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Workplace
Original article
Cognitive function and plasma BDNF levels among manganese-exposed smelters
  1. Yunfeng Zou1,
  2. Li Qing2,
  3. Xiaoyun Zeng2,
  4. Yuefei Shen3,
  5. Yaoqiu Zhong4,
  6. Jing Liu4,
  7. Qin Li1,
  8. Kangcheng Chen4,
  9. Yingnan Lv4,
  10. Damin Huang4,
  11. Guiqiang Liang1,
  12. Wei Zhang3,
  13. Lang Chen3,
  14. Yiping Yang1,
  15. Xiaobo Yang4,5
  1. 1Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi, People's Republic of China
  2. 2Department of Epidemiology and Health Statistics, School of Public Health, Guangxi Medical University, Nanning, Guangxi, People's Republic of China
  3. 3Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
  4. 4Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, People's Republic of China
  5. 5Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, People's Republic of China
  1. Correspondence to Dr Xiaobo Yang, Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, 22 Shuangyong Rd, Nanning, Guangxi 530021, People's Republic of China; yxbo21021{at}163.com

Abstract

Objectives To explore the potential dose–response relationship between manganese (Mn) exposure and cognitive function and also plasma brain-derived neurotrophic factor (BDNF) levels in occupational Mn exposure workers.

Methods A total 819 workers were identified from our Mn-exposed workers, and 293 control workers were recruited in the same region. All exposed workers were divided into three groups based on Mn cumulative exposure index. The Montreal Cognitive Assessment (MoCA) test was applied to estimate cognitive function for all subjects. Plasma BDNF levels were determined by ELISA in 248 selected exposed workers and 100 controls.

Results Mn-exposed workers had significantly lower MoCA scores than those in the control group (25.62±0.25): those in high-exposure group had the lowest scores (21.33±0.32), compared with the intermediate-exposure group (23.22±0.30) and low-exposure group (23.57±0.23). Mn exposure levels were inversely associated with MoCA total scores, all p<0.05. A positive correlation was found between plasma BDNF levels and MoCA total scores (r=0.278, p<0.01). Moreover, compared with the control group (288.7±181.7 pg/mL), BDNF levels were lower in the high-exposure group (127.5±99.8 pg/mL), and in the intermediate-exposure (178.2±138.1 pg/mL) and low-exposure groups (223.4±178.3 pg/mL). Additionally, plasma BDNF levels decreased significantly as Mn exposure levels increased (ptrend<0.01).

Conclusions Mn exposure may be associated with decreased plasma BDNF levels and cognition impairment in this large cross-sectional study.

https://doi.org/10.1136/oemed-2013-101896

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    What this paper adds

    • This is the first study to explore the relationship between manganese exposure and cognitive function based on the Montreal Cognitive Assessment (MoCA) test and plasma brain-derived neurotrophic factor (BDNF) levels.

    • There is an inverse correlation between manganese exposure and cognitive function and an inverse association between manganese exposure and plasma BDNF levels.

    • Manganese exposure impaired cognitive ability and decreased plasma BDNF levels.

    Introduction

    Manganese (Mn) is an essential trace element involved in the metabolism of amino acids, proteins and lipids, but it also may produce neurotoxic effects when in excess and accumulates in the central nervous system (CNS), particularly the basal ganglia.1 Long-term occupational exposure to high airborne Mn via inhalation in industries such as mining, smelting, welding, ferroalloy and dry battery production,2–,4 may lead to manganism, a severe and irreversible disorder of the CNS, which was described for the first time in connection with mining in 1837.5 A few cases of manganism have been reported, which mainly displayed early impairment of the CNS, including changes in eye–hand coordination, hand steadiness, postural stability, attention, concentration, reaction time, cognitive flexibility and visuospatial function.2 ,6 ,7

    During the past two decades, many investigations of workers exposed to Mn have shown that they have alterations in cognitive performance, including working memory, delayed recall, visuospatial function, attention and concentration, reaction time and a dose–response relationship between exposure levels and cognitive function. 6–,10 In these studies, several tests were used to estimate cognitive function, such as the Wechsler Adult Intelligence Scale, Wechsler Memory Scale III, Boston Naming Test and neurobehavioral test battery.11–,13 These tests are comprehensive and widely used, but a simpler test to assess cognitive function of Mn-exposed workers is needed. The Montreal Cognitive Assessment (MoCA) tool was originally developed by Nasreddine and colleagues14 for screening mild cognitive impairment but is now widely used to detect global cognitive function, and is more economical, quicker and simpler than other cognitive tests. In this study, we used MoCA to evaluate cognition in Mn-exposed and healthcare workers.

