Elevated Levels Of Manganese Research Articles

Evaluating water, sanitation, and hygiene in schools of Bangladesh: progress toward SDG compliance

ABSTRACT The availability of safe water, sanitation, and hygiene (WASH) facilities in schools is essential for a healthy learning environment and achieving sustainable development goals (SDGs) 4 and 6. Despite its importance, comprehensive studies on drinking water quality, sanitation, and hygiene in schools are scarce. This study explicitly assessed the WASH services and gaps in 43 educational institutions, located in Tongi, Bangladesh, through field and laboratory investigations. Thirteen physicochemical and bacteriological parameters were analyzed, and water quality was classified using an Integrated Water Quality Index (IWQI). Hygiene and sanitation were evaluated through observations and data from school administrators on water sources, toilets, handwashing facilities, and solid waste management. Results showed that WASH services exceeded the national average, but all schools had dangerously high Escherichia coli levels (mean: 43.95 CFU/100 mL) in drinking water, posing health risks. Additionally, 89.72% of samples showed elevated manganese levels, 35% had high iron, and 41.86% had increased conductivity. About 35% of water was unsuitable for drinking based on IWQI. Schools lacked the capacity to monitor WASH quality, especially drinking water. A strategic framework for safe WASH facilities is recommended. The findings can lead the policymakers to prioritize the improvements in WASH facilities for attaining SDG 6.

Dopaminergic REST/NRSF is protective against manganese-induced neurotoxicity in mice

Chronic exposure to elevated levels of manganese (Mn) may cause a neurological disorder referred to as manganism. The transcription factor REST is dysregulated in several neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. REST upregulated tyrosine hydroxylase and induced protection against Mn toxicity in neuronal cultures. In the present study, we investigated if dopaminergic REST plays a critical role in protecting against Mn-induced toxicity in vivo using dopaminergic REST conditional knockout (REST-cKO) mice and REST loxP mice as wild-type (WT) controls. Restoration of REST in the substantia nigra (SN) with neuronal REST AAV vector infusion was performed to further support the role of REST in Mn toxicity. Mice were exposed to Mn (330 ug, intranasal, daily for 3 weeks), followed by behavioral tests and molecular biology experiments. Results showed that Mn decreased REST mRNA/protein levels in the SN-containing midbrain, as well as locomotor activity and motor coordination in WT mice, which were further decreased in REST-cKO. Mn-induced mitochondrial insults, such as impairment of fission/fusion and mitophagy, apoptosis, and oxidative stress, in the midbrain of WT mice were more pronounced in REST-cKO. However, REST restoration in the SN of REST cKO mice attenuated Mn-induced neurotoxicity. REST’s molecular target for its protection is unclear, but REST attenuated Mn-induced mitochondrial dysregulation, indicating that it is a primary intracellular target for both Mn and REST. These novel findings suggest that dopaminergic REST in the nigrostriatal pathway is critical in protecting against Mn toxicity, underscoring REST as a potential therapeutic target for treating manganism.

Microglial Sp1 induced LRRK2 upregulation in response to manganese exposure, and 17β-estradiol afforded protection against this manganese toxicity

Chronic exposure to elevated levels of manganese (Mn) causes a neurological disorder referred to as manganism, presenting symptoms similar to those of Parkinson’s disease (PD), yet the mechanisms by which Mn induces its neurotoxicity are not completely understood. 17β-estradiol (E2) affords neuroprotection against Mn toxicity in various neural cell types including microglia. Our previous studies have shown that leucine-rich repeat kinase 2 (LRRK2) mediates Mn-induced inflammatory toxicity in microglia. The LRRK2 promoter sequences contain three putative binding sites of the transcription factor (TF), specificity protein 1 (Sp1), which increases LRRK2 promoter activity. In the present study, we tested if the Sp1-LRRK2 pathway plays a role in both Mn toxicity and the protection afforded by E2 against Mn toxicity in BV2 microglial cells. The results showed that Mn induced cytotoxicity, oxidative stress, and tumor necrosis factor-α production, which were attenuated by an LRRK2 inhibitor, GSK2578215A. The overexpression of Sp1 increased LRRK2 promoter activity, mRNA and protein levels, while inhibition of Sp1 with its pharmacological inhibitor, mithramycin A, attenuated the Mn-induced increases in LRRK2 expression. Furthermore, E2 attenuated the Mn-induced Sp1 expression by decreasing the expression of Sp1 via the promotion of the ubiquitin-dependent degradation pathway, which was accompanied by increased protein levels of RING finger protein 4, the E3-ligase of Sp1, Sp1 ubiquitination, and SUMOylation. Taken together, our novel findings suggest that Sp1 serves as a critical TF in Mn-induced LRRK2 expression as well as in the protection afforded by E2 against Mn toxicity through reduction of LRRK2 expression in microglia.

