Class Of Endocrine Disruptors Research Articles

Cyano-functionalized ionic porous polymer: A novel adsorbent for effectively enriching trace estrogens in water and milk

Estrogens have been recognized as a class of endocrine disruptors. It is of utmost significance to develop a sensitive analytical method for the reliable determination of estrogen in environmental and food samples. Herein, a series of cyano-functionalized ionic porous organic polymers (CN-iPOPs) were successfully prepared for the first time using (1-imidazolyl)acetonitrile and biphenyl dichlorobenzene as building blocks via Friedel-Crafts alkylation reaction. The optimized CN-iPOPs (CN-iPOP3) displayed exceptional sorption capacity for estrogens, making it an advanced adsorbent for solid phase extraction (SPE) of estrogens. In combination, CN-iPOP3 based SPE with high performance liquid chromatography, a sensitive and reliable method was developed for determination of four estrogens in lake water and milk samples. Under optimal conditions, good linear response was obtained to be 0.09–100.0 ng mL−1 for lake water and 0.90–1000.0 ng mL−1 for milk, with detection limits (S/N = 3) of 0.03–0.05 ng mL−1 and 0.30–0.70 ng mL−1 respectively. The method recoveries were in the range of 85.0%-119.0% with the relative standard deviations lower than 7.8%. The synergistic effect of electrostatic force, hydrogen bond, π-π stacking interaction and hydrophobic interaction was proved to be the main adsorption mechanism. This research provides a promising approach to design iPOP-based adsorbents for effectively enriching or removing organic pollutants.

Facile Development of a Hybrid-Silica-Assisted Nanointerface for Active Electrochemical Recognition of an Endocrine Disruptor

Paraben, a conventional preservative used in most personal care products, falls under the class of endocrine disruptors. From small living organisms to human beings, everyone is exposed to this end...

Exposure and tiered ecological risk assessment of phthalate esters in the surface water of Poyang Lake, China

Phthalate esters (PAEs) are a class of endocrine disruptors that are produced and used extensively in China. Given its presence in various products, a great quantity of PAEs flows into different aquatic systems each year. Hence, it is important to study the pollution levels and ecological risk of PAEs. This study investigated the distribution and seasonal variation of six priority PAEs in the surface water of Poyang Lake, the largest freshwater lake in China. In the wet season, the mean concentration of the total PAEs was 0.544 ± 0.173 μg/L, while the dry season concentration (1.003 ± 0.451 μg/L) nearly doubled. The most abundant PAE congeners were di-n-butyl phthalate (DBP), followed by bis (2-ethylhexyl) phthalate (DEHP). To evaluate the ecological risks in Poyang Lake, the predicted no-effect concentrations (PNECs) of four PAEs based on non-lethal effects were derived. For diethyl phthalate (DEP), butyl benzyl phthalate (BBP), DBP, and DEHP, the PNECs were 31.6, 3.30, 2.31, and 0.0210 μg/L, respectively. The tiered ecological risk assessment showed that DEP and BBP posed no risk in Poyang Lake. Meanwhile, DBP posed a potential risk in Poyang Lake, but the risk of DEHP was unacceptable and requires more actions. Specifically, the probabilities of exceeding the threshold for the protection of 95% of the aquatic organisms (HC5) were 3.30% and 4.43% for DEHP in the wet and dry season, respectively. This study provides an appropriate reference for the surface water management of PAE pollution in China.

A fast-multiclass method for the determination of 21 endocrine disruptors in human urine by using vortex-assisted dispersive liquid-liquid microextraction (VADLLME) and LC-MS/MS

Simplicity, speed, and reduced cost are essential demands for routine analysis in human biomonitoring studies. Moreover, the availability of higher volumes of human specimens is becoming more restrictive due to ethical controls and to the costs associated with sample transportation and storage. Thus, analytical methods requiring much lower sample volumes associated with simultaneous detection capability (multiclass analysis) are with a very high claim. In this sense, the present approach aimed at the development of a method for preconcentration and simultaneous determination of four classes of endocrine disruptors (seven bisphenols, seven parabens, five benzophenones, and two antimicrobials) in the urine. The approach is based on vortex-assisted dispersive liquid-liquid microextraction (VADLLME) and high-performance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). After optimization of the significant parameters of VADLLME extraction, the proposed procedure showed to be simple, fast, sensitive, requiring only 1.0 mL of urine, 400 μL of organic solvents with a total stirring time of 20 s. Moreover, a variation of inter-day and between-day runs were lower than 10.0% and 11.0%, respectively. Finally, the proposed method was successfully applied to the analysis of 50 urine samples of Brazilian pregnant women to establish reference ranges.

