Serum Clara-Cell Protein and β₂-Microglobulin as Early Markers of Occupational Exposure to Nitric Oxides

Abstract

Biochemical effects of NOx on 60 workers (both genders) of nitric acid production were studied. The control group consisted of 61 nonexposed people employed elsewhere in the plant. Although the actual threshold limit valuetime weighted averages (TLV-TWA) were not exceeded in the specific conditions of our study, the subjects were exposed to NO2 and NO during several exposure episodes with peak maximal concentrations of 140 ppm and 515 ppm, respectively. Additional cross-week evaluation of several biochemical biomarkers in 15 NOx-exposed workers from one shift was performed. The objective of the study was to evaluate the value of serum Clara-cell protein (CC16) as a marker of bronchoalveolar epithelium activity. Antioxidant status was assessed by measuring activity of enzymes: glutathione peroxidase (GSH-Px), ceruloplasmin (Cp) in plasma, or superoxide dismutase (SOD), gluthatione S-transferase (GST), and nonenzymatic alpha-tocopherol in erythrocytes and thiobarbituric acid-reactive substances (TBARS) in plasma. Serum hyaluronic acid (HA) determining the connective tissue matrix status of airways, and beta2-microglobulin in serum (beta2M-S) and urine (beta2M-U) as a marker of renal function in occupational exposure to NOx were also employed. Exposure to NOx initiates peroxidative chain depleting of lipoprotein pool (alpha-tocopherol) in blood. Serum CC16 levels in NOx-exposed workers were found to be closely connected with alpha-tocopherol content. In NOx-exposed workers, the beta2M-S level was significantly higher than in the nonexposed ones, with the exception of smokers. Results of the cross-week study confirm cumulative systemic effects of NOx on several examined biomarkers. SOD and GST were found to be depleted. A transient higher level of HA after a 5-d shift significantly inversely correlated with CC16 level. The data imply that NOx-depleted levels of CC16 are detectable already after an 8-h shift. Our results demonstrate that even low NOx human exposure can cause characteristic changes in bronchiolar epithelium cells and renal effects. Serum CC16 level, although a nonspecific marker, was lowest in NOx-exposed subjects. The most sensitive parameters in exposed workers were beta2M-S and a-tocopherol. Spirometric assessment was not useful to describe low occupational exposure to NOx. In studying the effects of NOx on biomarkers, it is essential to carefully select suitable time of sampling. Screening of CC16, beta2M-S, and a-tocopherol can be successfully employed for biological monitoring of exposure to NOx.

Serum Clara Cell Protein as an Indicator of Pulmonary Impairment in Occupational Exposure at Aluminum Foundry

“…Linear regression analysis (Table 5), eliminating the effects of respective confounding factors (e.g., age, tobacco smoking) shows that CC16 and Al-S correlation was very strong (p = 0.006). It should be noted that this close relation supports the opinion that both markers (Al-S and CC16) are related, at least in part, to the daily fluctuation as already observed in cross-week CC16 evaluation in blood of shipyard welders and workers of a chemical plant exposed to nitric oxide [21,22]. Thus, inhibition of Clara cell protein secretion in smelters heavily exposed to Al can probably enhance Al-S levels by suppressing anti-inflammatory effect in the respiratory tract.…”

“…As a cell-specific marker for non-ciliated bronchiolar epithelial cells, which play a part in immunomodulatory and/or anti-inflammatory processes, assessment of Clara cell protein in serum (CC16) was proposed by various authors [14][15][16][17]. Recent studies on humans and rats have shown that CC16 is a sensitive biomarker of respiratory epithelial injury in exposures to welder fumes, glutaraldehyde, nitric oxides, or Al foundry dusts [18][19][20][21][22][23]. Clara cell proteins are involved in the pathogenic mechanisms leading to fibrosis [15,24], chronic obstructive pulmonary disease (COPD) [25,26], and asthma in humans [27][28][29] and in murine asthma model [30,31].…”

Early biomarkers of cadmium exposure and nephrotoxicity

“…For example, urinary metallothionein and Cd are markers of Cd exposure as well as proximal tubular injury, and identifying the critical levels to indicate the onset of injury has been problematic (Chen et al 2006b;Nakajima et al 2005;Shaikh and Tohyama 1984;Shaikh and Smith 1986;Shaikh et al 1990;Suwazono et al 2006). Moreover, the urinary excretion of proteins such as b 2 -microglobulin can be influenced by actions of toxicants on organs other than the kidney (Halatek et al 2005;Hantson et al 2008;Roels et al 1999). Most significantly, these markers only identify later stages of Cd-induced kidney injury.…”

“…In addition, urinary levels of some markers may be influenced by toxic actions of Cd on organs other than the kidney. For example, as the invariant light-chain component of class I major histocompatibility antigens, b 2 microglobulin is derived from many tissues, and serum levels of the protein can be influenced by pathologic processes in a variety of organs (Broeckaert et al 2000;Halatek et al 2005;Kobryn et al 1989;Poulik et al 1979).While an argument can be made that this lack of organ specificity could actually be desirable for biomonitoring the effects of a substance, such as Cd, that can affect multiple organ systems, this same lack of organ specificity can greatly complicate the use of the biomarker for mechanistic studies. For these reasons, any interpretation of results with any biomarkers must include some reference to levels of Cd in blood, tissues and/or urine.…”

Prognostic significance of low serum levels of Clara cell phospholipid-binding protein in occupational aluminium neurotoxicity

“…As a cell-specific marker for nonciliated bronchiolar epithelial Clara cells, which play a part in immunomodulatory and/or antiinflammatory processes, assessment of Clara cell protein in serum (CC16) was proposed by various authors [6,7]. Recent studies have shown that CC16 is a sensitive biomarker of respiratory epithelial injury in exposures of humans and animals to welder fumes [8], nitric oxides [9], glutaraldehyde [10], or low CC16 levels in serum were noted in active smokers [11,12] and in silicaexposed workers [13].…”