Background. In this PhD thesis were investigated the effects of polychlorinated biphenyls (PCBs) on primary human thyrocytes, focusing on the Aryl hydrocarbon receptor (AhR), a key transcriptional factor involved in xenobiotic response, and the nuclear factor erythroid-2 related factor 2 (Nrf-2)/ heme oxygenase-1 (HO-1) pathway, which plays a pivotal role against the oxidative stress. Methods. Primary human thyrocytes were cultured and exposed to the dioxin-like congeners PCB118 and PCB126 at 2.5 and 5µM concentrations. Real-time PCR was used to evaluate mRNA expression, Western Blot and ELISA were used to assess protein expression, and densitometric analysis was used to determine protein quantification. Results. PCB118 and PCB126 caused a significant (p < 0.01) rise in the mRNA and protein levels of the pro-inflammatory cytokines IL-1b and IL-6 in cultured thyrocytes. Furthermore, PCBs reduced thyroglobulin (TG) and NIS levels (p < 0.05), suggesting that these thyroid-specific genes were down-regulated in PCB-induced inflammation. Additionally, ROS production increased (p < 0.001). The activation of AhR and Nrf-2 pathways in response to PCB exposure is suggested by the increase in mRNA levels of AhR and the downstream molecules cytochrome P450 1A, Nrf-2/HO-1, and related protein levels (p < 0.001). Interestingly, AhR silencing reduced inflammatory cytokines and oxidative stress indicators (p< 0.05), restored sodium iodide symporter (NIS) and iodinated thyroglobulin (TG) expression, and decreased AhR-related gene expression. Conclusions. Dioxin-like PCBs (PCB118 and PCB126) may cause oxidative stress and inflammation in thyrocytes, affecting the expression of genes essential for thyroid function. The activation of the AhR and Nrf-2 pathways is partially related to these effects. These findings could help clarify the mechanisms behind PCB-induced thyroid toxicity, emphasizing the pollutants' possible function as an inducer of autoimmune thyroid inflammation and damage.

Polychlorinated Biphenyls (PCBs) Induced Oxidative Stress and Inflammation in Human Thyroid Cells: Role of AhR and NRF-2/HO-1 Signaling Pathways

MINUTI, AURELIO
2025-01-01

Abstract

Background. In this PhD thesis were investigated the effects of polychlorinated biphenyls (PCBs) on primary human thyrocytes, focusing on the Aryl hydrocarbon receptor (AhR), a key transcriptional factor involved in xenobiotic response, and the nuclear factor erythroid-2 related factor 2 (Nrf-2)/ heme oxygenase-1 (HO-1) pathway, which plays a pivotal role against the oxidative stress. Methods. Primary human thyrocytes were cultured and exposed to the dioxin-like congeners PCB118 and PCB126 at 2.5 and 5µM concentrations. Real-time PCR was used to evaluate mRNA expression, Western Blot and ELISA were used to assess protein expression, and densitometric analysis was used to determine protein quantification. Results. PCB118 and PCB126 caused a significant (p < 0.01) rise in the mRNA and protein levels of the pro-inflammatory cytokines IL-1b and IL-6 in cultured thyrocytes. Furthermore, PCBs reduced thyroglobulin (TG) and NIS levels (p < 0.05), suggesting that these thyroid-specific genes were down-regulated in PCB-induced inflammation. Additionally, ROS production increased (p < 0.001). The activation of AhR and Nrf-2 pathways in response to PCB exposure is suggested by the increase in mRNA levels of AhR and the downstream molecules cytochrome P450 1A, Nrf-2/HO-1, and related protein levels (p < 0.001). Interestingly, AhR silencing reduced inflammatory cytokines and oxidative stress indicators (p< 0.05), restored sodium iodide symporter (NIS) and iodinated thyroglobulin (TG) expression, and decreased AhR-related gene expression. Conclusions. Dioxin-like PCBs (PCB118 and PCB126) may cause oxidative stress and inflammation in thyrocytes, affecting the expression of genes essential for thyroid function. The activation of the AhR and Nrf-2 pathways is partially related to these effects. These findings could help clarify the mechanisms behind PCB-induced thyroid toxicity, emphasizing the pollutants' possible function as an inducer of autoimmune thyroid inflammation and damage.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11570/3322193
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