Manganese in autism spectrum disorder and attention deficit hyperactivity disorder: The state of the art.

The objective of the present narrative review was to synthesize existing clinical and epidemiological findings linking manganese (Mn) exposure biomarkers to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), and to discuss key pathophysiological mechanisms of neurodevelopmental disorders that may be affected by this metal. Existing epidemiological data demonstrated both direct and inverse association between Mn body burden and ASD, or lack of any relationship. In contrast, the majority of studies revealed significantly higher Mn levels in subjects with ADHD, as well as direct relationship between Mn body burden with hyperactivity and inattention scores in children, although several studies reported contradictory results. Existing laboratory studies demonstrated that impaired attention and hyperactivity in animals following Mn exposure was associated with dopaminergic dysfunction and neuroinflammation. Despite lack of direct evidence on Mn-induced neurobiological alterations in patients with ASD and ADHD, a plethora of studies demonstrated that neurotoxic effects of Mn overexposure may interfere with key mechanisms of pathogenesis inherent to these neurodevelopmental disorders. Specifically, Mn overload was shown to impair not only dopaminergic neurotransmission, but also affect metabolism of glutamine/glutamate, GABA, serotonin, noradrenaline, thus affecting neuronal signaling. In turn, neurotoxic effects of Mn may be associated with its ability to induce oxidative stress, apoptosis, and neuroinflammation, and/or impair neurogenesis. Nonetheless, additional detailed studies are required to evaluate the association between environmental Mn exposure and/or Mn body burden and neurodevelopmental disorders at a wide range of concentrations to estimate the potential dose-dependent effects, as well as environmental and genetic factors affecting this association.

Role of gut microbiota in the modulation of the health effects of advanced glycation end­products (Review).

The aim of the present review was to summarize the potential interactive effects between the gut microbiota and advanced glycation end­product (AGE) accumulation and toxicity in the host, and to reveal potential the mediatory effects of the gut microbiota on AGE­related health effects. The existing data demonstrate that dietary AGEs can have a significant impact on the richness and diversity of the gut microbiota, although the particular effect is dependent on the type of species, as well as the exposure dose. In addition, the gut microbiota may metabolize dietary AGEs. It has been also demonstrated that the characteristics of the gut microbiota, including its richness and relative abundance of certain taxa, is tightly associated with AGE accumulation in the host organism. In turn, a bilateral interplay between AGE toxicity and the modulation of the gut microbiota may contribute to pathogenesis of ageing and diabetes­associated diseases. Bacterial endotoxin lipopolysaccharide appears as the molecule that mediates the interactions between the gut microbiota and AGE toxicity, specifically via the modulation of the receptor for AGE signaling. Therefore, it is proposed that the modulation of the gut microbiota using probiotics or other dietary interventions may have a significant impact on AGE­induced glycative stress and systemic inflammation.

The Role of Persistent Organic Pollutants in Obesity: A Review of Laboratory and Epidemiological Studies.

Persistent organic pollutants (POPs) are considered as potential obesogens that may affect adipose tissue development and functioning, thus promoting obesity. However, various POPs may have different mechanisms of action. The objective of the present review is to discuss the key mechanisms linking exposure to POPs to adipose tissue dysfunction and obesity. Laboratory data clearly demonstrate that the mechanisms associated with the interference of exposure to POPs with obesity include: (a) dysregulation of adipogenesis regulators (PPARγ and C/EBPα); (b) affinity and binding to nuclear receptors; (c) epigenetic effects; and/or (d) proinflammatory activity. Although in vivo data are generally corroborative of the in vitro results, studies in living organisms have shown that the impact of POPs on adipogenesis is affected by biological factors such as sex, age, and period of exposure. Epidemiological data demonstrate a significant association between exposure to POPs and obesity and obesity-associated metabolic disturbances (e.g., type 2 diabetes mellitus and metabolic syndrome), although the existing data are considered insufficient. In conclusion, both laboratory and epidemiological data underline the significant role of POPs as environmental obesogens. However, further studies are required to better characterize both the mechanisms and the dose/concentration-response effects of exposure to POPs in the development of obesity and other metabolic diseases.