Sources and Treatment Methods of Excessive Manganese Ion in Groundwater in A Certain Area

Trace element manganese is an essential element for human body, but the high concentration of manganese will adversely affect human health and all aspects of daily production and life. Elevated levels of manganese directly affect the color of the water, making it more prone to discoloration when used to wash clothes or dishes. Prolonged exposure to this water may cause organ damage. The groundwater in the study area is sampled and tested, and the test data is analyzed. The main results are as follows: the groundwater manganese ions in the study area exceed the standard, and the concentration of manganese ions in the southwest mountainous area is higher than that in other areas. In southwest China, due to the planting of a large number of tea trees, the main source of manganese in groundwater is manganese-containing fertilizer, and sewage recovery and treatment should be considered in combination with slope rainwater recovery equipment. In other fields, the manganese in groundwater is mainly from domestic sewage. The combined treatment of manganese ions in groundwater by chemical method and contact oxidation method is considered.

Manganese Exacerbates ConA-Induced Liver Inflammation via the cGAS-STING Signaling Pathway.

There is a potential association between the dysregulation of trace elements and impaired liver function. Elevated levels of manganese, an essential metal ion, have been observed in liver-related diseases, and excessive intake of manganese can worsen liver damage. However, the specific mechanisms underlying manganese-induced liver injury are not well understood. The aim of our study was to investigate the effects of excess manganese on autoimmune hepatitis(AIH) and elucidate its mechanisms. Our findings revealed that manganese exacerbates liver damage under ConA-induced inflammatory conditions. Transcriptomic and experimental data suggested that manganese enhances inflammatory signaling and contributes to the inflammatory microenvironment in the liver of AIH mice. Further investigations demonstrated that manganese exacerbates liver injury by activating the cGAS-STING signaling pathway and its downstream pro-inflammatory factors such as IFN[Formula: see text], IFN[Formula: see text], TNF[Formula: see text], and IL-6 in the liver of AIH mice. These results suggest that manganese overload promotes the progression of AIH by activating cGAS-STING-mediated inflammation, providing a new perspective for the treatment and prognosis of AIH.

Mechanisms of manganese-induced neurotoxicity and the pursuit of neurotherapeutic strategies.

Chronic exposure to elevated levels of manganese via occupational or environmental settings causes a neurological disorder known as manganism, resembling the symptoms of Parkinson's disease, such as motor deficits and cognitive impairment. Numerous studies have been conducted to characterize manganese's neurotoxicity mechanisms in search of effective therapeutics, including natural and synthetic compounds to treat manganese toxicity. Several potential molecular targets of manganese toxicity at the epigenetic and transcriptional levels have been identified recently, which may contribute to develop more precise and effective gene therapies. This review updates findings on manganese-induced neurotoxicity mechanisms on intracellular insults such as oxidative stress, inflammation, excitotoxicity, and mitophagy, as well as transcriptional dysregulations involving Yin Yang 1, RE1-silencing transcription factor, transcription factor EB, and nuclear factor erythroid 2-related factor 2 that could be targets of manganese neurotoxicity therapies. This review also features intracellular proteins such as PTEN-inducible kinase 1, parkin, sirtuins, leucine-rich repeat kinase 2, and α-synuclein, which are associated with manganese-induced dysregulation of autophagy/mitophagy. In addition, newer therapeutic approaches to treat manganese's neurotoxicity including natural and synthetic compounds modulating excitotoxicity, autophagy, and mitophagy, were reviewed. Taken together, in-depth mechanistic knowledge accompanied by advances in gene and drug delivery strategies will make significant progress in the development of reliable therapeutic interventions against manganese-induced neurotoxicity.

