The Effects of Chronic Lifelong Activation of the AHR Pathway by Industrial Chemical Pollutants on Female Human Reproduction

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.

[1]  M. Ishizuka,et al.  Constitutive Effects of Lead on Aryl Hydrocarbon Receptor Gene Battery and Protection by β-carotene and Ascorbic Acid in Human HepG2 Cells. , 2016, Journal of food science.

[2]  J. Pru,et al.  Non-canonical progesterone signaling in granulosa cell function. , 2014, Reproduction.

[3]  J. Grilo,et al.  Development of a New Method for the Determination of Manganese , Cadmium , Mercury and Lead in Whole Blood and Amniotic Fluid by Inductively Coupled Plasma Mass Spectrometry , 2014 .

[4]  A. Di Carlo,et al.  Effects of low concentrations of Regorafenib and Sorafenib on human HCC cell AFP, migration, invasion, and growth in vitro , 2013, Journal of cellular physiology.

[5]  Yi-jun Zhou,et al.  The effects of low-level prenatal lead exposure on birth outcomes. , 2013, Environmental pollution.

[6]  T. Cataldi,et al.  Dibenzo-p-dioxins and dibenzofurans in human breast milk collected in the area of Taranto (Southern Italy): first case study , 2013, Analytical and Bioanalytical Chemistry.

[7]  G. S. Mugnozza,et al.  Contamination of the Environmental Matrices in Agricultural Areas Produced by Industrial Discharges: The Case Study of the Land of the City of Statte (Taranto, Southern Italy) , 2013 .

[8]  M. Vigotti,et al.  Spatial variability of air pollutants in the city of Taranto, Italy and its potential impact on exposure assessment , 2013, Environmental Monitoring and Assessment.

[9]  G. Garruti,et al.  GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer (IVF/ET) , 2012, Reproductive Biology and Endocrinology.

[10]  J. Peluso,et al.  The relationship between follicle development and progesterone receptor membrane component-1 expression in women undergoing in vitro fertilization. , 2012, Fertility and sterility.

[11]  Bin Zhao,et al.  Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. , 2011, Toxicological sciences : an official journal of the Society of Toxicology.

[12]  S. Banu,et al.  Chromium-VI arrests cell cycle and decreases granulosa cell proliferation by down-regulating cyclin-dependent kinases (CDK) and cyclins and up-regulating CDK-inhibitors. , 2011, Reproductive toxicology.

[13]  P. Hoyer,et al.  Hexavalent chromium-induced apoptosis of granulosa cells involves selective sub-cellular translocation of Bcl-2 members, ERK1/2 and p53. , 2011, Toxicology and applied pharmacology.

[14]  P. Parsons,et al.  Toxic trace metals and embryo quality indicators during in vitro fertilization (IVF). , 2011, Reproductive toxicology.

[15]  S. Massari,et al.  Residential proximity to industrial sites in the area of Taranto (Southern Italy). A case-control cancer incidence study. , 2011, Annali dell'Istituto superiore di sanita.

[16]  T. Zacharewski,et al.  Automated dose-response analysis and comparative toxicogenomic evaluation of the hepatic effects elicited by TCDD, TCDF, and PCB126 in C57BL/6 mice. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[17]  Sarita Gupta,et al.  Biochemical and molecular effects of gestational and lactational coexposure to lead and cadmium on ovarian steroidogenesis are associated with oxidative stress in f1 generation rats , 2010, Journal of biochemical and molecular toxicology.

[18]  B. Prieto,et al.  Serum oxidizability and antioxidant status in patients undergoing in vitro fertilization. , 2010, Fertility and sterility.

[19]  A. Buccolieri,et al.  Monitoring of total and bioavailable heavy metals concentration in agricultural soils , 2010, Environmental monitoring and assessment.

[20]  M. Urbanek,et al.  The role of genetic variation in the lamin a/c gene in the etiology of polycystic ovary syndrome. , 2009, The Journal of clinical endocrinology and metabolism.

[21]  D. Keefe,et al.  Trace element concentrations in follicular fluid of small follicles differ from those in blood serum, and may represent long-term exposure. , 2009, Fertility and sterility.

[22]  S. Bione,et al.  Alterations in the expression, structure and function of progesterone receptor membrane component-1 (PGRMC1) in premature ovarian failure. , 2008, Human molecular genetics.

[23]  I. Al-Saleh,et al.  Exposure to heavy metals (lead, cadmium and mercury) and its effect on the outcome of in-vitro fertilization treatment. , 2008, International journal of hygiene and environmental health.

[24]  A. El-Kadi,et al.  Transcriptional activation and posttranscriptional modification of Cyp1a1 by arsenite, cadmium, and chromium. , 2007, Toxicology letters.

[25]  Sarita Gupta,et al.  Effect of co-exposure to lead and cadmium on antioxidant status in rat ovarian granulose cells , 2007, Archives of Toxicology.

[26]  D. Keefe,et al.  Lead concentrates in ovarian follicle compromises pregnancy. , 2006, Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements.

[27]  A. Buccolieri,et al.  Heavy metals in marine sediments of Taranto Gulf (Ionian Sea, Southern Italy) , 2006 .

[28]  A. Visconti,et al.  Investigations on cellular proliferation induced by zearalenone and its derivatives in relation to the estrogenic parameters. , 2005, Toxicology letters.

[29]  Masayuki Yamamoto,et al.  Intrinsic Function of the Aryl Hydrocarbon (Dioxin) Receptor as a Key Factor in Female Reproduction , 2005, Molecular and Cellular Biology.

[30]  A. El-Kadi,et al.  Regulatory mechanisms modulating the expression of cytochrome P450 1A1 gene by heavy metals. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[31]  T. Klonisch,et al.  Molecular actions of polyhalogenated arylhydrocarbons (PAHs) in female reproduction. , 2005, Current medicinal chemistry.

[32]  W. Foster,et al.  Environmental and occupational factors affecting fertility and IVF success. , 2005, Human reproduction update.

[33]  A. Agarwal,et al.  Effect of oxidative stress in follicular fluid on the outcome of assisted reproductive procedures. , 2004, Fertility and sterility.

[34]  M. Barone,et al.  Distribution of Estrogen Receptor Subtypes, Expression of Their Variant Forms, and Clinicopathological Characteristics of Human Colorectal Cancer , 2002, Digestive Diseases and Sciences.

[35]  Y. Richard,et al.  Lead Reduces Messenger RNA and Protein Levels of Cytochrome P450 Aromatase and Estrogen Receptor β in Human Ovarian Granulosa Cells1 , 2003, Biology of reproduction.

[36]  W. Foster,et al.  Levels of Environmental Contaminants in Human Follicular Fluid, Serum, and Seminal Plasma of Couples Undergoing In Vitro Fertilization , 2002, Archives of environmental contamination and toxicology.

[37]  G. de Gennaro,et al.  Analysis of heavy metals in atmospheric particulate by ion chromatography. , 2000, Journal of chromatography. A.

[38]  D. Nebert,et al.  Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. , 2000, Biochemical pharmacology.

[39]  L. Veeck.  Atlas of the human oocyte and early conceptus , 1986 .