Journal of Environmental Science and Health, Part C, 33:229–254, 2015 C Taylor & Francis Group, LLC Copyright  ISSN: 1059-0501 print / 1532-4095 online DOI: 10.1080/10590501.2015.1030530

A Current Review for Biological Monitoring of Manganese with Exposure, Susceptibility, and Response Biomarkers Gyuri Kim,1 Ho-Sun Lee,1 Joon Seok Bang,2 Boram Kim,1 Dahae Ko,1 and Mihi Yang1 1

Research Center for Cell Fate Control, Department of Toxicology, College of Pharmacy, Sookmyung Women’s University, Seoul, Republic of Korea 2 Graduate School of Clinical Pharmacy, Sookmyung Women’s University, Seoul, Republic of Korea People can be easily exposed to manganese (Mn), the twelfth most abundant element, through various exposure routes. However, overexposure to Mn causes manganism, a motor syndrome similar to Parkinson disease, via interference of the several neurotransmitter systems, particularly the dopaminergic system in areas. At cellular levels, Mn preferentially accumulates in mitochondria and increases the generation of reactive oxygen species, which changes expression and activity of manganoproteins. Many studies have provided invaluable insights into the causes, effects, and mechanisms of the Mn-induced neurotoxicity. To regulate Mn exposure, many countries have performed biological monitoring of Mn with three major biomarkers: exposure, susceptibility, and response biomarkers. In this study, we review current statuses of Mn exposure via various exposure routes including food, high susceptible population, effects of genetic polymorphisms of metabolic enzymes or transporters (CYP2D6, PARK9, SLC30A10, etc.), alterations of the Mn-responsive proteins (i.e., glutamine synthetase, Mn-SOD, metallothioneins, and divalent metal trnsporter1), and epigenetic changes due to the Mn exposure. To minimize the effects of Mn exposure, further biological monitoring of Mn should be done with more sensitive and selective biomarkers. Keywords: biological monitoring; manganese (Mn), exposure; susceptibility; genetic polymorphism; epigenetic changes

Address correspondence to Mihi Yang, PhD and D.A.B.T., College of Pharmacy, Sookmyung Women’s University, Cheongpa-ro 47-gil 100, Youngsan-Gu, Seoul 140-742, Republic of Korea. E-mail: myang @sm.ac.kr Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lesc.

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INTRODUCTION Manganese (Mn) is the twelfth most abundant element, comprising approximately 0.1% of the earth’s crust and the fifth most abundant metal [1]. It is also an essential nutrient involved in the formation of bones and in the specific metabolic reactions related to amino acids, cholesterols, and carbohydrates [2]. However, overexposure to Mn can interfere with several neurotransmitter systems, particularly the dopaminergic system in areas of the brain responsible for motor coordination, attention, and cognition [3]. For example, exposure to Mn (>5 mg/m3) showed association with devastating neurologic impairment, clinically known as “manganism,” a motor syndrome similar to but partially distinguishable from idiopathic Parkinson disease (PD) [4, 5]. Many studies have provided invaluable insights into the causes, effects, and mechanisms of Mn-induced neurotoxicity for the past several decades. Particularly, chronic excessive exposures to Mn represent global health concerns with growing evidence, which suggests that Mn accumulation in the brain may be a predisposing factor for several neurodegenerative diseases [6, 7]. The distinct neurological toxicity of Mn may come from its preferential uptake by the brain [6]. In the brain, the striatum, globus pallidus, and substantia nigra were reported as the target sites for Mn accumulation and toxicity [6, 7]. Among populations, children are highly susceptible to Mn toxicity because they present striking differences from adults in terms of susceptibility to Mn exposure [8]. For example, inverse association between Mn exposure levels in children’s hair and their full scale IQ or verbal IQ were reported [8–10]. Concerning the exposure routes, fetus can be exposed to Mn through the mother’s placenta and at the later stages through breastfeeding. During the stages of childhood and preadolescence, Mn exposure continues to be multiplied by food and drinking, inhalation, and/or dermal absorption [8]. Considering the health risks of Mn exposure, many countries have performed biological monitoring in humans to control Mn exposure. However, the health risks of Mn cannot be predicted by merely elucidating the Mn exposure levels in populations with different genetic backgrounds [11]. Some epidemiologic studies showed that only a fraction of workers who were exposed to Mn developed dysfunctions in the nervous system, which suggests the presence of genetic predisposition for manganism, characterized by slow and clumsy movements, tremors, walking difficulties, and facial spasms [12, 13]. Particularly, several polymorphisms in genes, which are involved in absorption, distribution, metabolism, and excretion (ADME) of Mn, have been emphasized as the causes of individual variation of manganism [12]. In the present study, we reviewed the current status of Mn exposure focusing on the individual variations susceptible to Mn toxicity.

