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PubMed2002

Gene expression profile induced by 17alpha-ethynyl estradiol, bisphenol A, and genistein in the developing female reproductive system of the rat.

Exposure to some compounds with estrogenic activity, during fetal development, has been shown to alter development of reproductive organs, leading to abnormal function and disease either after birth or during adulthood. In order to understand the molecular events associated with the estrogenicity of different chemicals and to determine whether common sets of gene expression changes can be predictive of estrogenic activity, we have used microarray technology to determine the transcriptional program influenced by exposure to this class of compounds during organogenesis and development. Changes in patterns of gene expression were determined in the developing uterus and ovaries of Sprague-Dawley rats on GD 20, exposed to graded dosages (sc) of 17alpha-ethynyl estradiol (EE), genistein, or bisphenol A (BPA) from GD 11 to GD 20. Dose levels were roughly equipotent in estrogenic activity. We compared the transcript profiles between treatment groups and controls, using oligonucleotide arrays to determine the expression level of approximately 7000 rat genes and over 1000 expressed squence tags (ESTs). At the highest tested doses of EE, BPA, or genistein, we determined that less than 2% of the mRNA detected by the array showed a 2-fold or greater change in their expression level (increase or decrease). A dose-dependent analysis of the transcript profile revealed a common set of genes whose expression is significantly and reproducibly modified in the same way by each of the 3 chemicals tested. Additionally, each compound induces changes in the expression of other transcripts that are not in common with the others, which indicated not all compounds with estrogenic activity act alike. The results of this study demonstrate that transplacental exposure to chemicals with estrogenic activity changes the gene expression profile of estrogen-sensitive tissues, and that the analysis of the transcript profile of these tissues could be a valuable approach to determining the estrogenicity of different compounds.

Animals↗

PubMed2003

Prenatal exposure to estrogenic compounds alters the expression pattern of platelet-derived growth factor receptors alpha and beta in neonatal rat testis: identification of gonocytes as targets of estrogen exposure.

We examined the effects of maternal exposure to estrogens on platelet-derived growth factor (PDGF) receptor (PDGFR) expression in newborn rat testis. Pregnant rats were treated from gestation Day 14 to birth with corn oil containing diethylstilbestrol, bisphenol A, genistein, or coumestrol by gavage or subcutaneous injection. These treatments induced a dose-dependent increase in the expression of PDGFR alpha and beta mRNAs, determined by semiquantitative reverse transcription polymerase chain reaction, though diethylstilbestrol had a biphasic effect on both mRNAs. In situ hybridization analysis showed that PDGFRalpha mRNA increased mostly in the interstitium, while PDGFRbeta mRNA increased both in the interstitium and seminiferous cords. Immunohistochemical studies of PDGFRalpha and beta proteins revealed that both receptors were present in testis before and after birth and that they were upregulated upon treatment with estrogens in 3-day-old rats, with PDGFRbeta increasing dramatically in gonocytes. PDGFRalpha and beta mRNAs and proteins were also found in purified gonocytes. Our previous finding that PDGF and 17beta-estradiol induce gonocyte proliferation in vitro, together with the present finding that in vivo exposure to estrogens upregulates PDGF receptors in testis, suggest that PDGF pathway is a target of estrogens in testis. In addition, these data identify PDGFRbeta in gonocytes as a major target of gestational estrogen exposure, suggesting that estrogen may have a physiological interaction with PDGF during gonocyte development. These results, however, do not exclude the possibility that the effects of the compounds examined in this study might be due to estrogen receptor-independent action(s).

Animals↗

PubMed2002

Nonylphenol, octyphenol, and bisphenol A in groundwaters as a result of agronomic practices.

Due to increasing concern about the assessment and protection of the quality of groundwater as a limited natural resource, an extensive monitoring program has been carried out, covering a highly agricultural area of Catalonia where different types of crops have been grown during the last 5-10 years. The paper reports the analytical protocol used (sampling, filtration, preconcentration, and analysis) and the most relevant organic compounds present in groundwaters from agricultural areas as well as the concentration levels found.

Agriculture↗

PubMed1991

Formation of 4,4'-methylenedianiline in polyurethane potting materials by either gamma-ray or autoclave sterilization.

