Effect of low-dose tungsten on human thyroid stem/precursor cells and their progeny

Abstract

Thyroid cancer incidence is increased in volcanic areas where environment pollution biocontaminates residents. Tungsten (W) is the most increased heavy metal in drinking water of Mount Etna volcanic area where it exceeds the normal range in the urine of 27% inhabitants. The possible connection between increased tungsten and thyroid cancer has never been studied. We investigated in vitro the effect tungsten on both human thyrocytes in primary culture, thyrospheres (aggregates of stem/precursor thyroid cells) and thyrocytes differentiated from tungsten-exposed thyrospheres. Chronic exposure to low-dose (nanomolar range, as in the urines of volcanic area residents) soluble tungsten had major biological effects on thyroid stem/precursor cells, promoting growth with a biphasic (hormetic) dose-response and reducing apoptosis. No such effects were observed in mature thyrocytes. In addition, tungsten-exposed thyrospheres had abnormal expression of genes commonly altered also in thyroid cancer and increased activation of the DNA-repair proteins H2AX and 53BP1. Moreover, exposure to tungsten decreased thyrosphere differentiation, as indicated by the reduced expression of thyroid-specific genes in derived thyrocytes that also showed preneoplastic changes such as increased anchorage-independent growth, clonogenic growth and migration capacity. The mechanism of action of tungsten on thyroid stem/precursor cells is unclear but involves membrane G-proteins and activation of the ERK signaling pathway. These data indicate that chronic exposure to slightly increased tungsten, harmless for mature thyrocytes, importantly affects the biology of stem/precursor thyroid cells and of their progeny, inducing characteristics of preneoplastic transformation.

Heavy Metals in the Environment and Thyroid Cancer

“…In vitro chronic exposure of human thyrospheres to nanomolar concentrations of soluble W in the chemical form of sodium tungstate dehydrate (Na 2 WO 4 2H 2 O) not only stimulated proliferation (as already shown in Table 1), but had the following effects [61]:…”

Thyroid Stem Cells But Not Differentiated Thyrocytes Are Sensitive to Slightly Increased Concentrations of Heavy Metals

“…To investigate the mechanism involved in the metal-induced growth in human thyrospheres, we measured the extracellular signal-regulated protein kinase phosphorylation (ERK1/2), a pathway that is already reported to be activated by cell exposure to metals ( 17 , 21 – 24 ).…”

“…Immature thyroid cells, therefore, may suffer cytotoxic damage from metal concentrations that are not unhealthy for well-differentiated thyrocytes. If progenitors exposed to such a low dose of metals produce a progeny of mature thyroid cells prone to transformation (17,(30)(31)(32), this process could favor an increased incidence of thyroid cancer in the population.…”

“…The isolation and culture of human thyroid cells were performed as previously reported ( 17 ). Briefly, after the meticulous removal of fibrous tissue, the just excised fresh thyroid tissue was first minced with sterile scissors and then digested with collagenase IV (1 mg/ml, Sigma-Aldrich) for 2 h at 37°C.…”

“…Finally, another possibility is that cells at a lower level of differentiation, such as embryonic cells, may be more sensitive to the detrimental effects of metals ( 16 ). We recently documented that tungsten, at concentrations in the range of values measured in the urine of residents from the volcanic area, promoted proliferation, inhibited apoptosis and induced the characteristics of a transformed phenotype in human thyroid stem/precursor cells but not in differentiated thyrocytes ( 17 ). These data indicate that a small increase in tungsten in the culture medium, which is harmless for differentiated thyrocytes, can affect the biology of stem/precursor thyroid cells, inducing the characteristics of pre-neoplastic transformation.…”