Biological Monitoring of Manganese

EXPOSURE TO Mn Mn is ubiquitous in the environment and exposure to humans easily arises from both natural and anthropogenic activities [1]. Therefore, the general population can be exposed to Mn through various routes such as consumption of food and water, inhalation of air, and dermal contact with air, water, soil, and consumer products [1]. For example, smokers or second-hand smokers are highly exposed to Mn over others [1]. In addition, abusers of the Mn-containing Bazooka (a cocaine-based drug) are also leading to Mn neurotoxicity [14]. The recent introduction of an Mn-containing fuel additive, methylcyclopentadienyl Mn tricarbonyl, to gasoline has also raised concerns over potential chronic exposures to Mn [15]. Inhaled Mn can bypass the gut and enter into the brain in two ways: by olfactory (nasal airway) neural pathways that provide a direct path to brain tissue, and by pulmonary uptake with long residence time that could provide a source of continuing exposure [16]. The most important source of Mn in the atmosphere results from the air erosion of dusts or soils. The mean concentration of Mn in ambient air in the United States is 0.02 μg/m3; however, ambient levels near industrial sources can range from 0.22 to 0.3 μg/m3 [17]. Therefore, people living in proximity to mining activities and Mn industries (i.e., occupational exposure) may be exposed by inhalation route to high levels of Mn in dust [1, 18–20]. Occupational exposure of Mn is linked to the majority of reported cases of Mn intoxication [18]. Increased incidences of manganism have been observed among miners and industrial welders as well as farmers R (manganese exposed to Mn-based pesticides such as fungicides, maneb  R ethylene-bis-dithiocarbamate), and mancozeb [(dithiocarboxy) amino]ethyl]carbamodithioato (2-)-κS,κS ]-zinc] [21]. For example, relatively high levels of Mn in hair, 5.32 ± 9.03 (mg/kg), were detected in southern Brazil, where R was routinely used for tobacco farming [22]. A cohort study from mancozeb the Center for the Health Assessment of Mothers and Children of Salinas in California showed that Mn dust concentrations and loadings have increased with the number of farmworkers in home and the amount of fungicides [23]. In Mn-alloy metal production workers, a Norwegian study showed the geometric mean of urinary Mn-concentration of exposed workers was 0.9 (range 0.1–26.3) nmol/mmol creatinine (Cr) versus 0.4 (range 0.1–13.1) nmol/mmol Cr for the referents [24]. In a Chinese population, ambient Mn levels in breathing zones were 0.01, 0.24, and 2.21 mg/m3 for control, low, and high exposed groups by the welding profession, respectively [25]. In the general population, the primary source of Mn intake can be ordinary diet [1]. Mn is naturally present in food, with the highest concentrations in nuts, cereals, legumes, fruits, vegetables, grains, and teas, and in drinking water in low levels [26]. The lowest observable adverse effect level of Mn in water is estimated by the US Environmental Protection Agency (EPA) as

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0.06 mg/kg/d or 4.2 mg/d for a 70 kg individual [27]. In addition, the estimated safe and adequate daily dietary intake of Mn for adults is 2–5 mg/d [27]. Considering the lack of information about dietary intake of Mn, an interim guidance value of 0.16 mg Mn/kg/d, based on the tolerable upper intake level for 70 kg adults of 11 mg Mn/d, has been recommended by the Agency for Toxic Substances and Disease Registry public health assessments of oral exposure to the inorganic forms [1]. The EPA concluded that an appropriate reference dose for oral Mn is 10 mg/d (0.14 mg/kg/d) [28]. Therefore, dietary Mn exposure can be estimated by evaluating daily intake of major food sources. For example, daily Mn intake from each food group is estimated as 1.9 mg from cereals, 0.5 mg from vegetables, 0.4 mg from pulses, and 0.2 mg from seasonings in the Korean population [29]. Mn intake from the major 20 foods was 74.0% of the total dietary Mn intake in South Korea. Using 16-day semiweighed diet records, the mean daily intake of Mn for women and men was 4.9 mg/d and 5.1 mg/d, respectively [30]. In the United States, 1.28 ug of Mn/calories was estimated to be ingested in food [17]. Therefore, 3.8 mg of Mn was estimated as Mn intake by food for 70 kg adults who consumed 3000 kcal. Adverse neurological effects of Mn also occurred in people who drank Mncontaminated water in many countries [15]. Although the World Health Organization discontinued Drinking Water Guideline [31] as 500 ug/L in 1958 and 400 ug/L in 2004, the latter guideline was criticized as still too high to adequately protect public health. Therefore, the EPA recently issued a drinking water health advisory for Mn that yielded a lifetime health advisory value of 300 μg/L in drinking water [32]. However, there is an accumulating body of evidence suggesting that exposure to excess levels of Mn in drinking water (≥0.2 mg/L) may lead to neurological deficits in children, including poor school performance, impaired cognitive function, increased oppositional behavior, and hyperactivity [1, 13, 33]. Several cases of apparent manganism in both children and adults have been reported where exposure to high levels of Mn in drinking water were implicated as the probable cause [1]. Bouchard and colleagues [9, 34] measured Mn in children’s hair at a community in Quebec, Canada, which was served by municipal water supplied from two wells with different Mn concentrations (0.61 mg/L vs. 0.16 mg/L). They showed that the children living in houses supplied with water at higher Mn concentrations had significantly higher levels of Mn in their hair, and the Mn concentrations in the hair were positively associated with higher scores for hyperactive and oppositional behaviors in the classroom after adjusting for age, gender, and family income [33, 34]. In Taiwan, Kuo and colleagues compared metal exposure for residents who lived within 30 meters of diesel transport roads with a control group. Mn levels in outdoor and indoor PM10 at the near road-resident area were approximately 2- to 4-fold higher than those in the control area [35]. The exposed

Biological Monitoring of Manganese Table 1: Mn Exposure due to Different Routes Exposure Route Inhalation

Region Toronto, Canada Montreal, Canada

China

U.S.A. Salinas Valley, CA, U.S.A. Norway

Diet

Taiwan Korea

U.S.A. Japan Taiwan Drinking water

Quebec, Canada

Soil

U.S.A. Taiwan Southern Brazil

Exposure Levels of Mn

References

PM2.5 : smokers, 27 ng/m3; nonsmoker, 10 ng/m3 250 ng/m3 in garage mechanics and 24 ng/m3 in taxi drivers; 1–34 ng/m3 in office worker 0.01, 0.24 and 2.21 mg/m3 for control, low, and high exposed groups by the welding profession, respectively In ambient air, 0.02 µg/ m3; near industrial sources, 0.22 to 0.3 µg/m3 In house dust, 179 ug/g (concentration); 1910 ug/m2 (loading) Alloy production plant workers, 0.9 nmol/mmol creatinine in urine; nonoccupationally exposed group, 0.4 nmol/mmol creatinine In house dust, 90.7–108 ug/d Daily intake per 1000 kcal: 1.9 mg from cereals, 0.5 mg from vegetables, 0.4 mg from pulses and 0.2 mg from seasonings 3.8 mg/d/70kg Women, 4.9 mg/d; men, 5.1 mg/d Rice,1.98–2.34 ug/d; nonrice dishes, 0.29–0.34 34 ug/d Home tap water, 34 µg/L (range, 1–2700 µg/L). 4 ug/L 1.51–2.0 ug/d 1.23, 1.13, and 0.88 mg/kg for the field without agricultural practices, tobacco field, and seedling production, respectively