In this experiment, we found that a potential carcinogen, 4,4'-methylenedianiline (MDA), was produced from gamma-ray irradiated potting materials, medical thermosetting polyurethane (PU). gamma-Ray irradiated PUs were immersed in either methanol or in equine serum. The time course of MDA leached from the potting materials and other variables were compared. A significant relationship was noted between the amount extracted and the rigidity of the potting material. The accumulated amount of extracted MDA (a few ppm in the original sample) increased with increasing irradiation dose by a second-order equation. One sample indicated reduced MDA elution after irradiation in the early stage. MDA extraction with serum was 82-87% that with methanol. In one case, MDA leaching into serum in the early stage was higher than that into methanol. Autoclave sterilization did not promote MDA formation, thus indicating that autoclaving would be preferable.

Aniline Compounds↗

PubMed1990

Monitoring exposure to 4,4'-methylenedianiline by the gas chromatography-mass spectrometry determination of adducts to hemoglobin.

The determination of the covalently bound reaction products of 4,4'-methylenedianiline (MDA) to hemoglobin was investigated as a possible method for biological dosimetry in humans. The extent of binding to rat hemoglobin of MDA was determined by dosing animals with the 14C-ring-labeled compound. Two adducts were released from the hemoglobin on hydrolysis under mildly basic conditions which were identified as MDA and N-acetyl-MDA and accounted for between 36 and 45% of the total radioactivity bound to the protein. A quantitative assay procedure was subsequently developed for measuring both of the base released adducts in rat hemoglobin. The method utilized solvent extraction followed by derivatization with pentafluoropropionic anhydride and subsequent separation and quantitation by capillary gas chromatography with selective ion monitoring mass spectrometry using deuterium-labeled analogues of MDA and N-acetyl-MDA as internal standards. A dose-response relationship was established in orally dosed rats between production of each of the hemoglobin released adducts and dose of MDA (1-12 mg/kg). The possible use of such adduct determinations as dosimeters for industrial workers exposed to MDA is discussed.

Aniline Compounds↗

PubMed1992

Identification of metabolites of 4,4'-diaminodiphenylmethane (methylene dianiline) using liquid chromatographic and mass spectrometric techniques.

The in vitro metabolism of 4,4'-diaminodiphenylmethane (methylene dianiline, MDA) was investigated using rabbit liver microsomes. Minimal clean-up of the microsomal incubations was carried out using zinc sulphate precipitation followed by solid-phase extraction on Sep-Pak C18 cartridges. Three metabolites were detected in hepatic microsomal incubations, namely the azodiphenylmethane (azo) azoxydiphenylmethane (azoxy) and 4-nitroso-4'-aminodiphenylmethane (nitroso) compounds. The azo and azoxy metabolites were produced enzymatically whereas the nitroso compound may have been formed via a non-enzymatic process. Reversed-phase high-performance liquid chromatography-plasma spray mass spectrometry was used to initially detect these metabolites. Fast atom bombardment mass spectrometry and fast atom bombardment tandem mass spectrometry were utilized to further structurally characterise these compounds. Comparison of mass spectral data obtained from synthesised standards with data obtained on the putative metabolites substantiated the characterisation of these compounds.

Aniline Compounds↗

PubMed1995

Determination of 4,4'-methylenediphenyldianiline (MDA) and identification of isomers in technical-grade MDA in hydrolysed plasma and urine from workers exposed to methylene diphenyldiisocyanate by gas chromatography-mass spectrometry.

Gas chromatography-mass spectrometry using chemical ionization with ammonia as reagent gas monitoring both positive and negative ions was applied. Negative-ion monitoring using ammonia and the pentafluoropropionic anhydride (PFPA) derivatives were chosen owing to low detection limits and good separation for the isomers studied. Technical-grade methylenediphenyldiioscyanate (MDI) was analysed and three isomers, 4,4'-, 2.4'- and 2,2'-methylenediphenyldianiline (MDA), were determined in addition to methylated MDA. Plasma and urine from an exposed worker were hydrolysed and analysed and the MDA isomers were identified in the biological samples.

Allergens↗

PubMed2004

Monitoring of estrogens, pesticides and bisphenol A in natural waters and drinking water treatment plants by solid-phase extraction-liquid chromatography-mass spectrometry.