Urinary phthalate metabolites in relation to serum anti-M\xfcllerian hormone and inhibin B levels among women from a fertility center: a retrospective analysis

BackgroundPhthalates, a class of endocrine disruptors, have been demonstrated to accelerate loss of ovarian follicle pool via disrupting folliculogenesis, and lead to diminished ovarian reserve. However, human data are limited. Here, we aimed to examine whether urinary phthalate metabolites are correlated with markers of ovarian reserve among women attending a fertility clinic.MethodsWe measured eight phthalate metabolites in urine samples collected from 415 women seeking infertility treatment at the Reproductive Medicine Center of Tongji Hospital, Wuhan, China. Data on measures of ovarian reserve, as indicated by serum anti-Müllerian hormone (AMH) and inhibin B (INHB) levels, were retrieved retrospectively through electronic medical charts. Multivariate linear models were performed to estimate the associations of urinary phthalate metabolites and serum AMH and INHB. We further explored the potential nonlinearity of the relationships with restricted cubic spline analysis.ResultsOverall, we found largely null associations between urinary phthalate metabolites and serum AMH. The multivariable adjusted differences in serum INHB levels comparing the highest quartile of urinary MEHP to the lowest were − 18.29% (95% CI: − 31.89%, − 1.98%; P-trend = 0.04). Women in the second to fourth quartiles of MEOHP had a significant decrease of − 23.74% (95% CI: −35.85%, − 9.24%), − 19.91% (95% CI: −33.30%, − 3.82%) and − 20.23% (95% CI: −34.43%, − 2.96%), respectively, in INHB levels compared to the first quartile. In the spline analysis, we identified a nonlinear relationship between MEOHP exposure and serum INHB.ConclusionsWe provided evidence for a negative association between urinary concentrations of certain phthalate metabolites and serum INHB levels, suggesting an adverse effect of phthalates exposure on growing antral follicles. Whether phthalates exposure at environmentally level will pose a risk for ovarian reserve needs further investigation.

Parabens inhibit the early phase of folliculogenesis and steroidogenesis in the ovaries of neonatal rats

Parabens are widely used as anti-microbial agents in the cosmetic and pharmaceutical industries. Recently, parabens have been shown to act as xenoestrogens, a class of endocrine disruptors. In the present study, 55 female pups were given daily subcutaneous injections of methyl-, propyl-, and butyl-paraben or 17beta-estradiol (E2) during neonatal Day 1-7. The ovaries were excised on postnatal Day 8, then fixed and stained with hematoxylin and eosin for histological analysis. The follicles were counted and classified as being in the primordial, early primary, or primary stages. The number of primordial follicles increased while early primary follicles decreased at the high doses of propyl- and butyl-paraben. The levels of anti-Mullerian hormone (AMH) and Foxl2 mRNA increased by propyl- and butyl-parabens whereas kit ligand/stem cell factor (KITL) expression was up regulated only by butyl-paraben. The mRNA levels of StAR and Cyp11a1 were significantly decreased after treatment with methyl-, propyl-, and butyl-parabens. Consistent with its use as a positive control, E2 regulated the expression of KITL, StAR, and Cyp11a1 genes, but surprisingly did not affect AMH and Foxl2 levels. Thus, E2 and parabens had different effects on the regulation of folliculogenic and steroidogenic genes, demonstrating the estrogenic and nonestrogenic properties of parabens in the ovary. Taken together, our data show that parabens stimulated AMH mRNA expression and consequently inhibited the early phase of folliculogenesis in the ovaries of neonatal female rat. The levels of steroidogenic enzymes, indicators of follicle differentiation, appeared to be regulated by parabens through inhibition of their transcriptional repressor, Foxl2.