[1] [19–20]

[4]

[17] [24] [25]

[35] [29]

[17] [30] [35] [9] [17] [35] [23]

residents showed significantly higher Mn levels than the controls in drinking water (2.33 vs. 1.21 ug/L, respectively) and in rice (4.59 vs. 3.44 ng/g, respectively). In Table 1, we summarize Mn exposure levels due to different routes. Excess exposure to Mn can be revealed by tests to detect heightened levels in body fluids as well as in hair samples, compared to normal ranges: 4–15 μg/L

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in blood, 1–8 μg/L in urine, and 0.4–0.85 μg/L in serum [1]. One of the perplexing problems in clinics is that blood levels of Mn usually poorly reflect the body burden of Mn and the ensuing disease status [36]. Characteristically accumulated Mn in the brain regions known as the basal ganglia can be revealed by magnetic resonance imaging as a distinctive symmetrical high-signal lesion in the globus pallidus region of the basal ganglia [1].

SUSCEPTIBILITY TO Mn EXPOSURE AND RESPONSE Mn is absorbed in the small intestines, while the absorption process is slow, and the total absorption rate is exceptionally high (about 40%) [37] and excess Mn is excreted in bile and the pancreatic secretion. Only a small amount is excreted in the urine. The half-life of Mn can be affected by physiological or environmental factors, such as gender or Fe intake: the half-life of 54Mn is significantly longer in men than in women (15.3 ± 4.5 days vs. 12.2 ± 5.0 days, respectively, p < 0.05, in days 10–20 for 8-week intake) [38]. Considering gene and environmental interactions, we estimate the effects of genetic polymorphisms in Mn-metabolic enzymes or transporters on the kinetics of Mn.

Highly Susceptible Population Actual threshold levels at which Mn exposure produces neurological effects in humans has not been clearly established [1]. Children consuming the same concentration of Mn as adults, however, may be ultimately exposed to a higher amount of Mn/kg-body weight than adults. Lower body weight in children contributes to their higher daily consumption volume and greater retention of Mn. Several factors predispose children to Mn overexposure and subsequent toxic effects. Exposure to Mn by ingestion or inhalation can have different consequences in children than adults through different mechanisms [33]: First, the observed intestinal absorption rate of ingested Mn in children is higher than adults. Second, high demand for iron (Fe) linked to growth could further enhance the absorption of ingested Mn. Third, a low excretion rate has been observed in infants due to poorly developed biliary excretion in neonatal animals [1]. Therefore, children can be more sensitive to Mn toxicity than adults. For infants, the high Mn concentration in infant milk formula drew the attention by Collipp and colleagues who conducted two studies in the United States [33, 39]. First, the Mn concentration in hair was measured in children fed infant formula and exclusively breastfed. As a result, hair Mn levels were significantly increased from 0.19 μg/g at birth to 0.69 μg/g at 4 months in the infant formula group [39]. Secondly Mn levels in the hair of children with hyperactivity (0.43 μg/g) were significantly higher than in controls (0.27 μg/g) [39].

Biological Monitoring of Manganese

With respect to prenatal exposure, Ericson and associates [40] evaluated Mn-related neurobehavioral effects with scales that measure the degree of behavioral disinhibition. They reported relationships between prenatal and early postnatal Mn, as reflected in Mn deposits in tooth enamel formed around the twentieth and sixty-third gestational weeks, and childhood behavioral outcome, and found Mn concentrations in the umbilical cord blood were 33%–50% higher than those in maternal blood, suggesting presence of not only an active transport system via placenta but also an Mn concentrating mechanism in fetus [41]. This suggests that prenatal accretion of Mn is significantly associated with childhood behavioral outcomes [40]. Children with high Mn levels in the uterine phase were more impulsive, inattentive, aggressive, destructive, and hyperactive with higher scores on all scales of disinhibitory behavior [33, 40]. Because Mn neurotoxicity preferentially affects dopaminergic neuronal networks, a correlation between Mn and measures of dopamine-mediated behavior was observed, in particular, behavioral disinhibition, which is considered the preeminent symptom of attention deficit hyperactivity disorder [42]. Therefore, absorption of excess amounts of Mn before or during the twentieth gestational week could result in reduced numbers and/or altered functioning of neurons, resulting in dysplasticity of neuronal networks that mediate behavioral inhibition [40, 43, 44].

Genetic Polymorphisms The influence of Mn exposure on individuals can be determined by a combination of variables, including age and nutritional status [34]. Nonetheless, the neurotoxic effects of Mn tend to vary greatly among individuals [45]. This variation is most likely due to genetic variability that renders an individual more or less sensitive to the toxic effects of Mn, which eventually manifests in variable clinical courses [45]. Many epidemiologic studies have shown that some genetic polymorphisms might alter individual susceptibility to manganism [12, 46]. For example, inherited differences in the metabolic enzymes or transporters can result in variation of Mn detoxification or Mn-induced neurotoxicity [12]. Therefore, the individuals who carry risky genotypes can be highly susceptible to Mn exposure. CYP2D6 Cytochrome P450s (CYPs) constitute a major enzyme family capable of catalyzing oxidative biotransformation of the most drugs, environmentally toxic chemicals, and endogenous substances [47]. Among them, CYP2D6 has shown the greatest impact on many xenobiotics due to its wide spectrum of genetic variants, from null alleles to several-fold gene amplification, and its extraordinarily broad substrate selectivity [47]. Particularly, the single nucleotide polymorphism (SNP) at the CYP2D6 (C>T 2850, rs16947) brought out significant