Biochemical assessment of oat genotypes revealed variability in grain quality with nutrition and crop improvement implications

Oat is a potent source of nutrients and bioactive compounds offering potential health benefits and role in combating micronutrient malnutrition problems. To exploit nutritional and quality traits of oats, a biochemical assessment of 112 oat genotypes was conducted. The high range of variability for total phenol (1.7–31.3 mg/g), β-glucan (1.0–8.0 mg/g), calcium (1.91–4.34 mg/g), zinc (3.80–6.50 mg/100 g), iron (0.66–4.89 mg/100 g) and manganese (2.88–8.0 mg/100 g) was revealed among genotypes. A higher amount of iron and zinc was found in genotypes OS-6, HFO-638, HFO-915 & HFO-918, whereas, elevated levels of manganese and zinc were recorded in genotypes OS-403 & OL-1804. The results revealed groups of low phytic acid oat genotypes containing high crude protein (HFO-52, HFO-270, HFO-330), β-glucan (HFO-62, HFO-588, HFO-926). A significant positive correlation was obtained between copper with iron, manganese, and calcium content. These findings could be useful for developing value-added oat food products and novel oat varieties.

Integrated modelling and management of manganese for a conventional potable water treatment plant

A reliable simulation of the manganese cycle in water supply system is essential for timely and effective manganese treatment strategies. A data-driven model estimating manganese levels in the treated water was developed through a threshold-based approach using raw water and supernatant return manganese levels. This data-driven model and a three-dimensional manganese cycle model for the source reservoir were integrated to simulate the overall manganese variations from the lake to the treated water. A decision support system based on the developed data-driven model was established to allow operators to react to situations that could result in elevated levels of manganese in the treated water. Scenario analyses were completed to examine the manganese variations in the reservoir, raw water and treated water due to different precipitations and wind conditions and to allow the identification of optimal strategies for manganese management from the reservoir to the water supply system.

S2570 Elevated Manganese Levels: A Case Report of an Unusual Presentation in a Patient With Cirrhosis and Iron-Deficiency Anemia

INTRODUCTION: Manganese (Mn) is an essential element for human health found in nuts, grains, and legumes. Toxic levels can result in parkinsonian features, due to damage to the dopaminergic neurons of the basal ganglia and gliosis. Common causes for toxicity include occupational hazards such as welding, steel industry and ingestion of contaminated water. CASE DESCRIPTION/METHODS: A 55 year old woman with a history of decompensated alcohol related cirrhosis, presented to the ER with a three week history of worsening neck pain and generalized weakness. Physical examination revealed bradykinesia, dysarthria, and dystonia of the neck. She had severe motor weakness and was unable to feed herself or ambulate independently. She denied any hematemesis, hematochezia or melena. The patient had been started by her PCP on Levodopa-Carbidopa 2 weeks prior to admission for these Parkinson like symptoms. Her labs showed anemia with hemoglobin of 7.4 g/dL, ferritin was 5 ng/mL and 20% transferrin saturation. Folate, thiamine and vitamin B12 levels were normal. MRI of the brain revealed T1-weighted signal hyperintensity of the globus pallidus bilaterally. EGD showed small varices and mild PHG, colonoscopy showed internal hemorrhoids and 2 small polyps, no active GI bleeding was seen. Multiple heavy metal levels were checked and blood Mn was elevated to 24.1 ug/L (normal 4.2-16.5). The patient’s symptoms improved following the two week course of Levodopa-Carbidopa prior to discharge. DISCUSSION: Pallidal signal hyperintensity on T1-weighted MRI has been well described in patients with Parkinson’s disease and in patients with Mn toxicity. Increased Mn levels have been reported in patients with cirrhosis and may result from decreased uptake by the liver and increased portosystemic shunting. Although hepatic encephalopathy can present with a large array of neurologic symptoms, the severity of our patient’s neck pain that brought her to the ED and her profound weakness had prompted more thorough workup. Furthermore, Mn and iron share similar mechanisms of absorption and transport, which allows for Mn to influence iron homeostasis and vice versa. Some studies have shown that iron deficiency can lead to accumulation of Mn in the blood and reduce enzymatic protective effect from Mn-induced oxidative stress. It is possible that the concurrent iron deficiency anemia in our patient has led to increased levels of Mn. Early recognition of these findings especially in presence of iron deficiency may warrant evaluation for Mn toxicity.Figure 1.: Hyperintense globi pallidi on T1-weighted magnetic resonance imaging.