    Many studies of the molecular mechanisms of Mn neurotoxicity have been carried out, but the conclusions are inconsistent and contradictory. The cyclic AMP (cAMP)/cAMP response element binding protein (CREB) signalling pathway has been shown to be important for induction and persistence of long-term potentiation (LTP) and long-term memory (LTM).15 ,16 Additionally, downstream proteins of the cAMP/CREB signalling pathway, such as brain-derived neurotrophic factor (BDNF), B-cell lymphoma/leukaemia-2 (Bcl-2) and c-fos, were found to be essential for the process of learning and memory.17 Whether the cAMP/CREB signalling pathway is involved in Mn neurotoxicity is unknown. We hypothesised that Mn exposure might affect cognitive function via the cAMP/CREB/BDNF signalling pathway.

    BDNF is a member of the neurotrophin family and is expressed throughout the brain, especially in the prefrontal cortex and the hippocampus.18 It is a well-known regulator of synaptic plasticity and plays a key role in cognition.19 It is an important factor in the induction of LTP20 and LTM.21 BDNF is necessary for inducing persistent LTM storage in rats,22 and it has been shown to modulate LTP indirectly by inhibiting synaptic fatigue.23 These studies indicated that BDNF is important for the process of learning and for improvements in cognitive function. Recent findings have suggested that a decrease in hippocampal BDNF levels is related to cognitive deficits in rats with chronic cerebral hypoperfusion, and that cognitive impairment is restored after environmental enrichment, which increases hippocampal BDNF levels.24 In addition, low BDNF levels were associated with cognitive decline in patients with major depression and schizophrenia.25 ,26 However, to the best of our knowledge, there has been no investigation of the relationship between cognitive function and plasma BDNF levels in occupational Mn-exposed workers. Therefore, this study was designed to assess the relationship between Mn exposure levels and cognitive abilities based on the Beijing version of the MoCA test, and also the effect of occupational exposure to Mn on plasma BDNF levels.

    Materials and methods

    Subjects

    A total of 843 occupational Mn-exposed workers were included in this cross-sectional epidemiological study; they formed one part of our Mn-exposed workers healthy cohort (MEWHC), as previously described.27 To compare the cognitive function of Mn-exposed workers with that of the healthy population, we recruited a group of union 293 workers with no Mn exposure from a sugar refinery in the same region as the Mn-exposed workers. The main inclusion criteria for participation were age ≥18 years, working time of at least 3 months, no diabetes mellitus or serious kidney or liver diseases, CNS diseases that are probably unrelated to Mn exposure, no physical disability or surgical history. Additionally, control workers had no history of exposure to neurotoxic substances and exposure workers had no history of exposure to neurotoxic substances apart from Mn. The exclusion criteria included a history of medication and drug use in the past 2 weeks and unwillingness to participate in interviews.

    This study was approved by the ethics and human subjects committee of Guangxi Medical University. Written informed consent was obtained from each participant.

    Questionnaires and cognitive testing

    All participants completed a comprehensive questionnaire including demographic information, drinking status, smoking status, disease history, medication and occupational history. Drinking status was defined as current drinking (drinking at least once each week for more than 3 months), former drinking (stopped drinking for at least 3 months) and never drinking. Smoking status was defined as current smoking (smoking at least one cigarette daily for more than 3 months), former smoking (stopped smoking for at least 3 months) and never smoking.

    The Beijing version of the MoCA was translated from the English MoCA, which is a screening measure of global cognitive function and was revised by Wang Wei. The MoCA test form and instructions are available for download at the MoCA official website (http://www.mocatest.org). It is a 10 min test evaluating seven cognitive domains: visuospatial/executive abilities (five), naming (three), attention (six), language (three), abstraction (two), 5 min delayed-recall (five) and orientation (six). Total MoCA scores range from 0 to 30. To correct for education effects, one point was added for workers with <12 years’ education14; higher scores indicate better cognitive function.