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interindividual and interethnic differences in the metabolism and disposition of Mn [11]. Dopamine serves as a tonic inhibitor of prolactin release in some diseases [48]. In addition, the variant CYP2D6∗ 2 can regulate plasma prolactin levels and induce the fast metabolism of blood manganese [11] and therefore has been suspected to be protective for Mn toxicity. Generally, many studies showed an accordance that the CYP2D6∗ 2 had a protective effect on delaying manganism. For example, CYP2D6∗ 2A/∗ 2A subjects showed lower Mn levels in blood (21.4 ± 8.9 μg/L) than heterozygous individuals (34.4 ± 6.9 μg/L), or the wild type subjects (36.3 ± 8.5 μg/L) in Indian Mn- exposed and nonexposed subjects (N = 200) [11]. Individuals with the mutant homozygous type (CYP2D6∗ 2A/∗ 2A) of CYP2D6 had a 90% decreased risk of chronic manganism compared to the homozygous wild-type (CYP2D6∗ 1A/∗ 1A) (OR = 0.10, 95% CI = 0.01∼0.82) in a Chinese population (N = 99). The frequency of the CYP2D6∗ 2A was also significantly lowered in the cases (16.3%) than in the control (29.0%) (p = 0.03) [12]. In addition, there was a significant association between the CYP2D6 genetic polymorphism and the latency of chronic manganese poisoning [11, 12]. The patients who were homozygous of the mutant (CYP2D6∗ 2A/∗ 2A) or heterozygous (CYP2D6∗ 1A/CYP2D6∗ 2A) developed manganism 10 years later than those who were homozygous of CYP2D6∗ 1A (p = 0.02). Coexistence of other CYP2D6 polymorphic polymorphisms, such as CYP2D6∗ 17 or CYP2D6∗ 8, can affect the metabolism or elimination process of Mn, which results in loss or increase of the enzyme activities [12]. Considering the high frequency of the mutant (CYP2D6∗ 2) in Caucasians, we expect future studies to be done in many other populations besides Asians. GSTM1 The glutathione S-transferases (GSTs) are known to catalyze the conjugating reaction of glutathione (GSH) with xenobiotic compounds and convert them into more water-soluble forms [11, 49]. GSTs are an important part of the cellular detoxification system by involving endogenous molecules, possibly the products of oxidative stress, in the metabolism [50, 51] and evolving them to protect cells against reactive oxygen metabolites [49]. Some reports also showed that GST plays an important role in the detoxification of heavy metals, such as copper, chromium, iron, and vanadium [11, 52]. Glutathione is the most abundant intracellular antioxidant, found in many kinds of cells and tissues [53]. Therefore, specific polymorphisms of several genes associated with glutathione synthesis and transport have been linked to an increased risk of human diseases. These include GSTM1 and GSTT1 [53–55]. Since many toxicant exposures and deleterious effects are closely associated with depleted glutathione levels, polymorphisms that reduce levels or impair glutathione transport are likely to increase the susceptibility to Mn-induced neurotoxicity [53].

Biological Monitoring of Manganese

Reduction of the glutathione conjugated with xenobiotic compounds has shown associations with manganism [12]. However, Mn-exposed miners with the GSTM1-null genotype showed a nonsignificant increase (37.4 ± 7.5 μ/L) in Mn levels, compared with that of GSTM1 present individuals (30.6 ± 7. μ/L) [11]. Blood levels of Mn in the GSTM1-null subjects were similar to those in GSTM1 present subjects. These results coincide with the Zheng and colleagues’ study [12] that the genetic polymorphism in GSTs did not have any influence on Mn exposure. Therefore, GSTM1 polymorphisms do not have an important role for Mn detoxification. NQO1 The cytosolic enzyme NAD(P)H:quinone oxidoreductase1 (NQO1), an antioxidative enzyme, has important roles on the detoxification of environmental carcinogens [56]. It catalyzes the two-electron reduction of quinone compounds and prevents the production of the semiquinone free radicals and reactive oxygen species. Thus it protects cells from the oxidative damages [57]. However, Mn exposure causes auto-oxidation of dopamine leading to the formation of toxic (semi) quinones and free radicals [11, 58]. Shinji and colleagues investigated cytotoxicity and oxidative DNA damage induced by dopamine with or without Mn and reported that Mn has the ability to enhance the dopaminergic neurotoxicity in the cells [58]. Vinayagamoorthy and associates studied the correlation of NQO1∗ 2(C>T 609, rs1800566) polymorphism with Mn in Mn miners [11]. The study subjects were divided into two groups, heterozygous (H)/variant (V) and wild (W), and correlated with their Mn levels in the blood. Exposed miners with the NQO1∗ 2 hetero-genotype showed a nonsignificant increase (40.6 ± 6.7 μ/L) in Mn level when compared to that of NQO1 (W) individuals (34.9 ± 7.9 μ/L). These results indicate that genetic polymorphism in NQO1 does not influence the accumulation of Mn [11]. Gene–gene interactions between CYP2D6∗ 2, GSTM1, and NQO1 were studied by comparing the blood concentrations of Mn in an exposed population categorized into groups according to genotype combination. In the group 1, the GSTM1 (null)/CYP2D6∗ 2A (variant, V) group showed a statistically significant decrease in Mn levels, compared with GSTM1 (null)/CYP2D6∗ 2 (wild, W/heterozygote, H): 9.9 ± 10.4 μ/L vs. 62.4 ± 5.7 μ/L, respectively. In the group 2, GSTM1 (present)/NQO1 (W) individuals showed a statistically nonsignificant increase in blood Mn levels compared with the subjects with the GSTM1 (null)/NQO1 (W) genotype: 36.8 ± 7.9 μ/L vs. 29.7±8.5 μ/L, respectively. In group 3, the NQO1 (W)/ CYP2D6∗ 2A (V) group showed a statistically significant decrease in Mn concentrations compared with those in the NQO1 (W)/CYP2D6∗ 2 (W/H) group: 5.2 ± 7.9 μ/L vs. 49.5 ± 6.7 μ/L, respectively [11]. The study showed that the subject with the GSTM1 (null)/CYP2D6∗ 2A (V) genotype combination had low levels of Mn compared to the other genotype

