Salivary endothelin and vascular disorders in vibration-exposed workers.

OBJECTIVES: This study investigated the relation between salivary endothelin, vibration exposure, and vascular disorders in a group of forestry workers. METHODS: Altogether 54 forestry workers and 52 controls underwent a medical examination and a cold test with measurement of the percentage of change in finger systolic blood pressure after finger cooling from 30 degrees C to 10 degrees C (FSBP% (10 degrees)). Salivary endothelin concentration (ET(1-21), in fmol/ml) was measured by a commercially available enzyme-linked immunosorbent assay before and after the cold challenge. The anamnestic diagnosis of vibration-induced white finger (VWF), assisted by color charts, was based on the Stockholm Workshop criteria. RESULTS: Six forestry workers (11%) and one control (2%) reported white fingers. Before the cold challenge, the salivary ET(1-21) concentration was significantly greater in the VWF workers than in the controls (P=0.036). The cold response of digital arteries was stronger in the VWF workers than in the controls (P<0.001) and the asymptomatic forestry workers (P=0.008). After the cold test, there was a small, not significant, increase in the salivary ET(1-21) concentration in both the controls and the forestry workers. For the latter, the salivary ET(1-21) concentration was significantly associated with both daily and total operating time with vibrating tools. A significant inverse relation between FSBP% (10 degrees )and the salivary ET(1-21) concentration was observed for the forestry workers with an abnormal cold response in their digital arteries. CONCLUSIONS: This study showed an association between salivary ET(1-21) concentration, daily and cumulative vibration exposure, and vascular disorders in the fingers of professional forestry workers. Since ET(1-21) can induce powerful and long-lasting constriction of human vessels, these findings suggest a possible role of this vasopeptide in the pathogenesis of VWF.

Long-term exposure to occupational noise alters the cortical organization of sound processing.

OBJECTIVE: Long-term exposure to noise may cause an altered hemispheric lateralization of speech processing even in silent conditions. We examined whether this lateralization shift is speech specific or occurs also for other sounds. METHODS: Brain responses from 10 healthy noise-exposed workers (>5 years) and 10 matched controls were recorded with a 32-channel electroencephalogram in two conditions, one including standard and deviant speech sounds, the other non-speech sounds, with novel sounds in both. RESULTS: The deviant-sound elicited mismatch negativity (MMN) was larger to non-speech than speech sounds in control subjects, while it did not differ between the sound types in the noise-exposed subjects. Moreover, the MMN to speech sounds was lateralized to the right hemisphere in exposed workers, while it was left-hemisphere predominant in control subjects. No group topography difference was found for non-speech sounds. The deviant sounds that were close in formant space to the standards elicited a longer MMN latency in both speech and non-speech conditions in exposed subjects than controls. No group differences were found for cortical responses to novel sounds. CONCLUSIONS: Long-term noise exposure altered the strength and the hemispheric organization of speech-sound discrimination and decreased the speed of sound-change processing. SIGNIFICANCE: Subpathological changes in cortical responses to sounds may occur even in subjects without a peripheral damage but continuously exposed to noisy auditory environments.

Subcytotoxic mercury chloride inhibits gap junction intercellular communication by a redox- and phosphorylation-mediated mechanism.

Gap junctions play a central role in coordinating intercellular signal-transduction pathways to control tissue homeostasis. Deregulation of gap junctional intercellular communication is a common phenotype of cancer cells and supports its involvement in the carcinogenesis process. Many carcinogens, like environmental heavy-metal chemical pollutants, are known to activate various signal transduction mechanisms and modulate GJIC. They act as tumor promoters on preexisting "initiated" cells, rather than as genotoxic initiators, albeit their mode of action is often unknown. In this study we investigated the effect of Hg(II) (HgCl(2)) on GJIC in cultured human keratinocytes. It is shown that subcytotoxic concentrations of HgCl(2) as low as 10 nM cause inhibition of the GJIC, assessed by dye transfer assay, despite enhanced expression of connexins. In addition, HgCl(2)-treated keratinocytes exhibited a decrease of free thiols and accumulation of mitochondria-derived reactive oxygen species, albeit no effect on the respiratory chain activity was observed. Treatment of HgCl(2)-exposed keratinocytes with the PKC inhibitor calphostin C and with all-trans retinoic acid resulted in rescue of the mitochondrial ROS overproduction and full recovery of the GJIC. Similar results were obtained with the PKA activator db-cAMP. Overall, the presented results support a cross-talk between the altered intracellular redox tone and PKA- and PKC-mediated signaling in HgCl(2)-challenged keratinocytes. These events, although not cytotoxic, lead to inhibition of GJIC and possibly to carcinogenic priming.

