich source of a myriad of micronutrients with positive repercussions on human health. Herein, we studied an observational cohort of children and adolescents with obesity (N = 26) to explore the association between circulating blood trace elements and the degree of MD adherence, as assessed through the KIDMED questionnaire. Participants with higher MD adherence showed better glycemic/insulinemic control and a healthier lipid profile, as well as raised plasma levels of selenium, zinc, cobalt, molybdenum, and arsenic, and increased erythroid content of selenium. Interestingly, we found that these MD-related mineral alterations were closely correlated with the characteristic metabolic complications behind childhood obesity, namely hyperglycemia, hyperinsulinemia, and dyslipidemia (p < 0.05, |r| > 0.35). These findings highlight the pivotal role that dietary trace elements may play in the pathogenesis of obesity and related disorders.

Contribution of anthropogenic and natural sources in PM10 during North African dust events in Southern Europe.

The influence of North African (NAF) dust events on the air quality at the regional level (12 representative monitoring stations) in Southern Europe during a long time series (2007-2014) was studied. PM10 levels and chemical composition were separated by Atlantic (ATL) and NAF air masses. An increase in the average PM10 concentrations was observed on sampling days with NAF dust influence (42 µg m-3) when compared to ATL air masses (29 µg m-3). Major compounds such as crustal components and secondary inorganic compounds (SIC), as well as toxic trace elements derived from industrial emissions, also showed higher concentrations of NAF events. A source contribution analysis using positive matrix factorisation (PMF) 5.0 of the PM10 chemical data, discriminating ATL and NAF air mass origins, allowed the identification of five sources: crustal, sea salt, traffic, regional, and industrial. A higher contribution (74%) of the natural sources to PM10 concentrations was confirmed under NAF episodes compared with ATL. Furthermore, there was an increase in anthropogenic sources during these events (51%), indicating the important influence of the NAF air masses on these sources. The results of this study highlight that environmental managers should take appropriate actions to reduce local emissions during NAF events to ensure good air quality.

Aerosol analysis by micro laser-induced breakdown spectroscopy: A new protocol for particulate matter characterization in filters.

Atmospheric aerosols (particulate matter - PM) affect the air quality and climate, even in remote areas, such as the Antarctic Region. Current techniques for continuous PM monitoring are usually complex, costly, time consuming and do not provide real-time measurements. In this work, based on micro laser-induced breakdown spectroscopy (LIBS), an innovative method with an optical design and multi-elemental scanning imaging, is presented to characterize PM collected in filters from Antarctica. After following a simple protocol and under atmospheric pressure, the new approach allows to obtain a global visualization of the elemental PM composition of the filters with a minimum sample destruction and preparation. For the first time, we were able to map the localization of pollutants in filters at high spatial resolution and speed. This recent method offers a new insight on the characterization of PM, particularly in isolated areas, where no complex equipment and real time measurements are demanded.

Source contribution and origin of PM10 and arsenic in a complex industrial region (Huelva, SW Spain).

Air pollution coming from industrial activities is a matter of interest since their emissions can seriously affect to the human health of nearby populations. A more detailed study about industrial emissions is required in order to discriminate different activities contributing to pollutant sources. In this sense, gaseous pollutants (NO2, SO2 and O3) and PM10 levels has been studied in a complex industrial area in the southwest of Spain (La Rabida and the nearby city of Huelva) during the period 1996-2017. Hourly, daily, monthly and annual variations of PM10 and gaseous pollutants concentrations point to the industrial activity as the main SO2 source. Furthermore, traffic and resuspension emissions contribute to the NO2 and PM10 levels, respectively. Results from chemical composition of PM10 at both sites during the period 2015-2017 are characterized by high concentrations of the crustal components derived from natural and local resuspension. Arsenic is found to be the main geochemical anomaly at La Rabida (annual mean of 7 ng m-3), exceeding the European annual target of 6 ng m-3, which supposes a risk for the nearby population. An emission source from Cu-smelter has been identified in La Rabida and Huelva. A second source corresponding to emissions from polymetallic sulfides handling in a port area has been described for the first time in La Rabida. In addition, arsenic speciation results have identified three different As impacts scenarios as a function of the dominant wind direction, the SO2 episodes and the As extraction efficiency: impact of the Cu-smelter, impact of the bulk polymetallic sulfides and a mixed impact of both sources.