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combinations. Therefore, these findings suggest that the CYP2D6∗ 2 variant interaction is eventually related to reduction in Mn levels [11[. PARK2, ATP13A2 (PARK9) Genetic predisposition to Mn toxicity showed a correlation with Parkin (PARK2), a gene involved in the autosomal recessive PD, and ATP13A2 (PARK9), a putative Mn transporter [59–62]. In detail, the PARK2, the most commonly mutated in autosomal recessive PD, encodes an E3 ubiquitin protein ligases thought to be involved both in the protein degradation and oxidative stress protection [62]. It has been shown that Mn exposure causes up-regulation of the α-synuclein and downregulation of the tyrosine hydroxylase (TH) and PARK2 in the dopaminergic neurons, resulting in the increased oxidative stress and eventually cell death [55, 63]. Loss of parkin is associated with mitochondrial dysfunction and cytotoxicity, suggesting its neuroprotective role for maintenance of the mitochondrial integrity [64, 65]. On the other hand, overexpression of PARK2 rescued dopaminergic neurons from cell death caused by Mn toxicity [66]. A recent Czech study reported high-frequency deletion of exon 2 and the low-frequent mutant type of the V380L genetic polymorphism at the PARK2 among the PD patients, compared to the control group [67]. ATP13A2, mutated in less than 5% of autosomal recessive PD, encodes a cationic transporter ATPase that transports Mn [60, 68]. The patients carrying autosomal recessive mutations in the PARK2 and ATP13A2 showed increased risk for Mn toxicity [59, 61, 69]. Particularly, the genetic polymorphisms of the ATP13A2 influence both PD and Mn toxicity [70]. The SNPs as intron variants, rs4920608 and rs2871776, significantly modified the effects of Mn exposure on the impaired motor coordination in the elderly (p = 0.029 and p = 0.041, respectively), also after adjustments for age and gender (p = 0.032 and p = 0.044) [71]. In addition, the rs2871776 G allele that was associated with the worst effect of Mn on motor coordination was linked to alteration of a binding site for the transcription factor Insulinoma-associated 1 (INSM1) [70]. None of the polymorphisms alone had a significant influence on the motor coordination. After combination with Mn exposure, the rs4920608 CT and CC carriers showed decreased motor coordination, compared with TT carriers [71]. In addition, motor coordination was also reduced in the rs2871776- GG and -GA carriers, compared with the AA individuals with increasing of Mn exposure [71]. However, there was no genetic modification among the adolescents for ATP13A2. The protective role of ATP13A2 of the toxicity induced by α-synuclein in the animal models of PD as well as the toxic effects of Mn exposure suggest that polymorphisms in this gene may render susceptibility to PD and Mn toxicity [60]. The rs2871776 G allele that was associated with an adverse effect of Mn on motor coordination was associated with destroying a binding site

Biological Monitoring of Manganese

for the transcription factor INSM1 that plays an important role in developing the central nervous system as shown in mouse and human embryos [72–74]. Absence of the binding site for this transcription factor on ATP13A2 hypothetically might explain why adult carriers in our study population perform more poorly in the motor coordination test upon Mn exposure [71]. The effect of Mn exposure on the nervous system was, in the elderly, influenced by the genetic polymorphism of PARK9, a susceptible gene for PD [71]. SLC30A10 Mutations in a putative Mn exporter gene SLC30A10 have been recently described. These mutations are associated with the marked motor impairment, including a Parkinsonism-like syndrome [75]. The cause of flawed Mn metabolism was identified as an autosomal recessive mutation in SLC30A10 [76]. SLC30A10 was originally thought to be a Zinc (Zn) transporter based on the sequence analysis, but was identified as an Mn efflux protein in closer examination [75]. It is expressed in the liver and neuronal cells of the globus pallidus under normal conditions, and is absent from the liver upon SLC30A10 mutation [61]. The presence of missense (c.266T>C [p.Leu89Pro]) and nonsense (c.585del [p.Thr196Profs∗ 17]) mutations in SLC30A10 failed to restore the Mn resistance; therefore, the mutant-transformed yeasts showed higher toxicity of Mn by inhibition of the growth [74]. Interestingly, patients with the SLC30A10 mutations also showed low Fe and increased total Fe binding capacity, which suggests deficiency of Fe [74, 75]. Therefore, the SLC30A10 mutation-related symptoms, including Parkinsonism, could be improved with oral Fe supplementations, adding weight to the case for Fe deficiency as a risk factor for Mn accumulation–associated Parkinsonism. Along with the highly circulating levels, Mn appears to be accumulated in the brain of patients with the SLC30A10 mutations—dystonia or Parkinsonism is found in all cases with the mutation on SLC30A10. SLC30A10 mutations are the first example of a genetic cause correlating neurological symptoms directly with Mn accumulation in humans [73].