Endocrine disruptor activity in bottled mineral and flavoured water

A panel of reporter gene assays (RGAs) coupled with a single solid phase extraction (SPE) step was developed and used to screen bottled mineral water for the presence of four classes of endocrine disruptors (EDs), oestrogens, androgens, progestagens and glucocorticoids.Fourteen brands of bottled mineral water in triplicate (42 samples) were analysed. Overall, hormonal activity was found in 78% of the samples. Oestrogenic, androgenic, progestagenic and glucocorticoid activity was found in 38%, 38%, 36% and 55% of the samples, respectively at an average concentration of 10ng/l 17β-estradiol equivalent (EEQ), 26ng/l testosterone equivalent (TEQ), 123ng/l progesterone equivalent (PEQ) and 13.5ng/l hydrocortisone equivalent (HEQ).The level of oestrogenic, androgenic and progestagenic activity observed is not considered a matter of concern for the consumers’ health. It is unknown whether the glucocorticoid levels observed are safe. The ED source, long term exposure and mixture effects remain to be investigated.

131 EFFECT OF PARABENS ON THE DISRUPTION OF OVARIAN FOLLICLE MATURATION IN A NEONATAL FEMALE RAT MODEL

Parabens are widely used as an antimicrobial agent in the preparation of cosmetic consumer products and pharmaceuticals. Parabens are esters of para-hydroxybenzoic acid typically including methyl-, ethyl-, butyl-, isobutyl- and isopropyl-paraben. Recently, parabens have been shown to act as xenoestrogens, a class of endocrine disruptors. In this study, we hypothesised that parabens might disrupt ovarian follicle maturation in female Sprague-Dawley rats during the neonatal period. A total of 55 female rats were divided into 11 groups, each composed of 5 rats. The pups were given daily subcutaneous injections of methyl-, propyl- or butyl-paraben at increasing concentrations of 62.5, 250, or 1000 mg kg–1 per day on neonatal Day 1 to 7. 17α-Ethinylestradiol (1 mg kg–1 per day) was used as a positive control. We examined the expression of anti-Müllerian hormone (AMH), which inhibits early folliculogenesis in the ovaries. Levels of AMH mRNA and protein were determined using real-time PCR and Western blot analysis, respectively. We found that the levels of AMH mRNA and protein were dose-dependently increased by methyl- and propyl-paraben compared with the vehicle. In particular, AMH mRNA and protein levels were markedly increased by parabens (methyl- and propyl-) at 1000 mg kg–1 per day. Data were analysed using a nonparametric one-way ANOVA followed by Dunnett's test for multiple comparisons. The ovaries were excised at postnatal Day 8 and fixed and stained with haematoxylin and eosin for histological analysis. The number of follicles were counted and classified into primordial, primary, or secondary stages via the largest serial sections at the centre of the ovary. Results showed that the total number of follicles and number of primordial follicles were increased by methyl- and propyl-parabens compared with the vehicle. Taken together, these results indicated that methyl- and propyl-parabens may have an estrogenic effect that disrupts the ovarian follicle development necessary for reproductive functions in a neonatal female rat model.

Cadmium reduces 11β-hydroxysteroid dehydrogenase type 2 activity and expression in human placental trophoblast cells

Cadmium, a common environmental pollutant and a major constituent of tobacco smoke, has been identified as a new class of endocrine disruptors with a wide range of detrimental effects on mammalian reproduction. During human pregnancy, maternal cadmium exposure, via the environment and/or cigarette smoking, leads to fetal growth restriction (FGR), but the underlying mechanisms are unknown. Although a substantial amount of evidence suggests that cadmium may affect fetal growth indirectly via the placenta, the molecular targets remain to be identified. Given that reduced placental 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2, encoded by HSD11B2 gene) is causally linked to FGR, the present study was undertaken to examine the hypothesis that cadmium induces FGR in part by targeting placental HSD11B2. Using cultured human trophoblast cells as a model system, we showed that cadmium exposure resulted in a time- and concentration-dependent decrease in 11 beta-HSD2 activity, such that an 80% reduction was observed after 24-h treatment at 1 microM. It also led to a similar decrease in levels of 11 beta-HSD2 protein and mRNA, suggesting that cadmium reduced 11 beta-HSD2 expression. Furthermore, cadmium diminished HSD11B2 promoter activity, indicative of repression of HSD11B2 gene transcription. In addition, the effect of cadmium was highly specific, in that other divalent metals (Zn(2+), Mg(2+), and Mn(2+)) as well as nicotine and cotinine (a major metabolite of nicotine) did not alter 11 beta-HSD2 activity. Taken together, these findings demonstrate that cadmium reduces human placental 11 beta-HSD2 expression and activity by suppressing HSD11B2 gene transcription. Thus the present study identifies placental 11 beta-HSD2 as a novel molecular target of cadmium. It also reveals a molecular mechanism by which this endocrine disruptor may affect human placental function and, consequently, fetal growth and development.

