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Neurofunctional dopaminergic impairment in elderly after lifetime exposure to manganese.

ABSTRACT: BACKGROUND:Manganese (Mn) is an essential element that can become neurotoxic through various exposure windows over the lifespan. While there is clear evidence of Mn neurotoxicity in pediatric and adult occupational populations, little is known about effects in the elderly who may exhibit enhanced susceptibilities due to compromised physiology compared to younger adults. In the province of Brescia, Italy, the Valcamonica area has been the site of three ferroalloy plants operating from 1902 to 2001. Metal emissions of Mn and to a lesser extent lead (Pb) have impacted the surrounding environment, where a high prevalence of Parkinsonism was previously observed. This study aimed to assess neurocognitive and motor functions in healthy elderly subjects residing for most of their lifetime in Valcamonica or in a reference area unimpacted by ferroalloy plant activity. METHODS:Subjects were enrolled for extensive neurobehavioral assessment of motor, cognitive and sensory functions. Exposure was assessed with 24h personal air sampling for PM10 airborne particles, surface soil and tap water measurement at individual households, Mn levels in blood and urine and Pb in blood. Dose-response relationships between exposure indicators and biomarkers and health outcomes were analyzed with generalized (linear and logistic) additive models (GAM). RESULTS:A total of 255 subjects (55% women) were examined; most (52.9%) were within the 65-70 years age class. Average airborne Mn was 26.41 ng/m(3) (median 18.42) in Valcamonica and 20.96 ng/m(3) (median 17.62) in the reference area. Average Mn in surface soil was 1026 ppm (median 923) in Valcamonica and 421 ppm (median 410) in the reference area. Manganese in drinking water was below the LDL of 1 ?g/L. The GAM analysis showed significant association between airborne Mn (p=0.0237) and the motor coordination tests of the Luria Nebraska Neuropsychological Battery. The calculation of the Benchmark Dose using this dose-response relationship yielded a lower level confidence interval of 22.7 ng/m(3) (median 26.4). For the odor identification score of the Sniffin Stick test, an association was observed with soil Mn (p=0.0006) and with a significant interaction with blood Pb (p=0.0856). Significant dose-responses resulted also for the Raven's Colored Progressive Matrices with the distance from exposure point source (p=0.0025) and Mn in soil (p=0.09), and for the Trail Making test, with urinary Mn (p=0.0074). Serum prolactin (PRL) levels were associated with air (p=0.061) and urinary (p=0.003) Mn, and with blood Pb (p=0.0303). In most of these associations age played a significant role as an effect modifier. CONCLUSION:Lifelong exposure to Mn was significantly associated with changes in odor discrimination, motor coordination, cognitive abilities and serum PRL levels. These effects are consistent with the hypothesis of a specific mechanism of toxicity of Mn on the dopaminergic system. Lead co-exposure, even at very low levels, can further enhance Mn toxicity.

SUBMITTER: Lucchini RG

PROVIDER: S-EPMC4247810 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Neurofunctional dopaminergic impairment in elderly after lifetime exposure to manganese.

Lucchini Roberto G RG Guazzetti Stefano S Zoni Silvia S Benedetti Chiara C Fedrighi Chiara C Peli Marco M Donna Filippo F Bontempi Elza E Borgese Laura L Micheletti Serena S Ferri Roberta R Marchetti Serena S Smith Donald R DR

Neurotoxicology 20140529

<h4>Background</h4>Manganese (Mn) is an essential element that can become neurotoxic through various exposure windows over the lifespan. While there is clear evidence of Mn neurotoxicity in pediatric and adult occupational populations, little is known about effects in the elderly who may exhibit enhanced susceptibilities due to compromised physiology compared to younger adults. In the province of Brescia, Italy, the Valcamonica area has been the site of three ferroalloy plants operating from 190 ...[more]

