ECE2023 Oral Communications Oral Communications 12: Environmental Endocrinology (8 abstracts)
1University of Messina, Dept Biomedical and Dental Sciences, and Morpho-Functional Images, Messina, Italy; 2University of Messina, Deot Biomedical and Dental Sciences, and Morphofunctional Images, Messina, Italy; 3University of Catania, Dept Clinical and Experimental Medicine, Catania, Italy; 4University of Messina, Department of Human Pathology of Adulthood and Childhood DETEV, Messina, Italy; 5University of Messina, Dept Clinical and Experimental Medicine, Messina, Italy
Background: PCBs are chemical pollutants able to promote inflammation and carcinogenesis. They can accumulate in human tissues through the food chain causing a variety of adverse health effects. The NF-E2 p45-related factor 2 (NRF2) and the aryl hydrocarbon receptor (AHR) are ligand activated transcription factors controlling pathways modulating xenobiotic metabolism. Increasing evidence indicate the involvement of AhR in regulating extracellular matrix (ECM) homeostasis. ECM is a complex network of multidomain macromolecules. Endothelial cell-specific molecule 1 (ESM-1), a soluble dermatan sulfate proteoglycan, also known as endocan, is up-regulated in different pathological conditions, including cancer, driving tumor progression, tumor vascularization and metastasis. In the landscape of non-coding RNAs, the long-non coding RNAs (>200 nucleotides) are a new class of epigenetic regulators that play a key role in homeostatic and pathological mechanisms, especially in cancer.
Purpose: The present study was aimed at investigating the effects of dioxin-like pentachlorobiphenyls (PCBs) on aryl hydrocarbon receptor (AHR)/nuclear factor erythroid 2 related factor 2 (NRF-2) pathway and related long noncoding RNAs (lncRNAs) and endothelial cell-specific molecule 1 (ESM-1) in thyrocytes.
Methods: Primary human thyrocytes were exposed to increasing doses (5 and 10 µM) of 2,3′,4,4′,5-pentachlorobiphenyl (PCB-118) and 3,3′,4′,4′,5 pentachlorobiphenyl (PCB-126) for 24 h. Cell culture and medium were collected to assess: mRNA levels of AHR, NRF-2, CYP1A1, lncRNAs (HOTAIR, MALAT-1, MEG-3), ESM-1, metalloproteinases (MMP) -3, MMP-9 and IL-1β by qPCR; protein levels of AHR and ESM-1 by western blot and ELISA, and ROS production by a commercial kit.
Results: Treatment with PCB-126 and PCB-118 at both doses after 24 h significantly increased mRNA levels of AHR, NRF-2, CYP1A1, MMP-3, MMP-9, IL-1β and intracellular ROS accumulation. Furthermore, PCBs, especially PCB-118, enhanced ESM-1, HOTAIR and MALAT-1 expression and reduced MEG-3 mRNA levels. Furthermore, AHR and ESM-1 protein levels increased after PCB-126 and PCB-118 exposure at both concentrations in a dose dependent manner.
Discussion: Our data demonstrated that PCB-118 and PCB-126 may induce AHR/NRF-2 pathway activation with a consequent ROS production and inflammatory responses in thyrocytes. This condition led to an increase in ESM-1, a circulating proteoglycan involved in angiogenesis and overexpressed in several tumors, and MMP-3 and MMP-9 that cause ECM remodeling. Furthermore, PCBs can induce epigenetic modifications by increasing lncRNAs MALAT-1 and HOTAIR expression and reduce anti-oncogenic lncRNA MEG3.
Conclusion: These results suggest new mechanisms underlying toxic effects of PCBs exposure on thyrocytes, indicating ESM-1 and lncRNAs as putative key factors of thyroid tumorigenesis.