RESPONSES TO Mn EXPOSURE Mn-Dependent Enzyme, Manganoproteins Mn is an essential constituent of many enzymes involved in the metabolisms of fat and protein, and is utilized by various antioxidant enzymes involved in the metabolisms of nitrogen and oxygen [77, 78]. For example, within the central nervous system (CNS), Mn is a cofactor for manganoproteins such as glutamine synthetase (GS) and superoxide dismutase (Mn-SOD) [79]. GS is selectively expressed in astroglial cells within the brain [80]. As

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an Mn-dependent enzyme, GS catalyzes the conversion process of glutamate to glutamine, thereby preventing an increase of the extracellular glutamate levels and glutamate-dependent overexcitation [77, 78]. Because GS contains four Mn ions per octamer, Mn has been proposed to regulate GS activity [80]. In fact, inhibition of the GS activity can cause serious results on the neuronal function, such as decreased levels of glutamate and gamma-aminobutyric acid (GABA) or inability to detoxify ammonia. Given its high susceptibility to rapid oxidative degradation, GS can serve as a sensitive marker for the presence of ROS in the brain [81, 82]. Another manganoprotein is Mn-SOD, which is preferentially located in the mitochondria of the neuronal cells in the brain [83, 84]. Mn-SOD removes superoxide by enzymatically converting it into the hydrogen peroxide. Then, hydrogen peroxide can be converted into oxygen and water by the catalase [85]. This specifically regulates and detoxifies superoxide, an extremely powerful oxidant and byproduct of the cellular metabolism [78]. Furthermore, Mn-SOD is a critical molecule in preventing or limiting the apoptotic and necrotic events resulting from the cellular damage caused by the ROS [86]. In general, the total Mn levels in the normal cells of the cerebral cortex are estimated as 2–12 μM [87, 88]. Upon entering the brain, Mn can be taken up into the astrocytes and neurons [89], then accumulates primarily within the astrocytes as 50–70 μM [87, 90]. However, increased accumulation of Mn in astrocytes may alter the release of glutamate and elicit the excitatory neurotoxicity [91]. At the cellular level, Mn preferentially accumulates in the mitochondria, where it disrupts oxidative phosphorylation and increases the generation of ROS [92]. Excessive production of ROS can change the concentration or the activity of biomarkers, which act as a signal of oxidative stress [93)]. It is possible that the expression and activity of manganoproteins may be regulated by the changes in cellular levels of Mn under physiological and pathological conditions [78]. Several studies have reported that substantial and significant alterations in Mn-dependent enzyme activities follow Mn treatment. Morello and colleagues. [78] examined whether chronic Mn overload affected the expression of GS and Mn-SOD in rats by using the immunocytochemical methods. After chronic Mn treatment, Mn contents were increased approximately three-fold in the cerebral cortex and the striatum, and four-fold in the globus pallidus [78, 94]. However, both the number of GS immunoreactive cells and the intensity of the GS-immunoreactivity were significantly reduced in the basal ganglia, especially in the globus pallidus (p < 0.01). The GS activity was significantly decreased in the striatum (35%, p < 0.05) and the globus pallidus (47%, p < 0.01) [76]. The reduction of GS activity, detected biochemically, was concordant with a reduced GS content, detected immunohistochemically. The globus pallidus was the most affected region by Mn [76]. Therefore, these results demonstrated that the changes in the GS expression and activity after the long-term

Biological Monitoring of Manganese

Mn treatment in vivo may affect the striatum and globus pallidus, consistent with previous in vivo [95, 96] and in vitro studies [87]. In addition, Morello and colleagues [76] showed that the striatum and the globus pallidus undergo a reduction in Mn-SOD protein levels after chronic Mn treatment. The gradient of Mn-SOD positive cells was cerebral cortex > striatum > globus pallidus [76]. However, among these different structures the striatum was characterized by the most intense Mn-SOD immunostaining, confirming previous results [78, 97]. After Mn treatment, both the number and staining intensity of Mn-SOD-positive cells significantly decreased in the striatum as well in the globus pallidus compared with control animals [78]. When MnCl2 was added to astrocytes, SOD enzyme activity was analyzed as the ratio of changes of optical absorbance and protein content [85, 96]. After 24 h of treatments, 0.2 mM of MnCl2 induced slightly injured astrocytes and a decrease in the cell number [85]. In addition to morphological changes, the 24 h exposure of Mn decreased SOD activities in a dose-dependent manner (0.05–0.2 mM) [85]. Thus, Mn overload selectively decreased the expression of some important manganoproteins in the brain, including GS in astrocytes and Mn-SOD in neurons. Furthermore, these decreases were region-specific events. That is, the striatum and globus pallidus were most affected [78]. The decreased levels of GS and Mn-SOD likely corresponds to a decrease in their functional activities. The reduced activity of GS in astrocytes may slow down the catabolism process of glutamate to glutamine, participating in the impairment of the extracellular glutamate scavenger system demonstrated in manganism [78, 98–100].

Metallothioneins Metallothioneins (MTs) are important for normal cellular homeostasis including gene regulation, adaptation to stress, and metal metabolism particularly in the brain where neural tissue is sensitive to any changes [101, 102]. In the CNS, MT exists in three isoforms (MT-I, MT-II, and MT-III). MT-I and MT-II are expressed predominately in astrocytes, whereas MT-III is in hippocampal cells [99, 103]. MT is a metal-binding protein with Zn serving as the primary regulator of MT metabolism and antioxidant protein induced in the brain in response to oxidative stress [104, 105]. It has been suggested that MTs can neutralize ROS through oxidative release of zinc from MT thiolate clusters [106]. Particularly, it was reported that toxic concentrations of Mn decreased the gene expression level of MT as markers of oxidative stress [82, 95]. MT-1 expression unexpectedly decreased in Mn-treated astrocytes, unlike its general increase in response to the elevated intracellular divalent metals [97, 105]. A number of explanations can account for this phenomenon. Among

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them, increased intracellular [Mn] might diminish the content of the other divalent metals, thereby exerting feedback inhibitions, and decreasing MT mRNA expressions [106], because increased Mn has been proven to interfere with the divalent metal metabolism in the brain [107]. Therefore, increased Mn altered the metabolism of divalent metals including Zn or Cu, each known as modulators of MT expression [99]. Furthermore, Ericson and colleagues [107] assessed MT mRNA levels of five different brain regions when induced by airborne Mn exposure in rats. A decrease of MT mRNA was observed at the cerebellum, olfactory bulb, and hippocampus in young male rats; at the hypothalamus in the young female rats; and at the hippocampus in the senescent males [107]. These results also demonstrated that age and gender were considerable variables, when assessing the neurotoxicity of Mn.

