Environmental determinants of endometriosis : role of organochlorines and heavy metals

Endometriosis is an estrogen-dependent disease. Peritoneal endometriosis and endometriotic (adenomyotic) nodules of the recto-vaginal septum are distinct clinical entities with different histopathogeneses. The mechanisms and etiological factors involved in the onset or the development of these entities remain incompletely elucidated. Environmental pollutants (e.g. heavy metals and organochlorines) are among suspected etiological factors of endometriosis. Cadmium and lead are known to exhibit endocrine disrupting properties. Dioxins and PCBs have been shown to promote the development of endometriosis experimentally in primate and rodent models but the results of epidemiological studies remain inconclusive. We designed a matched case-control study to compare risk factors associated with endometriosis (E) and deep endometriotic nodules (DEN). Eighty eight triplets of women suffering from DEN, E or controls were recruited. Controls were not recruited in infertility clinics. Particular attention was given to dioxin exposure, which occurs essentially via the consumption of contaminated food. Dioxin exposure was assessed through an individual dietary questionnaire, and by GC/HRMS measurement in serum in a subset of patients who volunteered to give blood. The questionnaire revealed a significant protection associated with (multiple)-parity and breastfeeding in women with E or DEN, whereas the use of tampons or sanitary towels was not significantly associated with any form of the disease. Alcohol consumption was more prevalent (Odds Ratio (OR) 5.82 [CI95% 1.20-28.3]) in women suffering from DEN and a limited physical activity at work appeared as a risk factor for DEN and E (OR 4.58 [CI95% 1.80-11.62] and 5.61 [CI95% 1.90-16.60], respectively). Environmental or occupational exposures as well as dietary habits assessed through a food frequency questionnaire focusing on the consumption of fatty foodstuffs, were not significantly associated with the diseases. We measured the serum concentration of dioxins (pg TEQ/ g lipids) in 71 patients (E (n=25), DEN (n=25), and controls (n=21)). Age and body mass index were traced by linear multiple regression as determinants of dioxins while dietary habits and parity had no apparent influence. A logistic regression analysis was performed to take into account serum dioxins, age, body mass index, cumulative use of oral contraceptive, age at menarche, menstrual characteristics and familial factors. Significantly increased risks associated with dioxin serum concentration were found when comparing patients suffering from DEN and E with controls (OR 7.70 (CI95% [1.97-30.17]) and 3.17 (CI95% [1.01-9.93] respectively). This is the first epidemiological evidence of an association between organochlorines and endometriosis. We also measured the concentrations of heavy metals (cadmium and lead) in urine and/or blood in order to explore their possible role in endometriosis. Our observations did not support a role for cadmium in the onset or growth of endometriotic diseases but suggest a relationship with lead. Because endometriosis is an estrogen-dependent disease and since aromatase (CYP19), a key enzyme in estrogen biosynthesis, was recently demonstrated to be expressed within endometriotic lesions, we hypothesized that organochlorines could modulate local estrogen production through an up-regulation of aromatase. To explore this hypothesis, we firstly assessed the expression of aromatase in biopsied endometriotic tissue (peritoneal and ovarian endometriosis and deep endometriotic nodules of the recto-vaginal septum). First, we found that the expression of aromatase was significantly different in each type of tissue, which strengthens the theory of three distinct clinical entities. Compared with peritoneal endometriosis, ovarian endometriosis exhibited an 8-fold higher expression of aromatase, suggesting that aromatase inhibitors may be particularly active in this form of endometriosis. We then considered the concentration of polychlorobiphenyls, polychlorinated-dibenzo-dioxins and polychlorinated-dibenzo-furans in serum of these patients. The relationship between these parameters and aromatase expression was traced by simple and multiple regression analysis. The results did not support our hypothesis that the examined compounds facilitate the growth of endometriotic lesions by up-regulating the expression of aromatase. Overall, this work has contributed to better delineate the association between environmental exposures to organochlorines and the onset or development of peritoneal endometriosis or deep endometriotic nodules of the rectovaginal septum.Thèse de doctorat en sciences biomédicales (toxicologie)(SBIM 3) -- UCL, 200

Organochlorines and endometriosis: a mini-review.

Organochlorines (polychlorinated biphenyls and dioxin-like compounds) are suspected to play a role in the etiopathogenesis of endometriosis. This hypothesis, based on experimental data, has been circulating for years in the scientific community and several epidemiologic surveys have attempted to obtain confirmatory human data. The purpose of this mini-review is to provide an overview of the twelve epidemiological studies that have assessed the relationship between endometriosis and organochlorine exposure. Several studies did not observe a significant association between peritoneal endometriosis and organochlorines. The deep nodular form of endometriosis appears associated with a higher serum level of both dioxin-like compounds and polychlorobiphenyls. The type of control women, the nature of the chemicals measured, and the definition of the disease could modulate the ability to detect the possible relationship between endometriosis and organochlorine exposure

Comparison of atomic absorption and fluorescence spectroscopic methods for the routine determination of urinary arsenic.