    Manganese exposure assessment

    The monitoring targets were three smelting branch workplaces of a ferro-Mn alloy plant. We collected 27, 9 and 8 samples of smelters and 7, 16 and 6 samples of auxiliary workers in the first, second and third smelting branch workplaces of smelters, respectively. Air samples were collected by FC-2 dust samplers according to the standard specification issued by the Ministry of Health in China—‘Specifications of air sampling for hazardous substances monitoring in the workplace’ (GBZ 159-2004). The samples were obtained in normal working conditions to avoid confounding factors. The concentration of Mn was determined according to the standard specification by flame atomic absorption spectrophotometry (FAAS). Briefly, air samples were firstly digested with 5 mL of HClO4–HNO3 mixture (1 : 9 vol/vol) at 200°C and detected at a wavelength of 279.5 nm using a model HITACHI Z-5000 acetylene–air flame atomic absorption spectrophotometer.

    To evaluate the Mn exposure level of workers in the exposure group, we calculated the cumulative exposure index (CEI) from the 8 h air Mn time-weighted average (TWA) in each department of the factory and multiplied it by the Mn exposure-years for each worker as follows:Embedded Image 1

    Where Ci is the TWA (mg/cm3), Ti is the Mn exposure-years (years).

    The TWA was calculated as follows:Embedded Image 2

    Where Ci is the air Mn concentration of each department (mg/cm3), Ti is the working time of each department (hours).

    We divided all exposed subjects into three subgroups based on the CEI—a low-exposure group (CEI<5.00 mg/m3.year), an intermediate-exposure group (CEI=5.00–10.00 mg/m3.year) and a high-exposure group (CEI>10.00 mg/m3.year).

    Measurement of plasma BDNF

    To explore the relationship between plasma BDNF levels and cognitive function, 248 male exposed workers and 100 male control workers were randomly selected from the total 1112 workers. Blood samples from all subjects were collected in the morning after an overnight fast. The plasma was separated, aliquoted and stored at −80°C before use. Plasma BDNF levels were measured using the Sandwich ELISA kit (Chemikine, USA), according to the manufacturer's instructions. All assays were performed blind to the subject's status. Intra- and interassay variation coefficients were 3.7% and 8.5%, respectively. The plasma BDNF concentrations were expressed as pg/mL.

    Statistical analyses

    The general demographic characteristics of workers in the exposure and control groups are shown as absolute numbers and as a proportion in the total 1112 workers and the 348 workers included in the second-stage study. We used analysis of covariance to compare the differences of MoCA subtests and total scores between different exposure subgroups and the control group, with adjustment for gender, education, smoking and drinking status. We performed analysis of partial correlation to estimate univariate correlations between MoCA subtests, total scores and Mn-CEI, with adjustment for gender, education,28 smoking and drinking status in the 1112 participants. Analysis of covariance was used to evaluate plasma BDNF levels between exposure subgroups and control groups after adjusting for age and drinking status. We evaluated the linear trend between plasma BDNF levels and different groups by the trend test. We performed Pearson correlation analysis to evaluate univariate correlations between plasma BDNF levels and MoCA total scores; all analyses were performed using the SPSS V.16.0 programme and were two-tailed, with significance set at p<0.05.

    Results

    Demographic characteristics

    As presented in table 1, this study included 819 exposed workers and 293 control workers—a total of 1112 subjects; all participants completed the structured questionnaire. The control group comprised 238 men (81.2%), 55 women (18.8%) and the exposure group comprised 605 men (73.9%) and 214 women (26.1%). Average ages were 35.7 years for control workers and 40.2 years for exposed workers. Of the 293 control workers, 153 (52.2%) were current smokers and 178 (60.8%) current drinkers. Of the 819 exposure workers, 356 (43.5%) were current smokers and 487 (59.5%) current drinkers.

    View this table:
    Table 1

    Demographic characteristics of control and exposure groups in this cross-sectional study

    Airborne manganese concentration

    The airborne Mn concentration of smelters ranged from 0.257 to 0.450 mg/m3 and exceeded the recommendation of the Ministry of Health of the People's Republic of China (2004, 0.15 mg/m3); that of auxiliary workers ranged from 0.038 to 0.054 mg/m3 in three smelting branches. The CEI was in the range 0.019–22.347 mg/m3.year in exposed workers.