Alterations in serum amino acid profiles in children with attention deficit/hyperactivity disorder.

The objective of the present study was to evaluate the circulating serum amino acid levels in children with attention deficit/hyperactivity disorder (ADHD). A total of 71 children with untreated ADHD and 31 neurotypical controls aged 7-14 years old were examined. Serum amino acid levels were evaluated using high-performance liquid chromatography (HPLC) with UV-detection. Laboratory quality control was performed with reference materials of human plasma amino acid levels. The obtained data demonstrated that children with ADHD were characterized by 29, 10 and 20% lower serum histidine (His), glutamine (Gln) and proline (Pro) levels compared with neurotypical children, respectively. In contrast, circulating aspartate (Asp), glutamate (Glu) and hydroxyproline (Hypro) levels exceeded the respective control values by 7, 7 and 42%. Correspondingly, the Gln-to-Glu and Pro-to-Hypro ratios were 28% and 49%, respectively, lower in ADHD cases compared with the controls. Total Gln/Glu levels were also significantly lower in ADHD patients. No significant group differences were observed between the groups in the other amino acids analyzed, including phenylalanine. Multiple linear regression analysis revealed significant associations between circulating serum Gln, lysine (Lys) (both negative) and Glu (positive) levels with total ADHD Rating Scale-IV scores. The observed alterations in Pro/Hypro and Gln/Glu levels and ratios are likely associated with the coexisting connective tissue pathology and alterations in glutamatergic neurotransmission in ADHD, respectively. Altered circulating levels of His, Lys and Asp may also be implicated in ADHD pathogenesis. However, further in vivo and in vitro studies are required in order to investigate the detailed mechanisms linking amino acid metabolism with ADHD pathogenesis.

Cobalt in athletes: hypoxia and doping - new crossroads.

Cobalt is an essential trace element that is known to mimic hypoxia and hypoxic training. Inorganic Co compounds are capable of Hypoxia-inducible factor-1 (HIF-1) activation, resulting in up-regulation of gene expression including erythropoietin (Epo). Experimental studies have demonstrated that Co treatment may increase hypoxic tolerance of different tissues, improve muscle metabolism and exercise performance. Other mechanisms may also involve modulation of steroid hormone and iron metabolism. Based on these experimental studies, in 2017 inorganic cobalt compounds were added into the World Anti-Doping Agency (WADA) prohibited list as doping agents. However, the existing data on beneficial effects of cobalt on exercise performance in athletes are scarce. Similarly, only experimental studies demonstrated exercise-induced decrease in tissue Co levels, whereas human data are inconsistent. In addition, multiple studies have demonstrated that excessive Co intake may be toxic due to prooxidant, proinflammatory, and proapoptotic activity. Therefore, monitoring of Co deficiency and overload is required to prevent potential health hazards in athletes. At the same time, modulation of Co status should be performed through supplementation avoiding excessive doses of inorganic cobalt that are used for doping and are accompanied by adverse health effects of metal toxicity.

The influence of physical activity on hair toxic and essential trace element content in male and female students.

The primary aim of the current study is to estimate the effect of different physical activity levels on hair trace element content in male and female students. A total of 113 students (59 women and 54 men) of P. G. Demidov Yaroslavl State University (Yaroslavl, Russia) took part in the current investigation. According to the level of the physical activity, all students were divided into three groups: high, medium, and low physical activity. Essential and toxic metal content (µg/g) in hair samples was assessed by inductively coupled plasma mass spectrometry using NexION 300D + NWR213 (Perkin-Elmer, USA). The obtained data show that hair iodine, zinc, arsenic, nickel, and tin levels are not related to physical activity in male and female students. At the same time, increased physical activity is associated with decreased hair copper, vanadium, bismuth, and mercury content in comparison to the low physical activity groups. Students with higher physical activity are also characterized by significantly higher hair cobalt, iron, manganese, selenium, cadmium, lithium, and lead concentrations. Finally, statistical analysis has revealed maximal gender differences in hair trace element content in the high physical activity groups, whereas in the low activity groups, the hair metal concentrations were nearly similar in females and males.