title: 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 μg/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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Occupational Health, University of Brescia, Italy; Preventive Medicine, Mount Sinai School of Medicine, NY, USA; Microbiology and Environmental Toxicology, University of California, Santa Cruz, USA. Electronic address: roberto.lucchini@mssm.edu.
authors.forename: Roberto G
authors.initials: RG
authors.lastname: Lucchini
authors.affiliation: Public Health Service, Reggio Emilia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Guazzetti
authors.affiliation: Occupational Health, University of Brescia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Zoni
authors.affiliation: Occupational Health, University of Brescia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Benedetti
authors.affiliation: Occupational Health, University of Brescia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fedrighi
authors.affiliation: Occupational Health, University of Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Peli
authors.affiliation: Occupational Health, University of Brescia, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Donna
authors.affiliation: INSTM and Chemistry for Technologies Laboratory, University of Brescia, Italy.
authors.forename: Elza
authors.initials: E
authors.lastname: Bontempi
authors.affiliation: INSTM and Chemistry for Technologies Laboratory, University of Brescia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Borgese
authors.affiliation: Department of Brain and Behavioral Sciences, University of Pavia, Italy and Child Neurology and Psychiatry Unit, Spedali Civili of Brescia, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Micheletti
authors.affiliation: Occupational Health, University of Brescia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ferri
authors.affiliation: Occupational Health, University of Brescia, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Marchetti
authors.affiliation: Microbiology and Environmental Toxicology, University of California, Santa Cruz, USA.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Smith
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis; D003071:Cognition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D019570:Inhalation Exposure / Q000032:analysis*; D007501:Iron; D007558:Italy; D007854:Lead / Q000097:blood; D008297:Male; D008345:Manganese / Q000097:blood / Q000652:urine; D020149:Manganese Poisoning / Q000523:psychology*; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D009483:Neuropsychological Tests; D055696:Olfactory Perception / Q000187:drug effects; D012989:Soil Pollutants / Q000506:poisoning
chemical_list: D015415:Biomarkers; D012989:Soil Pollutants; C083456:ferro-manganese alloy; D007854:Lead; D008345:Manganese; D007501:Iron
keywords: Ageing; Cognitive abilities; Manganese; Motor coordination; Odor identification