    Relationship between manganese exposure and cognitive function

    As shown in table 2, the total scores of exposed workers (low-exposure group 23.57, intermediate-exposure group 23.22 and high-exposure group 21.33) were lower than that of control workers (25.62), after controlling for gender, education, smoking and drinking status; this difference was also found in other subtest scores, all p<0.05. There was a significant inverse correlation between Mn-CEI and total scores (r=−0.210, p<0.01) and other subtests scores also (all p<0.01), with adjustment for confounding factors. There was no correlation between orientation and Mn-CEI (p=0.382).

    View this table:
    Table 2

    Comparisons of the MoCA subtests and total scores between control and exposure groups and correlation between Mn-CEI and MoCA subtests, total scores

    Correlation between plasma BDNF levels and cognitive function

    The general characteristics from randomly selected second-stage subjects are presented in table 3. The average Mn exposure-years were 9.1, 17.99 and 16.4 years for low-exposure workers, intermediate-exposure workers and high-exposure workers, respectively. The average CEIs were 2.7, 6.6 and 17.8 mg/m3 year for low-exposure, intermediate-exposure and high-exposure groups, respectively.

    View this table:
    Table 3

    General characteristics of different groups among the randomly selected second-stage subjects

    In the Pearson correlation analysis, a significant correlation between plasma BDNF levels and MoCA total scores (r=0.278, p<0.01) was shown in Mn-exposed workers, as shown in figure 1.

    Figure 1
    Figure 1

    Correlation of plasma brain-derived neurotrophic factor (BDNF) and Montreal Cognitive Assessment (MoCA) total scores. Data were analysed by linear regression r=0.278, p<0.01.

    Plasma BDNF levels in different exposure groups

    The exposure group was divided into three subgroups as previously described. As shown in figure 2, after adjusting for age and drinking status, there was a significant difference in plasma BDNF levels between the control group (288.7±181.7 pg/mL) and the three exposure subgroups (223.4±178.3 pg/mL, 178.2±138.1 pg/mL, 127.5±99.8 pg/mL for workers in low-exposure, intermediate-exposure and high-exposure groups, respectively; p<0.01). The linear trend of plasma BDNF levels and different groups was statistically significant (p<0.01), after controlling for age and drinking status.

    Figure 2
    Figure 2

    Comparison of plasma brain-derived neurotrophic factor (BDNF) between control group and exposure groups. (A) control group, (B) low-exposure group, (C) intermediate-exposure group, (D) high-exposure group. Analysis of covariance for plasma BDNF levels between control and exposure groups, after adjusting for age and drinking status, p<0.01. Analysis of linear trend: p<0.01.

    Discussion

    This study showed that workers exposed to higher airborne Mn concentrations had lower MoCA subtests and total scores, suggesting an association between Mn exposure and cognitive function. This finding was robust after adjustment for gender, education, smoking and drinking status. The association between Mn exposure levels and MoCA total scores is significant, with a 4.29 point difference between workers in the control group and in the high-exposure group. Furthermore, there is an inverse dose–response relationship between Mn-CEI and MoCA total scores and also MoCA subtests scores, except for orientation scores.

    The cognitive impairment of Mn-exposed workers is chronic and progressive, and several other studies have reported cognitive deficits induced by long-term exposure to Mn. The study of Bowler et al6 showed that welders had deficits in working memory, verbal skills (Controlled Oral Word Association Test), delayed memory and visuospatial skills. An epidemiological investigation of a machine-building factory showed that cognitive abilities decreased in welding workers in comparison with the control group.12 Other reports showed prolonged reaction time, poorer attention and concentration, poorer memory and visuospatial coordination in welders.29 ,30 Together, these studies indicate that occupational exposure to Mn can produce cognitive deficits.

    In this study, we applied the MoCA test to assess cognitive abilities in all subjects. MoCA is an instrument which quickly evaluates global cognitive function. It has been used to screen cognitive function deficits in Parkinson disease,31 vascular cognitive impairment after acute stroke,32 HIV-associated mild cognitive impairment33 and other cognitive deficits; the MoCA test is more widely used than other tests for screening cognitive function. The Mini-Mental State Examination (MMSE)34 is a simple instrument that can be used to assess general cognitive ability, but it has been proved that the MoCA with its good psychometric features and excellent sensitivity provides more accurate results than the MMSE.14 We found that a greater number of Mn-exposed workers had lower MoCA scores than controls, suggesting that the MoCA test is sufficiently sensitive for estimating cognitive impairment. However, although the MoCA is a useful tool for preliminary screening of cognitive function, its specificity is not as good as that of the MMSE, and therefore, it should be used cautiously.

