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BACKGROUND:Manganese (Mn) and iron (Fe) are the primary elements of welding rods. Mn has been shown to increase prolactin (PRL) production by decreasing dopamine (DA) levels in the hypothalamus. However, Fe increases DA levels and decreases PRL levels. The toxic mechanism of Mn and Fe co-inhalation-induced regulation of the hypothalamic-hypophyseal-pituitary axis remains unclear. OBJECTIVE:To evaluate the effects of co-inhaled Mn and Fe on hypothalamic DA levels and pituitary PRL production, to investigate whether these changes are reversible, and to determine the role of co-inhaled Mn and Fe. DESIGN, TIME AND SETTING:A randomized, controlled, animal experiment based on inhalation toxicity via whole-body exposure was performed. Hypothalamic DA levels, serum PRL, and PRL and Pit-1 mRNA levels were analyzed at the Institute of Environmental and Occupational Medicine, Inje University, Busan, Korea, from August 2007 to May 2009. MATERIALS:MnSO4 and FeSO4 were purchased from Sigma-Aldrich, St. Louis, MO, USA. High-performance liquid chromatography (HPLC) using an electrochemical detector (ECD) was purchased from Waters Corporation, Milford, MA, USA. mRNA Capture Kit and reverse transcription-polymerase chain reaction (RT-PCR) kit were obtained from Roche Molecular Biochemicals, Mannheim, Germany and Perkin-Elmer, Wellesley, MA, USA, respectively. Rat PRL enzyme-linked immunosorbent assay kit was purchased from Biocode Hycel, Liege, Belgium. METHODS:Eighty 15-week-old, male, Fischer 344 rats were assigned to two groups:one group treated with Mn and Fe and a control group. Each group was sub-divided into four groups on the basis of treatment period (0- and 13-week treated groups with both chemicals) and recovery periods (4- and 13-week recovery groups following 13-week exposure to both chemicals). The treatment condition was 6 hours per day, 5 days per week, for the entire body. Mn and Fe co-inhalation concentrations were 1.5 mg/m3 and 3.0 mg/m3, respectively.MAIN OUTCOME MEASURES:Hypothalamic DA levels were measured using HPLC-ECD analysis. mRNA levels of PRL and Pit-1 were analyzed by Northern blot hybridization and RT-PCR, respectively. Serum PRL levels were measured by enzyme-linked immunosorbent assay.RESULTS:HPLC-ECD analysis revealed that following 13-week co-inhalation of Mn and Fe, hypothalamic DA levels significantly deceased, whereas pituitary PRL mRNA, Pit-1 mRNA, and serum PRL levels significantly increased. At 4 weeks of recovery, DA level in the hypothalamic tissue was significantly increased, and PRL and Pit-1 mRNA levels in the pituitary were significantly decreased. After 13 weeks of recovery, DA and PRL levels recovered to normal. The changing pattern of serum PRL levels was in accordance with pituitary PRL mRNA levels.CONCLUSION:Subchronic co-inhalation of Mn and Fe significantly decreased hypothalamic DA levels, but induced pituitary PRL production, both of which were mediated by Pit-1. These results suggested that Mn dominates over Fe in terms of hypothalamic DA levels and pituitary PRL production, and these effects are reversible in a subchronic inhalation condition. Therefore, changes in hypothalamic DA levels and serum PRL production could be used as biomarkers for welders, who are exposed to Mn and Fe.