Epidemiological observations indicate an increased incidence of thyroid cancer in volcanic areas where volcano-originated, low-level, multi-elemental metal pollution contaminates the residents. For most of these metals, no data are available regarding their effect on the thyroid gland. This thesis aims to explore the relationship between heavy metal biocontamination and thyroid cancer and further investigate the potential mechanisms involved. According to these considerations, two independent experimental approaches were carried out using human thyroid tissues. 1) Ex-vivo: thyroid tissue levels of twenty-five metals were compared to the values measured in the muscle and adipose tissue of the same euthyroid individuals to evaluate tissue-specific metal accumulation. Tissue specimens were also obtained from normal rats. The content of As, Br, Cd, Hg, Mn, Se, and Sn was significantly (p < 0.01) higher in thyroid tissue compared to those measured in the sternothyroid muscle and the subcutaneous neck fat tissue of the same individual. In parallel experiments, concentrations of As, Br, Cu, Hg, Mn, Se, and Zn were higher in the thyroid of Wistar rats relative to the muscle (hindlimb) and adipose tissue (abdomen visceral fat). Many heavy metals increased in the thyroid of residents of the volcanic area relative to subjects living in adjacent non-volcanic areas. These differences, however, were not statistically significant. 2) In vitro: the effects of five heavy metals (Cu, Hg, Pd, W and Zn) at the nanomolar concentration, similar to the biocontamination level in residents of the volcanic area in Sicily, were investigated on both undifferentiated (thyrospheres) and mature human thyroid cells. Each metal was examined as a single component as well as their mixture to obtain information on the multi-elemental effect which better reflects the condition observed in the volcanic area. Thyrospheres chronically exposed to different metals show a biphasic increase in proliferation typical of hormesis. The molecular mechanisms include, for all metals investigated, the activation of the extracellular signal-regulated kinase (ERK1/2) pathway. A metal mixture, at the same concentration of individual metals, was more effective. Under the same conditions, mature thyrocytes were unaffected. These studies provide new insight into the association between heavy metals biocontamination and thyroid cancer, including (a) the metal accumulation in the thyroid gland relative to other tissues; (b) the hormesis as the nonlinear response to chemicals causing important biological effects at low concentrations; and (c) the specific effects of a mixture of different metals.
Osservazioni epidemiologiche indicano un aumento dell’incidenza del carcinoma tiroideo nelle aree vulcaniche, dove bassi livelli di inquinamento da metalli pesanti contaminano i residenti. Per la maggior parte di questi metalli non sono disponibili dati relativi al loro effetto sulla ghiandola tiroidea. Questa tesi si propone di esplorare la relazione tra la biocontaminazione da metalli pesanti e cancro della tiroide e indagare ulteriormente i potenziali meccanismi coinvolti. In base a queste considerazioni, sono stati condotti due approcci sperimentali indipendenti utilizzando tessuti tiroidei umani. 1) Ex-vivo: i livelli di venticinque metalli nel tessuto tiroideo sono stati confrontati con i valori misurati nel tessuto muscolare e adiposo degli stessi individui eutiroidei al fine di valutare l'accumulo di metalli tessuto-specifico. Sono stati ottenuti anche campioni di tessuto da ratti normali. Il contenuto di As, Br, Cd, Hg, Mn, Se e Sn era significativamente (p <0,01) più alto nel tessuto tiroideo rispetto a quello misurato nel muscolo sternotiroideo e nel tessuto adiposo sottocutaneo del collo dello stesso individuo. In esperimenti paralleli, le concentrazioni di As, Br, Cu, Hg, Mn, Se e Zn erano più elevate nella tiroide dei ratti Wistar rispetto al muscolo (arto posteriore) e al tessuto adiposo (grasso viscerale dell'addome). Molti metalli pesanti sono aumentati nella tiroide dei residenti dell'area vulcanica rispetto ai soggetti che vivono in aree adiacenti non vulcaniche. Queste differenze, tuttavia, non erano statisticamente significative. 2) In vitro: sono stati studiati gli effetti di cinque metalli pesanti (Cu, Hg, Pd, W e Zn) alla concentrazione nanomolare, simile al livello di biocontaminazione nei residenti dell'area vulcanica in Sicilia, sia in cellule tiroidee umane indifferenziate (tireosfere) che mature. Ogni metallo è stato esaminato sia singolarmente che in combinazione con gli altri elementi per ottenere informazioni sull'effetto multielemento che riflette meglio la condizione osservata nell'area vulcanica. Le tireosfere esposte cronicamente ai diversi metalli mostrano un aumento bifasico della proliferazione tipico dell'ormesi. I meccanismi molecolari includono, per tutti i metalli studiati, l'attivazione della via della chinasi regolate da segnali extracellulari (ERK1/2). La miscela dei metalli, alla stessa concentrazione dei singoli metalli, era più efficace. Nelle stesse condizioni, nessun effetto è stato osservato nei tireociti maturi. Questi studi forniscono nuove informazioni sull'associazione tra biocontaminazione da metalli pesanti e cancro della tiroide, quali (a) l'accumulo di metalli nella ghiandola tiroidea rispetto ad altri tessuti; (b) l'ormesi come risposta non lineare a sostanze chimiche che causano importanti effetti biologici a basse concentrazioni; e (c) gli effetti specifici della miscela di cinque diversi metalli.
