Effects of human blood levels of two PAH mixtures on the AHR signalling activation pathway and CYP1A1 and COMT target genes in granulosa non-tumor and granulosa tumor cell lines

Autor: Adam Grochowalski, Karolina Zajda, Elżbieta Fiedor, Ewa L. Gregoraszczuk, Agnieszka Rak, Anna Ptak, Tomasz Milewicz
Rok vydání: 2017
Předmět:
0301 basic medicine
Time Factors
Aryl hydrocarbon receptor nuclear translocator
Transcription
Genetic
proliferation
Repressor
Apoptosis
Aryl hydrocarbon receptor repressor
010501 environmental sciences
Catechol O-Methyltransferase
Toxicology
01 natural sciences
Gene Expression Regulation
Enzymologic
03 medical and health sciences
Cell Line
Tumor
Basic Helix-Loop-Helix Transcription Factors
Cytochrome P-450 CYP1A1
polycyclic compounds
Humans
RNA
Messenger
Polycyclic Aromatic Hydrocarbons
polycyclic aromatic hydrocarbons mixture
Carcinogen
Cell Proliferation
Granulosa Cell Tumor
0105 earth and related environmental sciences
Ovarian Neoplasms
Granulosa Cells
Catechol-O-methyl transferase
biology
Cell growth
Chemistry
Aryl Hydrocarbon Receptor Nuclear Translocator
apoptosis
Cytochrome P450
respiratory system
Fetal Blood
Aryl hydrocarbon receptor
Molecular biology
Gene Expression Regulation
Neoplastic
Repressor Proteins
030104 developmental biology
Receptors
Aryl Hydrocarbon
Biochemistry
acid phosphatase
granulosa and granulosa tumor cell lines
biology.protein
Female
aryl hydrocarbon receptor signalling pathway
Zdroj: Toxicology. 389:1-12
ISSN: 0300-483X
Popis: Epidemiological studies have shown a link between problems with offspring of couples living in a contaminated environment in comparison to those who live in an uncontaminated environment. We measured the concentrations of 16 priority polycyclic aromatic hydrocarbons (PAHs) in maternal and cord blood. To explore the mechanism of the effects of PAH mixtures on nonluteinized granulosa cells (HGrC1) and granulosa tumor cells (COV434), as well as cell proliferation and apoptosis, we investigated the effect of PAH mixtures on the expression of the aryl hydrocarbon receptor (AHR), aryl hydrocarbon receptor nuclear translocator (ARNT) and aryl hydrocarbon receptor repressor (AHRR) genes, as well as the expression and activity of target genes cytochrome P450 1A1 (CYP1A1) and catechol-O-methyltransferase (COMT). The cells were exposed to mixture 1 (M1), composed of all 16 priority PAHs, and mixture 2 (M2), composed of five PAHs which are not classified as human carcinogens, and which are observed in the highest amounts both in maternal and cord blood. All 16 priority PAHs were bioavailable in maternal and cord plasma, suggesting that perinatal exposure should be considered. In HGrC1 cells, M1 increased AHR and ARNT, but decreased AHRR expression, in parallel with increased CYP1A1 and COMT expression and activity. M2 decreased AHR and AHRR, and increased ARNT, with no effect on CYP1A1 expression and activity; however, it did increase COMT expression and activity. In tumor cells, M1 lowered AHR and up-regulated AHRR and ARNT expression, consequently decreasing CYP1A1 expression and COMT activity. M2 up-regulated AHR and ARNT, down-regulated AHRR, and had no effect on CYP1A1 and COMT expression, but decreased COMT activity. We hypothesise that, dependent on composition, mixtures of PAHs activate the AHR differently through varying transcription responses: in HGrC1, a canonical AHR mechanism of M1, with activation of CYP1A1 important for detoxication, while in COV434, a noncanonical AHR mechanism, probably by activation the nuclear factor NFkB.
Databáze: OpenAIRE
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