Is there any association between manganese level and schizophrenia? - a descriptive review

Abstract Introduction: Manganese has a role in the membrane transport systems, synthesis of protein, vitamin C, and vitamins B, catalysis of hematopoiesis, regulation of the endocrine, immune system, blood sugar, reproduction, digestion, and blood coagulation. Furthermore, the level of manganese concentrations in human body appears to affect the occurrence of schizophrenia. The aim of this study was to search for relationships between the manganese level and the onset of schizophrenia. Material and methods: A descriptive review was performed based on a literature search on Medline and Google scholar from 2003 to 2020, using keywords: schizophrenia, manganese, Mn. The included studies were meta-analyses, case-control studies, and cohort studies that examined differences in manganese concentrations in patients with schizophrenia and healthy controls. Result: Eight studies were selected for the review, with one reporting elevated levels of manganese, two showing no significant differences, and the rest including two meta-analyses stating lower manganese concentrations in patients with schizophrenia in comparison with controls. Conclusion: In most of the researched studies, manganese concentrations in patients with schizophrenia were lower than in control groups, but not all of them reached the same conclusions. The relationship between manganese levels and schizophrenia must be further investigated.

Early Postnatal Manganese Exposure Reduces Rat Cortical and Striatal Biogenic Amine Activity in Adulthood.

Growing evidence from studies with children and animal models suggests that elevated levels of manganese during early development lead to lasting cognitive and fine motor deficits. This study was performed to assess presynaptic biogenic amine function in forebrain of adult Long-Evans rats exposed orally to 0, 25, or 50 mg Mn/kg/day over postnatal day 1-21 or continuously from birth to the end of the study (approximately postnatal day 500). Intracerebral microdialysis in awake rats quantified evoked outflow of biogenic amines in the right medial prefrontal cortex and left striatum. Results indicated that brain manganese levels in the early life exposed groups (postnatal day 24) largely returned to control levels by postnatal day 66, whereas levels in the lifelong exposed groups remained elevated 10%-20% compared with controls at the same ages. Manganese exposure restricted to the early postnatal period caused lasting reductions in cortical potassium-stimulated extracellular norepinephrine, dopamine, and serotonin, and reductions in striatal extracellular dopamine. Lifelong manganese exposure produced similar effects with the addition of significant decreases in cortical dopamine that were not evident in the early postnatal exposed groups. These results indicate that early postnatal manganese exposure produces persistent deficits in cortical and striatal biogenic amine function. Given that these same animals exhibited lasting impairments in attention and fine motor function, these findings suggest that reductions in catecholaminergic activity are a primary factor underlying the behavioral effects caused by manganese, and indicate that children exposed to elevated levels of manganese during early development are at the greatest risk for neuronal deficiencies that persist into adulthood.

SLC30A10 transporter in the digestive system regulates brain manganese under basal conditions while brain SLC30A10 protects against neurotoxicity

The essential metal manganese becomes neurotoxic at elevated levels. Yet, the mechanisms by which brain manganese homeostasis is regulated are unclear. Loss-of-function mutations in SLC30A10, a cell surface-localized manganese efflux transporter in the brain and liver, induce familial manganese neurotoxicity. To elucidate the role of SLC30A10 in regulating brain manganese, we compared the phenotypes of whole-body and tissue-specific Slc30a10 knockout mice. Surprisingly, unlike whole-body knockouts, brain manganese levels were unaltered in pan-neuronal/glial Slc30a10 knockouts under basal physiological conditions. Further, although transport into bile is a major route of manganese excretion, manganese levels in the brain, blood, and liver of liver-specific Slc30a10 knockouts were only minimally elevated, suggesting that another organ compensated for loss-of-function in the liver. Additional assays revealed that SLC30A10 was also expressed in the gastrointestinal tract. In differentiated enterocytes, SLC30A10 localized to the apical/luminal domain and transported intracellular manganese to the lumen. Importantly, endoderm-specific knockouts, lacking SLC30A10 in the liver and gastrointestinal tract, had markedly elevated manganese levels in the brain, blood, and liver. Thus, under basal physiological conditions, brain manganese is regulated by activity of SLC30A10 in the liver and gastrointestinal tract, and not the brain or just the liver. Notably, however, brain manganese levels of endoderm-specific knockouts were lower than whole-body knockouts, and only whole-body knockouts exhibited manganese-induced neurobehavioral defects. Moreover, after elevated exposure, pan-neuronal/glial knockouts had higher manganese levels in the basal ganglia and thalamus than controls. Therefore, when manganese levels increase, activity of SLC30A10 in the brain protects against neurotoxicity.

LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia.

Long-term exposure to elevated levels of manganese (Mn) causes manganism, a neurodegenerative disorder with Parkinson’s disease (PD)-like symptoms. Increasing evidence suggests that leucine-rich repeat kinase 2 (LRRK2), which is highly expressed in microglia and macrophages, contributes to the inflammation and neurotoxicity seen in autosomal dominant and sporadic PD. As gene-environment interactions have emerged as important modulators of PD-associated toxicity, LRRK2 may also mediate Mn-induced inflammation and pathogenesis. In this study, we investigated the role of LRRK2 in Mn-induced toxicity using human microglial cells (HMC3), LRRK2-wild-type (WT) and LRRK2-knockout (KO) RAW264.7 macrophage cells. Results showed that Mn activated LRRK2 kinase by phosphorylation of its serine residue at the 1292 position (S1292) as a marker of its kinase activity in macrophage and microglia, while inhibition with GSK2578215A (GSK) and MLi-2 abolished Mn-induced LRRK2 activation. LRRK2 deletion and its pharmacological inhibition attenuated Mn-induced apoptosis in macrophages and microglia, along with concomitant decreases in the pro-apoptotic Bcl-2-associated X (Bax) protein. LRRK2 deletion also attenuated Mn-induced production of reactive oxygen species (ROS) and the pro-inflammatory cytokine TNF-α. Mn-induced phosphorylation of mitogen-activated protein kinase (MAPK) p38 and ERK signaling proteins was significantly attenuated in LRRK2 KO cells and GSK-treated cells. Moreover, inhibition of MAPK p38 and ERK as well as LRRK2 attenuated Mn-induced oxidative stress and cytotoxicity. These findings suggest that LRRK2 kinase activity plays a critical role in Mn-induced toxicity via downstream activation of MAPK signaling in macrophage and microglia. Collectively, these results suggest that LRRK2 could be a potential molecular target for developing therapeutics to treat Mn-related neurodegenerative disorders.

Valproic acid attenuates manganese-induced reduction in expression of GLT-1 and GLAST with concomitant changes in murine dopaminergic neurotoxicity

Exposure to elevated levels of manganese (Mn) causes manganism, a neurological disorder with similar characteristics to those of Parkinson’s disease (PD). Valproic acid (VPA), an antiepileptic, is known to inhibit histone deacetylases and exert neuroprotective effects in many experimental models of neurological disorders. In the present study, we investigated if VPA attenuated Mn-induced dopaminergic neurotoxicity and the possible mechanisms involved in VPA’s neuroprotection, focusing on modulation of astrocytic glutamate transporters (glutamate aspartate transporter, GLAST and glutamate transporter 1, GLT-1) and histone acetylation in H4 astrocyte culture and mouse models. The results showed that VPA increased promoter activity, mRNA/protein levels of GLAST/GLT-1 and glutamate uptake, and reversed Mn-reduced GLAST/GLT-1 in in vitro astrocyte cultures. VPA also attenuated Mn-induced reduction of GLAST and GLT-1 mRNA/protein levels in midbrain and striatal regions of the mouse brain when VPA (200 mg/kg, i.p., daily, 21 d) was administered 30 min prior to Mn exposure (30 mg/kg, intranasal instillation, daily, 21 d). Importantly, VPA attenuated Mn-induced dopaminergic neuronal damage by reversing Mn-induced decrease of tyrosine hydroxylase (TH) mRNA/protein levels in the nigrostriatal regions. VPA also reversed Mn-induced reduction of histone acetylation in astrocytes as well as mouse brain tissue. Taken together, VPA exerts attenuation against Mn-induced decrease of astrocytic glutamate transporters parallel with reversing Mn-induced dopaminergic neurotoxicity and Mn-reduced histone acetylation. Our findings suggest that VPA could serve as a potential neuroprotectant against Mn neurotoxicity as well as other neurodegenerative diseases associated with excitotoxicity and impaired astrocytic glutamate transporters.