    As far as we know, this is the first study to estimate the relationship between plasma BDNF levels and cognitive impairment among Mn-exposed workers. BDNF plays a key role in modulating synaptic transmission and plasticity, which are both important for learning and memory.35 Evidence shows that lower cerebrospinal fluid BDNF concentrations are associated with poorer immediate and delayed recall in older people,36 and the serum concentration of BDNF was lower in patients with Alzheimer's disease.3,7 Conversely, higher serum BDNF levels were associated with better neuropsychological function in healthy older adults.3,8

    We found that plasma BDNF levels were related to total MoCA scores; lower plasma BDNF levels indicated worse cognitive function. However, Driscoll and colleagues reported that plasma BDNF was not associated with cognitive function in older, non-demented adults.39 In the Finnish sample, worse general cognitive function was associated with a drop in plasma BDNF, but the associations were present only for women.40 The discrepancies between our findings and the two studies may reflect differences of methodology and subject sampling. In addition, we performed a covariance analysis to estimate the relationship between Mn exposure and plasma BDNF levels and showed that exposed workers had lower plasma BDNF levels than control workers. Analysis of the data showed that plasma BDNF levels decreased significantly with increasing Mn exposure levels, suggesting that Mn exposure may decrease the plasma BDNF levels.

    Evidence suggesting that peripheral BDNF reflects central BDNF is strong. A positive correlation was found between serum and hippocampal and cortical BDNF levels in rats.41 ,42 Other studies demonstrated positive correlations between whole-blood BDNF and hippocampal BDNF levels in rats,43 and between plasma BDNF and hippocampal BDNF levels in pigs.43 In addition, BDNF levels in human blood are associated with diseases in the brain, such as multiple sclerosis, depression and Alzheimer's disease.44–46 These studies support the statement that peripheral BDNF can reflect brain BDNF.

    An animal study found that inhibition of CREB phosphorylation downregulates BDNF levels, leading to neuronal apoptosis, which may be involved in the impairment of cognitive function.47 Our study showed that lower cognitive function was associated with decreased plasma BDNF levels. These facts suggest that the cAMP/CREB signalling pathway may influence the cognitive abilities of Mn-exposed workers by affecting the BDNF levels.

    Our study has some limitations. First, we calculated CEI based on exposure-years and air Mn concentration to assess individual Mn exposure levels. It would be better to use individual samplers to collect 8 h air samples, although our air samples covered every place of work in each branch. Second, we performed a binary correlation analysis and found that those subjects with higher Mn exposure levels had lower plasma BDNF concentrations and this was just a preliminary verification of the hypothesis that the cAMP/CREB signalling pathway is involved in Mn neurotoxicity, but the underlying mechanism is still not clear.

    Conclusions

    This study shows that the risk of decreasing cognitive function is associated with higher occupational Mn exposure levels and that the MoCA test can distinguish cognitive impairment in workers. Moreover, we found a negative dose–response relationship between plasma BDNF levels and Mn exposure levels. Our results are authoritative because of the large sample and imply that both the MoCA test and plasma BDNF levels can be potential markers of cognitive impairment induced by manganese exposure. These results provide clues for possible future exploration of the mechanism in animal and cell experiments.

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    Footnotes

    • YfZ and LQ contributed equally.

    • Correction The section head of this paper has been updated since it was published Online First.

    • Acknowledgements We thank all those who volunteered to participate in this study.

    • Contributors XfY and YfZ conceived and designed the study; all authors performed the investigation; LQ and JL analysed the data; LQ wrote the manuscript; all authors contributed to review and revision of the manuscript.

    • Funding This study was partially supported by grants from the National Natural Science Foundation of China (81060234, 21167004 and 81160339), Guangxi Science Fund for Distinguished Young Scholars (2012jjFA40011), Guangxi Natural Science Foundation (2011jjA40294), Guangxi Science and Technology Development Project (1355007-1), Research Fund for the Doctoral Program of Higher Education of China (20104503120006) and the Program for New Century Excellent Talents in University (NCET-12-0653).

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval Ethics and human subjects committee of Guangxi Medical University.

    • Provenance and peer review Not commissioned; externally peer reviewed.