DMT1 Mn enters into the brain from the bloodstream either across the cerebral capillaries or the cerebrospinal fluid [108]. Manganism is associated with elevated brain levels of Mn, primarily in those areas known to contain high concentration of nonheme iron, especially at the caudate–putamen, globus pallidus, substantia nigra, and subthalamic nuclei [108]. It appears that facilitated diffusion, active transport, divalent metal transport 1 (DMT1-mediated transport), ZIP8, and transferrin-dependent transport mechanisms are all involved in shuttling Mn across the blood-brain barrier [108]. Mn is mostly found in the divalent form, implicating the divalent metal transporter 1 (DMT1) as the most important transporter of this element [70]. DMT1 is highly presented in the basal ganglia, which is a target area for both Parkinsonism and Mn toxicity [109]. A role for DMT-1 has also been observed in enhanced Mn olfactory transport, especially in anemic animals [110]. Being actively transported through the olfactory tract, manganese can cause impairment of the olfactory function and motor coordination [70]. Odor and motor changes are interrelated and may be caused by an Mn-induced dopaminergic dysregulation affecting both functions [(70]. DMT1 is important in maintaining the stable homeostasis of essential elements in the brain’s extracellular fluids for optimal brain functions [111]. It was referred to as divalent cationic transporter (DCT1) because of its ability to transport cations, such as Mn2+, Co2+, Cd2+, Cu2+, Ni2+, Pb2+, and Fe2+ [112, 113]. Currently, there are two theories that explain the mechanisms of DMT1 functioning: (1) a transferrin receptor (TfR)-independent pathway and (2) a TfR-dependent pathway. In the TfR-independent pathway, it is hypothesized that DMT1 can act as a symporter that couples the pumping of a proton when Mn2+ is taken up [114]. Alternatively, the co-localization of DMT1 and TfR suggests that there exists an Mn uptake pathway by DMT1 that is regulated

Biological Monitoring of Manganese

by TfR. When an Mn2+ binds to the Tf–TfR complex, it causes internalization of the complex from the plasma membrane into the cellular endosomes [114]. Subsequently, V-ATPase is then being recruited and causes the Mn2+containing endosome to acidify and the Mn2+ to dissociate. It will, in turn, activate the DMT1 that is situated at the endosomal membrane to co-transport the Mn along with a proton into the cytosol [115]. A DMT1 haplotype has been identified as a risk factor for PD [34, 111, 116]. For example, the cytotoxic effect of Mn is dependent on its intracellular levels and genetic variations like polymorphisms and copy number variations involving key components of Mn transport such as DMT1, and the iron/Mn exporter ferroportin can alter Mn sensitivity [59, 116, 117]. At the same time, rats, which were exposed to Mn welding fumes, mimicking occupational exposure, have shown increased DMT1 mRNA expression related to neurodegeneration [118]. In addition, Mn exposure increased DMT1 levels in cultured choroidal epithelial cells: Real-time PCR (RT-PCR) revealed that the increased DMT1 mRNA levels were Mn dose-dependent and exposure time-associated events [119]. Following the Mn exposure, increase of DMT1 protein could come from Mn action at the transcriptional levels to increase DMT1 RNA production and/or RNA processing or at the post-transcriptional level by blocking DMT1 mRNA degradation [119]. In summary, Mn exposure may increase DMT1 expression in the blood–cerebrospinal fluid barrier. Mn exposure appears to increase the binding ability of cellular iron regulatory protein 1 (IRP1) to the iron response element (IRE)-DMT1 mRNA, stabilize the DMT1 mRNA and promote the expression of DMT1 protein [119]. Table 2 and Table 3 show the summarized effects of genetic polymorphisms and responsive gene expression for Mn exposure, respectively.

Epigenetic Alteration Epigenetic alterations are flexible genomic parameters that can change genome functions under exogenous influences [120]. The current field of epigenetics includes a number of mechanisms, including DNA methylation, histone modification, and microRNAs (miRs) [121]. Some studies have established an association between DNA methylation and environmental metals [122–124]. Metals are known to increase production of ROS in a catalytic fashion via redox cycling [125, 126. Oxidative DNA damage can interfere with the ability of methyltransferases to interact with DNA [127], resulting in a generalized altered methylation of cytosine residues at CpG sites [128]. Wang and colleagues reported that maternal developmental Mn exposure in mice affected neurogenesis targeting the immature granule cells in the neuroblast-producing subgranular zone of the dentate gyrus even at the adult stage, accompanied with a sustained increase in the immature population of reelin-synthesizing GABAergic interneurons 138 [129]. These changes may

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K. Gyuri et al. Table 2: Effects of Genetic Polymorphisms on Mn Exposure Gene CYP2D6∗ 2

ATP13A2 / PARK9

SLC30A10

GSTM1

NQO1∗ 2

Genetic Polymorphism

Susceptibility

C > T 2850, rs16947

The CYP2D6∗ 2 had a protective effect on delaying manganism. The CYP2D6∗ 2A/∗ 2A subjects showed low Mn levels in blood and had decreased risks of chronic manganism than the heterozygous individuals or the wild type subjects [11]. There was a significant association between the CYP2D6 genetic polymorphism and the latency of chronic manganese poisoning [11–12. The patients with the CYP2D6∗ 2A/∗ 2A or CYP2D6∗ 1A/CYP2D6∗ 2A developed manganism 10 years later than those who were homozygous of CYP2D6∗ 1A [12].

C > T, rs4920608, A > G, The polymorphisms of rs4920608 and rs2871776 rs2871776 significantly modified the effects of Mn exposure on impaired motor coordination in the elderly, also after adjustments for age and gender [59]. The rs2871776- G allele that was associated with the worst effect of Mn on motor coordination was also linked to the alteration of a binding site for the insulinoma-associated transcription factor 1 (INSM1) [67]. The rs4920608- CT and CC carriers had a decreased motor coordination, compared with TT carriers [59]. The Mn-related motor coordination was reduced among rs2871776- GG and -GA carriers, compared to the AA individuals [59]. T > C 266, 585 del,

These mutations are associated with marked motor impairment and a disorder of Mn metabolism with symptoms including hypermanganesemia, dystonia, polycythemia, and hepatic cirrhosis [71].

