Research A Proton Magnetic Resonance Spectroscopy Study of the Chronic Lead Effect on the Basal Ganglion and Frontal and Occipital Lobes in Middle-Age Adults Tsyh-Jyi Hsieh,1 Yi-Chun Chen,2 Chun-Wei Li,3 Gin-Chang Liu,1,4 Yu-Wen Chiu,2 and Hung-Yi Chuang 2,5 1Department of Medical Imaging and 2Department of Community Medicine, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan; 3Department of Medical Imaging and Radiation Technology, College of Health Sciences, and 4Department of Radiology, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan; 5Department of Public Health, College of Health Sciences, and Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan Background : Lead is known to be a health hazard to the human brain and nervous system based on data from epidemiologic studies. However, few studies have examined the mechanism or bio- chemical changes caused by lead in the human brain, although recently some have used magnetic resonance spectroscopy (MRS) to test brain metabolism in vivo. o Bjectivs : In this study, we used 3-T MRS to investigate brain metabolism in workers chronically exposed to lead and matched nonexposed controls. Materils and Msdohte : Twenty-two workers at a lead paint factory served as chronically exposed subjects of this study. These workers did not have any clinical syndromes. Eighteen age- and sex- matched nonexposed healthy volunteers served as controls. We measured blood and bone lead and used a 3-T MRS to measure their levels of brain N-acetyl aspartate (NAA), choline (Cho), and total creatine (tCr). A structural questionnaire was used to collect demographic, work, and health histo- ries and information about their life habits. r esult : All the MRS measures were lower in the lead-exposed group. Increased blood and bone lead levels correlated with declines in Cho:tCr ratios, especially in the occipital lobe, where changes in all gray, subcortical, and white matter were significant. Increases in blood and patella lead in every layer of the frontal lobe correlated with significant decreases in NAA:tCr ratios. One of the strongest regression coefficients was –0.023 (SE = 0.005, p < 0.001), which was found in the NAA:tCr ratio of frontal gray matter. d iscuon : We conclude that chronic exposure to lead might upset brain metabolism, especially NAA:tCr and Cho:tCr ratios. Brain NAA and Cho are negatively correlated to blood and bone lead levels, suggesting that lead induces neuronal and axonal damage or loss. The most significant changes occurred in frontal and occipital lobes, areas in which previous neurobehavioral studies have shown memory and visual performance to be adversely affected by lead toxicity. k ey words : bone lead KXRF, brain metabolism, lead, proton magnetic resonance spectroscopy. Environ Health Perspect 117:941–945 (2009). doi:10.1289/ehp.0800187 available via http://dx.doi. org/ [Online 9 February 2009] Lead has long been known to be a hazard to the human brain and nervous system based on data from epidemiologic studies (Castellino et al. 1995). Because leaded gasoline has been phased out and environmental levels of lead have been reduced, recent investigations have focused on subclinical damage and health effects of chronic exposure that do not result in the typical symptoms and signs. Typically, blood lead levels are measured. For exam- ple, studies of workers with low to moderate blood lead levels have reported abnormal elec- trophysiologic parameters and neurobehav- ioral performance (Baker et al. 1984; Chuang et al. 2000, 2005; Jeyaratnam et al. 1985; Lucchini et al. 2000). More recently, X-ray fluorescence (XRF) is being used to non- invasively measure the accumulation of lead in bones. Often the tibia and the patella are studied (Hu et al. 1995, 1998). Lead accu- mulation in the tibia, a cortical bone, can serve as a biomarker of cumulative lead dose, and there lead has a residual half-life of 25–30 years. Lead accumulation in the patella, a tra- becular bone, has a half-life clearance ranging from months to years and is considered to be a biomarker for both accumulation and short- term bioavailability. Identifying such subclinical changes in workers chronically exposed to lower levels of lead is important because brain damage occurs slowly. Neurobehavioral tests, which are now the method of determining whether lead exposure has affected brain function- ing (Baker et al. 1984; Chuang et al. 2005; Lucchini et al. 2000), are somewhat slow because they measure an outcome of brain damage. Few studies have examined the mechanism or biochemical changes caused by lead in the human brain, although recently some have used magnetic resonance spectros- copy (MRS) to test brain metabolism in vivo (Meng et al. 2005; Trope et al. 1998, 2001; Weisskopf et al. 2004, 2007a). MRS is a noninvasive method of exam- ining the biochemical aspects of neurologic disease in vivo. The development of spatially localized spectroscopic methods that sample the relative levels of metabolites from the vol- ume of tissues defined from magnetic reso- nance imaging (MRI) scanning has provided the basis for integrating the biochemical Environmental Health Perspectives • volume 117 | number 6 | June 2009 information with anatomical information obtained from the MRI (Cox 1996; Ross et al. 2006). MRS has been used to assess both neuronal viability and demyelination (Burlina et al. 2000; Ross et al. 2006). Although its use for the study of neurologic diseases has grown rapidly over the past decade, its use for investigating environmental insult to human brains is quite new (Weisskopf et al. 2007a). Because brains of children are very vulner- able to lead exposure (Castellino et al. 1995), the brain metabolites of children exposed to high levels of lead have been found by MRS studies to have abnormalities (Meng et al. 2005; Trope et al. 1998, 2001). Recently, the Veterans Normative Aging Study, a community-based cohort of elderly U.S. men, reported an association between bone lead and increased myoinositol-to-creatine ratio in 31 people with a mean age of 77 years (Weisskopf et al. 2007a). However, to our knowledge, little research has used this approach on highly exposed adults such as lead workers. Thus, in this in vivo study we used MRS as well as traditional measures of lead levels and a survey, to study the effects of long-term lead exposure on brain metabolism in a group of lead workers and age- and sex- matched nonexposed controls. Materials and Methods Participants. We conducted this study in a lead paint factory, where workers were required by law to receive annual health examinations. We enrolled 22 lead-exposed workers and Address correspondence to H. Chuang, Department of Community Medicine, Kaohsiung Medical University Hospital, and Center of Excellence for Environmental Medicine, Kaohsiung Medical University, No. 100 Shih-Chuan First Rd., Kaohsiung City 807, Taiwan. Telephone: 886-7311-5974. Fax: 886-7311-5948. E-mail: ericch@kmu.edu.tw We express our sincere appreciation to the workers and employers for their cooperation. This work was supported by Taiwan National Science Council grant (NSC96-2314-B-037-049) and National Health Research Institutes grant (NHRI-CN-PD9611P). The contents of this article are the sole responsibil- ity of the authors and do not necessarily represent the official view of the National Health Research Institutes of Taiwan. The authors declare they have no competing financial interests. Received 14 September 2008; accepted 9 February 2009. 941