OBJECTIVE: Interpretation of urinary arsenic measurements is sometimes difficult because of the absorption of seafood that contains trimethylated arsenic forms (arsenobetaine and arsenocholine). The objective of this study was to develop a rapid and robust technique for the measurement of the sum of inorganic arsenic metabolites. METHODS: Measurement of arsenic was performed in urine after hydride generation in acid medium. Using atomic fluorescence spectrometry (AFS) as the detection system, we developed a rapid (one determination in less than 2 min) technique using 50 microl urine without pre-treatment. Standardisation was done externally with a mixed standard solution containing inorganic trivalent arsenic (As(i) (III)), inorganic pentavalent arsenic (As(i) (V)), monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) (15/15/12.5/57.5). RESULTS: Samples distributed in the frame of an international comparison programme were used to assess accuracy of the AFS procedure, which gives a linear response up to 50 microg/l and proves more precise [coefficient of variation (CV)< 4% at 5 microg/l] and sensitive than the atomic absorption spectroscopy (AAS) technique using a quartz cell. An additional adaptation that allows the detection of non-directly reducible arsenic forms has also been validated for samples with high arsenic concentrations. CONCLUSIONS: The present study demonstrates the superiority of AFS over atomic absorption spectrometry (AAS) in arsenic determination and the interest of online mineralisation prior AFS detection for the determination of arsenic concentration in urine

Applications of liquid chromatography coupled to mass spectrometry-based metabolomics in clinical chemistry and toxicology: A review

The metabolome is the set of small molecular mass organic compounds found in a given biological media. It includes all organic substances naturally occurring from the metabolism of the studied living organism, except biological polymers, but also xenobiotics and their biotransformation products. The metabolic fingerprints of biofluids obtained by mass spectrometry (MS) or nuclear magnetic resonance (NMR)-based methods contain a few hundreds to thousands of signals related to both genetic and environmental contributions. Metabolomics, which refers to the untargeted quantitative or semi-quantitative analysis of the metabolome, is a promising tool for biomarker discovery. Although proof-of-concept studies by metabolomics-based approaches in the field of toxicology and clinical chemistry have initially been performed using NMR, the use of liquid chromatography hyphenated to mass spectrometry (LC/MS) has increased over the recent years, providing complementary results to those obtained with other approaches. This paper reviews and comments the input of LC/MS in this field. We describe here the overall process of analysis, review some seminal papers in the field and discuss the perspectives of metabolomics for the biomonitoring of exposure and diagnosis of diseases. (C) 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved

Mass spectrometry-based methods for the determination of sulfur and related metabolite concentrations in cell extracts

The sulfur metabolic pathway plays a central role in cell metabolism. It provides the sulfur amino acids methionine and cysteine, which are essential for protein synthesis, homocysteine, which lies at a critical juncture of this pathway, S-adenosylmethionine, the universal methyl donor in the cell, and glutathione (GSH), which has many crucial functions including protection against oxidative stress and xenobiotics. The intracellular level of these metabolites, which are closely connected with other cellular metabolic pathways, is of major importance for cell physiology and health. Three mass spectrometry-based methods for the determination of sulfur metabolites and also related compounds linked to the glutathione biosynthesis pathway are presented and discussed. The first one enables absolute quantification of these metabolites in cell extracts. It is based on liquid chromatography-electrospray triple quadrupole mass spectrometry coupled to N-15 uniform metabolic labeling of the yeast Saccharomyces cerevisiae. The two other methods are global approaches to metabolite detection involving a high-resolution mass spectrometer, the LTQ-Orbitrap. Ions related to metabolites of interest are picked up from complex and information-rich metabolic fingerprints. By these means, it is possible to detect analytical information outside the initial scope of investigation

Invasive aspergillosis in association with criminal arsenic poisoning.

A 26-year-old man suffered acute arsenic poisoning after a poisoning attempt. He developed multiple organ failure including encephalopathy, bleeding disorders, pancreatitis, renal and hepatocellular impairment. Generalized erythroderma also developed within one week after admission. The developed acute respiratory distress syndrome and Aspergillus fumigatus was isolated from the endotracheal aspirate. Despite intensive care support, antidote administration and various epuration techniques, the patient died on day 26 from subarachnoid bleeding. An autopsy was obtained and the concentration of arsenic was determined in different tissues. Multiple abscesses due to Aspergillus fumigatus were seen in the lungs, myocardium and kidneys. This uncommon complication in a previously immunocompetent patient could be related to impaired immunity directly caused by arsenic poisoning