Abstract
Environmental chemicals, such as heavy metals, affect female reproductive function. A biological sensor of the signals of many toxic chemical compounds seems to be the aryl hydrocarbon receptor (AHR). Previous studies demonstrated the environmental of heavy metals in Taranto city (Italy), an area that has been influenced by anthropogenic factors such as industrial activities and waste treatments since 1986. However, the impact of these elements on female fertility in this geographic area has never been analyzed. Thus, in the present study, we evaluated the AHR pathway, sex steroid receptor pattern and apoptotic process in granulosa cells (GCs) retrieved from 30 women, born and living in Taranto, and 30 women who are living in non-contaminated areas (control group), who were undergoing in vitro fertilization (IVF) protocol. In follicular fluids (FFs) of both groups the toxic and essential heavy metals, such as chromiun (Cr), Manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), cadmium (Cd) and lead (Pb), were also analyzed. Higher levels of Cr, Fe, Zn and Pb were found in the FFs of the women from Taranto as compared to the control group, as were the levels of AHR and AHR-dependent cytochrome P450 1A1 and 1B1; while CYP19A1 expression was decreased. The anti-apoptotic process found in the GCs of women fromTaranto was associated with the highest levels of progesterone receptor membrane component 1 (PGRMC1), a novel progesterone receptor, the expression of which is subjected to AHR activated by its highest affinity ligands (e.g., dioxins) or indirectly by other environmental pollutants, such as heavy metals. In conclusion, decreased production of estradiol and decreased number of retrieved mature oocytes found in women from Taranto could be due to chronic exposure to heavy metals, in particular to Cr and Pb.
Highlights
The anti-apoptotic process found in the granulosa cells (GCs) of women fromTaranto was associated with the highest levels of progesterone receptor membrane component 1 (PGRMC1), a novel progesterone receptor, the expression of which is subjected to aryl hydrocarbon receptor (AHR) activated by its highest affinity ligands or indirectly by other environmental pollutants, such as heavy metals
Nuclear receptor and aromatase mRNA expression qRT-PCR analysis in GCs showed a significant increase of AHR (1.14 ± 0.22 vs. 0.98 ± 0.24, TG vs NTG, P = 0.04) and for aryl hydrocarbon receptor nuclear translocator (ARNT) (0.78 ± 0.14 vs. 0.66 ± 0.17, TG vs. NTG, P = 0.04) mRNA expression, while no differences were observed for steroid receptor (ERα, ERβ, androgen receptor (AR) and progesterone receptor (PR)) expression between two groups (Fig 1A)
Various exogenous environmental pollutants can influence female reproductive health, preand postnatal development, by mechanisms not always well known and many studies have shown a significant relationship between heavy metal contamination in the follicular fluid and negative in vitro fertilization (IVF) outcomes [24,25,26]
Summary
In terms of reduced fecundity and fertility, has been reported in association with exposures to elevated concentrations of environmental toxic agents that are byproducts of many industrial processes, such as metal production and fuel combustion [1,2,3].the mechanisms of action of these toxic compounds are not always clear because the members of a group of pollutants do not operate through the same mechanism of action and some individual pollutants work through several modes of action.In female reproduction a biological sensor that responds to the signals of many toxic chemical compounds seems to be the aryl hydrocarbon receptor (AHR) [4].AHR is a physiological ligand-activated receptor which forms a heterodimer with the aryl hydrocarbon receptor nuclear translocator (ARNT), its cofactor.After translocation from the cytoplasm to the nucleus, the AHR/ARNT complex binds dioxin-responsive element (DRE), an eight-nucleotide motif located on the promoter of several target genes. The mechanisms of action of these toxic compounds are not always clear because the members of a group of pollutants do not operate through the same mechanism of action and some individual pollutants work through several modes of action. In female reproduction a biological sensor that responds to the signals of many toxic chemical compounds seems to be the aryl hydrocarbon receptor (AHR) [4]. AHR is a physiological ligand-activated receptor which forms a heterodimer with the aryl hydrocarbon receptor nuclear translocator (ARNT), its cofactor. After translocation from the cytoplasm to the nucleus, the AHR/ARNT complex binds dioxin-responsive element (DRE), an eight-nucleotide motif located on the promoter of several target genes. Two well-studied members of the AHR-regulated genes, cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1), are involved in detoxification of harmful toxicants
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