Role of the environment factors within inflammatory processes during polykistosis of ovaries

Objective. To study the indicators of inflammatory process in women with polycystic ovary syndrome (PCOS) having equal body mass indices and in the absence of pathogenic infections, and to determine the content of trace elements.Material and methods. Two groups of women were selected. The first (control) group consisted of 57 healthy women of reproductive age. In the second (main) group were 64 women with PCOS. Using PCR method excluded the presence of pathogenic infections. The analysis of the frequency of inflammatory processes was based upon microscopic characteristics of vaginal microbiocenosis.For studying levels of manganese, nickel, zinc in serum, were selected 32 women from the control group and 44 women from the main group. Samples were analyzed on a mass spectrometer with an inductively coupled plasma. Validity of results was verified using Mann-Whitney U test, Student’s t-test and χ2.Results. In the absence of sexually transmitted infections and equal body mass index, signs of inflammatory processes of vagina are much more common for women with PCOS. In control group, pathological samples were found in 10.52%, when as in group of women with PCOS – 84.38% (p = 0.000). For women with PCOS there was a tendency toward increase in the frequency of somatic diseases, but differences did not find statistical confirmation. The elevated levels of manganese and nickel exposure have been observed for women with PCOS. Authors associate elevated levels of zinc in the blood serum with the inflammatory process.Conclusion. In women with PCOS in absence of sexually transmitted infections and equal body mass index, signs of inflammation are much more common. Some role in vaginal microbiocenosis and inflammatory processes can play exposure to high levels of manganese and nickel.

Hypothyroidism induced by loss of the manganese efflux transporter SLC30A10 may be explained by reduced thyroxine production

SLC30A10 and SLC39A14 are manganese efflux and influx transporters, respectively. Loss-of-function mutations in genes encoding either transporter induce hereditary manganese toxicity. Patients have elevated manganese in the blood and brain and develop neurotoxicity. Liver manganese is increased in patients lacking SLC30A10 but not SLC39A14. These organ-specific changes in manganese were recently recapitulated in knockout mice. Surprisingly, Slc30a10 knockouts also had elevated thyroid manganese and developed hypothyroidism. To determine the mechanisms of manganese-induced hypothyroidism and understand how SLC30A10 and SLC39A14 cooperatively mediate manganese detoxification, here we produced Slc39a14 single and Slc30a10/Slc39a14 double knockout mice and compared their phenotypes with that of Slc30a10 single knockouts. Compared with wild-type controls, Slc39a14 single and Slc30a10/Slc39a14 double knockouts had higher manganese levels in the blood and brain but not in the liver. In contrast, Slc30a10 single knockouts had elevated manganese levels in the liver as well as in the blood and brain. Furthermore, SLC30A10 and SLC39A14 localized to the canalicular and basolateral domains of polarized hepatic cells, respectively. Thus, transport activities of both SLC39A14 and SLC30A10 are required for hepatic manganese excretion. Compared with Slc30a10 single knockouts, Slc39a14 single and Slc30a10/Slc39a14 double knockouts had lower thyroid manganese levels and normal thyroid function. Moreover, intrathyroid thyroxine levels of Slc30a10 single knockouts were lower than those of controls. Thus, the hypothyroidism phenotype of Slc30a10 single knockouts is induced by elevated thyroid manganese, which blocks thyroxine production. These findings provide new insights into the mechanisms of manganese detoxification and manganese-induced thyroid dysfunction.

Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice

Manganese is an essential metal that becomes toxic at elevated levels. Loss-of-function mutations in SLC30A10, a cell-surface-localized manganese efflux transporter, cause a heritable manganese metabolism disorder resulting in elevated manganese levels and parkinsonian-like movement deficits. The underlying disease mechanisms are unclear; therefore, treatment is challenging. To understand the consequences of loss of SLC30A10 function at the organism level, we generated Slc30a10 knock-out mice. During early development, knock-outs were indistinguishable from controls. Surprisingly, however, after weaning and compared with controls, knock-out mice failed to gain weight, were smaller, and died prematurely (by ∼6-8 weeks of age). At 6 weeks, manganese levels in the brain, blood, and liver of the knock-outs were ∼20-60-fold higher than controls. Unexpectedly, histological analyses revealed that the brain and liver of the knock-outs were largely unaffected, but their thyroid exhibited extensive alterations. Because hypothyroidism leads to growth defects and premature death in mice, we assayed for changes in thyroid and pituitary hormones. At 6 weeks and compared with controls, the knock-outs had markedly reduced thyroxine levels (∼50-80%) and profoundly increased thyroid-stimulating hormone levels (∼800-1000-fold), indicating that Slc30a10 knock-out mice develop hypothyroidism. Importantly, a low-manganese diet produced lower tissue manganese levels in the knock-outs and rescued the phenotype, suggesting that manganese toxicity was the underlying cause. Our unanticipated discovery highlights the importance of determining the role of thyroid dysfunction in the onset and progression of manganese-induced disease and identifies Slc30a10 knock-out mice as a new model for studying thyroid biology.

High prevalence of elevated Manganese levels in blood of one-two years old Beninese children

High prevalence of elevated Manganese levels in blood of one-two years old Beninese children

P73 gene in dopaminergic neurons is highly susceptible to manganese neurotoxicity

Chronic exposure to elevated levels of manganese (Mn) has been linked to a Parkinsonian-like movement disorder, resulting from dysfunction of the extrapyramidal motor system within the basal ganglia. However, the exact cellular and molecular mechanisms of Mn-induced neurotoxicity remain elusive. In this study, we treated C57BL/6J mice with 30mg/kg Mn via oral gavage for 30 days. Interestingly, in nigral tissues of Mn-exposed mice, we found a significant downregulation of the truncated isoform of p73 protein at the N-terminus (ΔNp73). To further determine the functional role of Mn-induced p73 downregulation in Mn neurotoxicity, we examined the interrelationship between the effect of Mn on p73 gene expression and apoptotic cell death in an N27 dopaminergic neuronal model. Consistent with our animal study, 300μM Mn treatment significantly suppressed p73 mRNA expression in N27 dopaminergic cells. We further determined that protein levels of the ΔNp73 isoform was also reduced in Mn-treated N27 cells and primary striatal cultures. Furthermore, overexpression of ΔNp73 conferred modest cellular protection against Mn-induced neurotoxicity. Taken together, our results demonstrate that Mn exposure downregulates p73 gene expression resulting in enhanced susceptibility to apoptotic cell death. Thus, further characterization of the cellular mechanism underlying p73 gene downregulation will improve our understanding of the molecular underpinnings of Mn neurotoxicity.

BIOCHEMICAL MARKERS OF HYPERANDROGENISM IN CONDITIONS OF INCREASED EXPOSURE OF MANGANESE AND NICKEL

The etiology of polycystic ovaries syndrome (PCOS) may be associated with high levels of exposure manganese and nickel. These trace elements can change the metabolism of androgensObjectives. Determination of biochemical markers of hyperandrogenism in women with PCOS in conditions with elevated levels of manganese and nickel.Methods. 43 women with PCOS were examined. The control group consisted of 27 healthy women of reproductive age. In serum, using chemiluminescent immunoassay method were determined the total (TT) and free (TF) testosterone, dehydroepiandrosterone sulfate (DHEA-S), 17-hydroxyprogesterone (17-HOP), dihydrotestosterone (DHT), Sex hormone-binding globulin (SHBG) and calculated Free Androgen Index (FAI).Results. In 16.27% of women with PCOS hyperandrogenism was not observed. Detected increased levels of TT (36.59%), TF (30%), DHEA-S (36.59%) 17 - HOP (56.41%), DHT (62.5%), FAI (3.85 %). There was only one increase of androgen 17-HOP (15,38%), TT (7.32%), DHT (6.25%) and DHEA-S (2.44%).Conclusions. Elevated levels of manganese and nickel cause accumulation of metabolites of testosterone in the body. Diagnostics of biochemical hyperandrogenism should be based on determination 17-HOP, TT and perhaps DHT.