G >A Intron 4, rs4147565 The GSTM1 polymorphisms did not show important roles on Mn detoxification: In the Mn-miners, exposed miners having GSTM1-null genotype showed a nonsignificant increase in Mn levels, compared to that of GSTM1 present individuals [11]. C > T 609, rs1800566

The genetic polymorphism in NQO1 did not influence Mn accumulation. Exposed miners having NQO1∗ 2 heterogenotype showed a nonsignificant increase in Mn levels, compared to that of NQO1 wild type individuals [11].

represent continued aberrations in neurogenesis and subsequent migration to cause an excessive response to overproduce immature granule cells through the adult stage. They also found that sustained promoter hypermethylation and transcript down-regulation through postnatal day 77 were confirmed with

Biological Monitoring of Manganese Table 3: Altered Gene Expression by Mn Exposure Biomarker

Alteration

Susceptibility

GS

Reduction

After long-term Mn treatment in vivo, the GS- expression and -activity were significantly reduced in the striatum and globus pallidus [77].

Mn-SOD

Reduction

After Mn treatment, both the number and staining intensity of Mn-SOD-positive cells were significantly decreased in the striatum as well in the globus pallidus, compared with control animals [77].

MT

Reduction

When rats were exposed to air-borne Mn, decrease of MT mRNA was observed in their cerebellum, olfactory bulb, hypothalamus, and hippocampus [110].

DMT1

Induction

Mn exposure increased DMT1 levels in the cultured choroidal epithelial cells. It indicates that Mn exposure increases DMT1 expression in the blood–CSF barrier due to the increase of DMT1 RNA production and/or RNA processing or at the post-transcriptional level [121]. Mn treatment appears to increase the binding ability of cellular IRP1 into IRE-containing DMT1 mRNA, which stabilizes the DMT1 mRNA and promote the expression of DMT1 protein [121].

Note. GS, glutamine synthetase; Mn-SOD, Mn-superoxide dismutase; MT, metallothionein; DMT1, divalent metal transport 1.

Mid1, Atp1a3, and Nr2f1, whereas Pvalb showed a transient hypermethylation only on weaning by CpG promoter microarray analysis on postnatal day 21 following 800-ppm Mn exposure [130]. In 63 healthy male steel workers with well-characterized exposure to metal-rich particles nearby Brescia, Italy the promoter DNA methylation levels of APC or p16, tumor suppressor genes, were significantly higher in postexposure (the fourth day) blood samples, compared to those in the baseline (the

Figure 1: Flow of Mn exposure, susceptibility, and response. ATP13A2, ATPase type 13A2; CYP2D6, cytochrome P450 2D6; DMT1, divalent metal transport 1; GS, glutamine synthetase; Mn-SOD, Mn-superoxide dismutase; MT, metallothionein; RfD, reference dose by US- EPA; SLC30A10, solute carrier family 30, member 10; A rhombus (♦) means a conditional/decision symbol to affect susceptibility or response.

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first day of the same work week) samples [131]. By contrast, the mean levels of p53 or RASSF1A promoter methylation was decreased in the postexposure samples. Among the particulate matters (PMs), PM10 and PM1 were positively associated with APC methylation (β = 0.27, 95% CI: 0.13–0.40; β = 0.23, 95% CI: 0.09–0.38, respectively). Mn occupied the third highest metal in PM10 , following Fe and Zn, showed some relationships with the previously mentioned four tumor suppressor genes (β and 95% CI for APC, p16, p53 and RASSF1A, 0.11, –0.03 to 0.26; –0.03, –0.22 to 0.15; –0.02, –0.15 to 0.11; 0.11, –0.05 to 0.28, respectively), although they were not significant. In the same subjects, expression of miR-222 and miR-21 was significantly increased in the postexposure samples (miR-222: baseline = 0.68 +/- 3.41, post-exposure = 2.16 +/- 2.25, p = 0.002; miR-21: baseline = 4.10 +/- 3.04, postexposure = 4.66 +/- 2.63, p = 0.05) [132]. In the postexposure samples, miR-222 expression was positively correlated with lead exposure (beta = 0.41, p = 0.02), whereas miR-21 expression was associated with blood 8-hydroxyguanine, an oxidative biomarker (beta = 0.11, p = 0.03) but not with individual PM size fractions or metal components, such as Mn. Cumulative exposure to Mn, defined as the product of years of employment by metal air levels, was not significantly associated with histone 3 lysine 4 dimethylation and histone 3 lysine 9 acetylation on histones from blood leukocytes, either, while that to Ni and As were positively correlated with them [133]. Figure 1 shows the summarized results of current biological monitoring of Mn [134, 135].

CONCLUSION The general population can be exposed to Mn through various exposure routes including food. Therefore, many countries have regulated Mn exposure to prevent severe toxicity of Mn, such as manganism, and have performed various biological monitoring of Mn. From these results, we can estimate most Mn exposure comes from diet (oral RfD, 10 mg/d). However, there are highly susceptible populations, for example children, pregnant women, and so on, and genetically risky people, for example, the wild type of CYP2D6, the mutants of ATP13A2 or SLC30A10, and so on. In addition, epigenetic and phenotypical changes by Mn exposure have been shown. Further biological monitoring of Mn are required with more sensitive and selective biomarkers of exposure, susceptibility, and response to minimize Mn toxicity.

FUNDING This work was supported by the grant of Sookmyung Women’s University (2012) and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2011-0030074).

Biological Monitoring of Manganese

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A current review for biological monitoring of manganese with exposure, susceptibility, and response biomarkers.

People can be easily exposed to manganese (Mn), the twelfth most abundant element, through various exposure routes. However, overexposure to Mn causes...
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