PMID: 24881811

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Project description:ObjectivesExposure to manganese (Mn) may cause movement disorders, but less is known whether the effects persist after the termination of exposure. This study investigated the association between former exposure to Mn and fine motor deficits in elderly men from an industrial area with steel production.MethodsData on the occupational history and fine motor tests were obtained from the second follow-up of the prospective Heinz Nixdorf Recall Study (2011-2014). The study population included 1232 men (median age 68 years). Mn in blood (MnB) was determined in archived samples (2000-2003). The association between Mn exposure (working as welder or in other at-risk occupations, cumulative exposure to inhalable Mn, MnB) with various motor functions (errors in line tracing, steadiness, or aiming and tapping hits) was investigated with Poisson and logistic regression, adjusted for iron status and other covariates. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated for substantially impaired dexterity (errors >90th percentile, tapping hits <10th percentile).ResultsThe median of cumulative exposure to inhalable Mn was 58 µg m-3 years in 322 men who ever worked in at-risk occupations. Although we observed a partly better motor performance of exposed workers at group level, we found fewer tapping hits in men with cumulative Mn exposure >184.8 µg m-3 years (OR 2.15, 95% CI 1.17-3.94). MnB ≥ 15 µg l-1, serum ferritin ≥ 400 µg l-1, and gamma-glutamyl transferase ≥74 U l-1 were associated with a greater number of errors in line tracing.ConclusionsWe found evidence that exposure to inhalable Mn may carry a risk for dexterity deficits. Whether these deficits can be exclusively attributed to Mn remains to be elucidated, as airborne Mn is strongly correlated with iron in metal fumes, and high ferritin was also associated with errors in line tracing. Furthermore, hand training effects must be taken into account when testing for fine motor skills.

Project description:Manganese (Mn) is an essential trace metal. It is also a component of welding fume. Chronic inhalation of manganese from welding fume has been associated with decreased neurological function. Currently, there is not a universally recognized biomarker for Mn exposure; however, hair and toenails have shown promise. In a cohort of 45 male welders and 35 age-matched factory control subjects, we assessed the sensitivity and specificity of toenail Mn to distinguish occupationally exposed subjects from unexposed controls. Further we examined the exposure time window that best correlates with the proposed biomarker, and investigated if non-occupational exposure factors impacted toenail Mn concentrations. Toenail clippings were analyzed for Mn using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Exposure to respirable Mn-containing particles (<4 µm) was estimated using an exposure model that combines personal air monitoring, work history information, and dietary intake to estimate an individual's exposure to Mn from inhalation of welding fume. We assessed the group differences in toenail concentrations using a Student's t-test between welders and control subjects and performed a receiver operating characteristic (ROC) curve analysis to identify a threshold in toenail concentration that has the highest sensitivity and specificity in distinguishing welders from control subjects. Additionally, we performed mixed-model regressions to investigate the association between different exposure windows and toenail Mn concentrations. We observed that toenail Mn concentrations were significantly elevated among welders compared to control subjects (6.87 ± 2.56 versus 2.70 ± 1.70 µg g-1; P < 0.001). Our results show that using a toenail Mn concentration of 4.14 µg g-1 as cutoff allows for discriminating between controls and welders with 91% specificity and 94% sensitivity [area under curve (AUC) = 0.98]. Additionally, we found that a threshold of 4.66 µg g-1 toenail Mn concentration enables a 90% sensitive and 90% specific discrimination (AUC = 0.96) between subjects with average exposure above or below the American Conference of Governmental Industrial Hygienist (ACGIH) Threshold Limit Value (TLV) of 0.02 mg m-3 during the exposure window of 7-12 months prior to the nail being clipped. Investigating which exposure window was best reflected by toenail Mn reproduced the result from another study of toenail Mn being significantly (P < 0.001) associated with exposure 7-12 months prior to the nail being clipped. Lastly, we found that dietary intake, body mass index, age, smoking status, and ethnicity had no significant effect on toenail Mn concentrations. Our results suggest that toenail Mn is a sensitive, specific, and easy-to-acquire biomarker of Mn exposure, which is feasible to be used in an industrial welder population.

Dataset Information

Neurofunctional dopaminergic impairment in elderly after lifetime exposure to manganese.

Publications

Neurofunctional dopaminergic impairment in elderly after lifetime exposure to manganese.

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