Carcinoma tiroideo, ambiente vulcanico e metalli pesanti / Giani', Fiorenza. - (2022 Dec 20).
Carcinoma tiroideo, ambiente vulcanico e metalli pesanti
GIANI', FIORENZA
2022-12-20
Abstract
Epidemiological observations indicate an increased incidence of thyroid cancer in volcanic areas where volcano-originated, low-level, multi-elemental metal pollution contaminates the residents. For most of these metals, no data are available regarding their effect on the thyroid gland. This thesis aims to explore the relationship between heavy metal biocontamination and thyroid cancer and further investigate the potential mechanisms involved. According to these considerations, two independent experimental approaches were carried out using human thyroid tissues. 1) Ex-vivo: thyroid tissue levels of twenty-five metals were compared to the values measured in the muscle and adipose tissue of the same euthyroid individuals to evaluate tissue-specific metal accumulation. Tissue specimens were also obtained from normal rats. The content of As, Br, Cd, Hg, Mn, Se, and Sn was significantly (p < 0.01) higher in thyroid tissue compared to those measured in the sternothyroid muscle and the subcutaneous neck fat tissue of the same individual. In parallel experiments, concentrations of As, Br, Cu, Hg, Mn, Se, and Zn were higher in the thyroid of Wistar rats relative to the muscle (hindlimb) and adipose tissue (abdomen visceral fat). Many heavy metals increased in the thyroid of residents of the volcanic area relative to subjects living in adjacent non-volcanic areas. These differences, however, were not statistically significant. 2) In vitro: the effects of five heavy metals (Cu, Hg, Pd, W and Zn) at the nanomolar concentration, similar to the biocontamination level in residents of the volcanic area in Sicily, were investigated on both undifferentiated (thyrospheres) and mature human thyroid cells. Each metal was examined as a single component as well as their mixture to obtain information on the multi-elemental effect which better reflects the condition observed in the volcanic area. Thyrospheres chronically exposed to different metals show a biphasic increase in proliferation typical of hormesis. The molecular mechanisms include, for all metals investigated, the activation of the extracellular signal-regulated kinase (ERK1/2) pathway. A metal mixture, at the same concentration of individual metals, was more effective. Under the same conditions, mature thyrocytes were unaffected. These studies provide new insight into the association between heavy metals biocontamination and thyroid cancer, including (a) the metal accumulation in the thyroid gland relative to other tissues; (b) the hormesis as the nonlinear response to chemicals causing important biological effects at low concentrations; and (c) the specific effects of a mixture of different metals.File | Dimensione | Formato | |
---|---|---|---|
Fiorenza Giani PhD thesis.pdf
accesso aperto
Tipologia:
Tesi di dottorato
Licenza:
PUBBLICO - Pubblico con Copyright
Dimensione
3.2 MB
Formato
Adobe PDF
|
3.2 MB | Adobe PDF | Visualizza/Apri |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.