Endocrine disruptors: effects on male fertility and screening tools for their assessment

During the recent decades, a lot of research has been performed concerning the so-called “endocrine disruptors”, which are widespread in the environment. These compounds of anthropogenic or natural origin mimic the action of sex hormones and can interfere with the endocrine system. The largest body of evidence exists for those compounds that are estrogenic in nature, but the amount of experimental data on other types of interactions, especially anti-androgenic, steadily increases. Because of the growing public and scientific concern, epidemiological studies have been initiated to analyse the short and long-term effects of endocrine disruptors. In addition, a number of assays have been developed and are undergoing validation, aiming at high throughput screening of chemical agents with suspected endocrine disrupting properties. In the present review, we briefly describe the results of epidemiological studies dealing with observed time trends in male fertility disorders. In the second part of the article, an overview is given of the different classes of endocrine disruptors, followed by a description of the most important in vitro and in vivo bioassays, used to screen for the possible endocrine disruptive capacity of chemicals, together with future research needs for in vitro test development.

Characterisation of the molecular responses to xenoestrogens using gene expression profiling

The two estrogen receptors (ERs), ERαand ERβ, are molecular targets of the xenoestrogen class of endocrine disruptors. These receptors are ligand-activated transcription factors regulated by naturally occurring estrogens. Activation of mammalian ERs by xenoestrogens has been associated with both adverse and beneficial effects. A more informed appraisal of the likely risks and benefits of xenoestrogens requires an understanding of their biological effects at the molecular level. Receptor binding and reporter-based transient transfection assays indicate that some compounds, including the phytoestrogens genistein and coumestrol, activate ERβpreferentially, suggesting that this receptor subtype may play a predominant role in mediating the effects of these compounds. We review recent advances in our understanding of the responses of mammalian cells to estrogenic compounds and describe an approach to decipher these effects at the molecular level.

An updated review of environmental estrogen and androgen mimics and antagonists

For the last 40 y, substantial evidence has surfaced on the hormone-like effects of environmental chemicals such as pesticides and industrial chemicals in wildlife and humans. The endocrine and reproductive effects of these chemicals are believed to be due to their ability to: (1) mimic the effect of endogenous hormones, (2) antagonize the effect of endogenous hormones, (3) disrupt the synthesis and metabolism of endogenous hormones, and (4) disrupt the synthesis and metabolism of hormone receptors. The discovery of hormone-like activity of these chemicals occurred long after they were released into the environment. Aviation crop dusters handling DDT were found to have reduced sperm counts, and workers at a plant producing the insecticide kepone were reported to have lost their libido, became impotent and had low sperm counts. Subsequently, experiments conducted in lab animals demonstrated unambiguously the estrogenic activity of these pesticides. Man-made compounds used in the manufacture of plastics were accidentally found to be estrogenic because they fouled experiments conducted in laboratories studying natural estrogens. For example, polystyrene tubes released nonylphenol, and polycarbonate flasks released bisphenol-A. Alkylphenols are used in the synthesis of detergents (alkylphenol polyethoxylates) and as antioxidants. These detergents are not estrogenic; however, upon degradation during sewage treatment they may release estrogenic alkylphenols. The surfactant nonoxynol is used as intravaginal spermicide and condom lubricant. When administered to lab animals it is metabolized to free nonylphenol. Bisphenol-A was found to contaminate the contents of canned foods; these tin cans are lined with lacquers such as polycarbonate. Bisphenol-A is also used in dental sealants and composites. We found that this estrogen leaches from the treated teeth into saliva; up to 950 μg of bisphenol-A were retrieved from saliva collected during the first hour after polymerization. Other xenoestrogens recently identified among chemicals used in large volumes are the plastizicers benzylbutylphthalate, dibutylphthalate, the antioxidant butylhydroxyanisole, the rubber additive p-phenylphenol and the disinfectant o-phenylphenol. These compounds act cumulatively. In fact, feminized male fish were found near sewage outlets in several rivers in the U.K.; a mixture of chemicals including alkyl phenols resulting from degradation of detergents during sewage treatment seemed to be the causal agent. Estrogen mimics are just a class of endocrine disruptors. Recent studies identified antiandrogenic activity in environmental chemicals such as vinclozolin, a fungicide, and DDE, and insecticide. Moreover, a single chemical may produce neurotoxic, estrogenic and antiandrogenic effects. It has been hypothesized that endocrine disruptors may play a role in the decrease in the quantity and quality of human semen during the last 50 y, as well as in the increased incidence of testicular cancer and cryptorchidism in males and breast cancer incidence in both females and males in the industrialized word. To explore this hypothesis it is necessary to identify putative causal agents by the systematic screening of environmental chemicals and chemicals present in human foods to assess their ability to disrupt the endocrine system. In addition, it will be necessary to develop methods to measure cumulative exposure to (a) estrogen mimics, (b) antiandrogens, and (c) other disruptors.