Mercury modulates interplay between IL-1beta, TNF-alpha, and gap junctional intercellular communication in keratinocytes: mitigation by lycopene.

Gap junctional intercellular communication (GJIC) is used to control cell proliferation. It is not surprising then that a lack of GJIC (i.e., during loss of contact inhibition among adjacent cells) is associated with cancer promotion/progression. There also seems to be a link between ineffective GJIC and increases in inflammatory events. Interestingly, many cytokines released during an inflammatory response also have critical roles in cancer cell survival. Specifically, TNFalpha and IL-1beta are important for initiating/augmenting CD8(+)- and NK-cell mediated killing; however, in what appears counterintuitive, each--at times--can act to protect cancer cells against apoptosis, a major mechanism for cell killing from within. It is thus plausible to assume that certain toxicants might act as cancer promoters in manners distinct from/augmentive of direct effects on DNA, i.e., by concurrently altering GJIC and cytokine formation in host or microenvironment of a cancer cell. Our research has evaluated effects of many toxicants upon keratinocytes; in particular, we have examined effects of mercury on GJIC and on TNFalpha and IL-1beta levels in (and secretion by) these cells. In the studies here, a tomato preparation (i.e., an oleoresin) bearing the antioxidant carotenoid lycopene was examined for its effects on GJIC and cytokine formation by keratinocytes in general, and its potential ability to mitigate/reverse the toxic effects of mercury in the cells in particular. It was shown that a 4-hr treatment with the oleoresin (containing 56, 6 nM lycopene) re-established GJIC among--and increased the formation of IL-1beta and TNFalpha that had been significantly reduced within--keratinocytes that had been pre-treated for 24 hr with 10 nM HgCl(2). These results show that effects of mercury likely depend on some level of oxidative stress and that its potential effects on keratinocyte GJIC and cytokine concentrations could, in an exposed host, be mitigated/reversed by increased dietary intake of carotenoids like lycopene.

In vivo assessment of epichlorohydrin effects: the chorioallantoic membrane model.

BACKGROUND: Previous studies on the effects of the epichlorohydrin (ECH) epoxide demonstrated this compound's toxicity and mutagenicity and suggested a carcinogenic activity also in humans. To gain a better understanding of ECH effects in vivo, the substance was tested on developing tissues utilizing the chick embryo chorioallantoic membrane (CAM) assay. MATERIAL/METHODS: Gelatin sponges adsorbed with ECH were implanted onto nine-day CAMs. After five days the membranes were fixed, cut in serial sections, and stained with toluidine blue. Sections of the ECH-treated CAMs were also submitted to immunocytochemistry for the basal lamina glycoprotein laminin and the gap junction protein connexin 43 (Cx43). Control CAMs were treated with saline solution and submitted to identical procedures. RESULTS: ECH-treated CAMs displayed proliferation of both the epithelial layers and the mesenchyme cells and vessels. The laminin immunolabeling was interrupted beneath the ectoderm thickenings, which penetrated the mesenchyme. The endoderm showed papilloma-like formations and its laminin-positive basal membrane protruded toward the mesenchyme, together with clusters of endodermal cells. The mesenchyme showed increased numbers of cells and microvessels. These reactions were restricted to regions corresponding to the implant. Cx43 expression was strongly decreased in the ECH-treated CAMs compared with the controls, where the connexin punctate pattern regularly decorated the epithelial cell contours. CONCLUSIONS: The study confirms that ECH elicits tissue proliferation at the contact site and corroborates the suggestion of an ECH carcinogenic effect due to hallmarks of tumoral growth, such as angiogenesis, basal membrane alterations, and loss of intercellular communication via gap junctions.