Zajda Karolina, Ptak Anna, Rak Agnieszka, Fiedor Elżbieta, Grochowalski Adam, Milewicz Tomasz, Gregoraszczuk Ewa L
Department of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Kraków, Poland.
Krakow University of Technology, Chemistry Department, Kraków, Poland.
Toxicology. 2017 Aug 15;389:1-12. doi: 10.1016/j.tox.2017.07.003. Epub 2017 Jul 11.
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.
流行病学研究表明，与生活在未受污染环境中的夫妇相比，生活在受污染环境中的夫妇其后代出现问题的情况之间存在关联。我们测量了母体血液和脐带血中16种优先多环芳烃（PAHs）的浓度。为了探究PAH混合物对非黄体化颗粒细胞（HGrC1）和颗粒细胞瘤细胞（COV434）的影响机制，以及细胞增殖和凋亡情况，我们研究了PAH混合物对芳烃受体（AHR）、芳烃受体核转运蛋白（ARNT）和芳烃受体阻遏蛋白（AHRR）基因表达的影响，以及对靶基因细胞色素P450 1A1（CYP1A1）和儿茶酚-O-甲基转移酶（COMT）的表达和活性的影响。将细胞暴露于由所有16种优先PAHs组成的混合物1（M1）和由五种未被归类为人类致癌物且在母体血液和脐带血中含量最高的PAHs组成的混合物2（M2）中。所有16种优先PAHs在母体血浆和脐带血浆中都具有生物可利用性，这表明应考虑围产期暴露。在HGrC1细胞中，M1增加了AHR和ARNT，但降低了AHRR的表达，同时增加了CYP1A1和COMT的表达及活性。M2降低了AHR和AHRR，并增加了ARNT，对CYP1A1的表达和活性没有影响；然而，它确实增加了COMT的表达和活性。在肿瘤细胞中，M1降低了AHR并上调了AHRR和ARNT的表达，从而降低了CYP1A1的表达和COMT的活性。M2上调了AHR和ARNT，下调了AHRR，对CYP1A1和COMT的表达没有影响，但降低了COMT的活性。我们假设，根据组成不同，PAH混合物通过不同的转录反应以不同方式激活AHR：在HGrC1中，M1的经典AHR机制，其中CYP1A1的激活对解毒很重要，而在COV434中，一种非经典AHR机制，可能是通过激活核因子NFkB。
Reprod Toxicol. 2011-11-25
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