The estrogenicity of bisphenol A-related diphenylalkanes with various substituents at the central carbon and the hydroxy groups.

The chemical structure of hydroxylated diphenylalkanes or bisphenols consists of two phenolic rings joined together through a bridging carbon. This class of endocrine disruptors that mimic estrogens is widely used in industry, particularly in plastics. Bisphenol F, bisphenol A, fluorine-containing bisphenol A (bisphenol AF), and other diphenylalkanes were found to be estrogenic in a bioassay with MCF7 human breast cancer cells in culture (E-SCREEN assay). Bisphenols promoted cell proliferation and increased the synthesis and secretion of cell type-specific proteins. When ranked by proliferative potency, the longer the alkyl substituent at the bridging carbon, the lower the concentration needed for maximal cell yield; the most active compound contained two propyl chains at the bridging carbon. Bisphenols with two hydroxyl groups in the para position and an angular configuration are suitable for appropriate hydrogen bonding to the acceptor site of the estrogen receptor. Our data suggest that estrogenicity is influenced not only by the length of the substituents at the bridging carbon but also by their nature. Because diphenylalkane derivatives are widespread and their production and use are increasing, potential exposure of humans to estrogenic bisphenols is becoming a significant issue. The hazardous effects of inadvertent exposure to bisphenol-releasing chemicals in professional workers and the general populations therefore deserve investigation.

Tributyltin (TBT) effects on Ocinebrina aciculata (Gastropoda: Muricidae): imposex development, sterilization, sex change and population decline

The anatomy and histology of the male and female genital systems of the prosobranch Ocinebrina aciculata are described and compared with Nucella lapillus and Ocenebra erinacea. O. aciculata, collected at Roscoff (France) from 1989 to 1993, exhibited imposex (pseudohermaphroditism; occurrence of male parts in addition to the female genital duct) in response to tributyltin (TBT) pollution. Two stages of imposex development (4 and 5) with three different types (a, b, c) in stage 5 can be distinguished and are documented for the first time with scanning electron micrographs. Furthermore, three additional alterations of the genital tract are shown. Evidence for TBT-induced sterilization and protogyne sex change is given. This species exhibits a higher TBT-sensitivity than Nucella lapillus, the most sensitive TBT indicator species known previously. Due to TBT pollution, populations of Ocinebrina aciculata are declining in France and corresponding symptoms for this extremely endangered species are described: high numbers of sterilized females, male-biased sex ratios and poor reproductive performance and recruitment. The question of whether chemicals in the environment can influence the hormonal systems of humans and animals has been discussed for many years. At the centre of interest from early on were compounds with a known or supposed estrogenic activity and their possible impact on male reproductive health. However, another class of endocrine disruptors, environmental androgens such as TBT with their detrimental effects on females, may also cause serious problems for wildlife and for mankind.