A multi-residue analytical method has been developed for the determination of various classes of selected endocrine disruptors. This method allows the simultaneous extraction and quantification of different estrogens (estradiol, estrone, estriol, estradiol-17-glucuronide, estradiol diacetate, estrone-3-sulfate, ethynyl estradiol and diethylstilbestrol), pesticides (atrazine, simazine, desethylatrazine, isoproturon and diuron), and bisphenol A in natural waters. In the method developed, 500 ml of water are preconcentrated on LiChrolut RP-18 cartridges. Further analysis is carried out by liquid chromatography-mass spectrometry (LC-MS) using atmospheric pressure chemical ionisation (APCI) in the positive ion mode for determination of pesticides and electrospray in the negative ionisation mode for determination of estrogens and bisphenol A. Recoveries for most compounds were between 90 and 119%, except for bisphenol A (81%) and diethylstilbestrol (70%), with relative standard deviations below 20%. Limits of detection ranged between 2 and 15 ng/l. The method was used to study the occurrence of the selected pollutants in surface and groundwater used for abstraction of drinking water in a waterworks and to evaluate the removal efficiency of the different water treatments applied. Water samples from the river, the aquifer, and after each treatment stage (sand filtration, ozonation, activated carbon filtration and post-chlorination) were taken monthly from February to August of 2002. The presence in river water of atrazine, simazine, diuron and bisphenol A were relatively frequent at concentrations usually below 0.1 microg/l. Lower levels, below 0.02 microg/l, were usual for isoproturon. Estrone-3-sulfate and estrone were detected occasionally in the river. Most of the compounds were completely removed during the water treatment, especially after activated carbon filtration.

Benzhydryl Compounds↗

PubMed1999

Structural similitudes between cytotoxic antiestrogen-binding site (AEBS) ligands and cytotoxic sigma receptor ligands. Evidence for a relationship between cytotoxicity and affinity for AEBS or sigma-2 receptor but not for sigma-1 receptor.

1-Benzyl-4-(N-2-pyrrolidinylethoxy)benzene (PBPE) is a cytotoxic derivative of the antitumoral drug tamoxifen. PBPE binds with high-affinity and specificity to the microsomal antiestrogen-binding site (AEBS). PBPE, as well as some other high-affinity AEBS ligands, shares structural features with high-affinity and selective sigma receptor ligands in the N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamine class, such as BD1008, which are cytotoxic against tumoral cells. Based on these structural and pharmacological similitudes, we set out to examine whether AEBS and sigma receptors could be related binding sites. We showed that BD1008 had a high affinity for AEBS. However, prototypical sigma receptor ligands were very low-affinity competitors on AEBS. Surprisingly, AEBS ligands displayed a high affinity for sigma-1 and sigma-2 receptor subtypes, showing that AEBS and sigma receptor-binding sites were not mutually exchangeable. Moreover, phenytoin, which is an allosteric modulator of sigma-1 receptor, was a competitive inhibitor of [3H]tamoxifen on AEBS. These results suggest that the tamoxifen-binding site on AEBS and the sigma ligand-binding site on sigma receptors were not identical but related entities. We also showed here that the high-affinity and specific AEBS ligands also bound sigma receptors with high affinity. Moreover, the compounds that were capable of displacing tamoxifen from AEBS were cytotoxic against tumoral cells but not against the AEBS-deficient cell line Rtx-6. These results confirm that AEBS and sigma receptors might belong to the same family of proteins, and that the tamoxifen-binding site might be involved in the cytotoxicity of AEBS ligands and some classes of sigma compounds.

Allosteric Regulation↗

PubMed1996

32P-postlabeling of a DNA adduct derived from 4,4'-methylenedianiline, in the olfactory epithelium of rats exposed by inhalation to 4,4'-methylenediphenyl diisocyanate.

Tissues obtained from female Wistar rats exposed to a 0.9 microm aerosol of 4,4'-methylenediphenyl diisocyanate (MDI) for 17 h per day, 5 days per week, for one year, at levels of 0, 0.3, 0.7 and 2.0 mg/m(3), were analyzed for DNA adducts. A 32P-postlabeling method was used to detect (i), adducts formed by the reaction of the isocyanate group(s) of MDI with DNA; and a 32P-postlabeling method was adapted to detect (ii), a DNA adduct formed by 4,4'- methylenedianiline (MDA), a hydrolysis/decarboxylation product of MDIV. In the lung, neither isocyanate adducts nor the arylamine adduct were detectable. The same negative result was seen in the liver, the bladder, the kidney, the respiratory epithelium and in peripheral lymphocytes. In the olfactory epithelium, on the other hand, the arylamine-derived DNA adduct was detected, at the very low levels of 5,9 and 10 adduct-nucleotides per 10(10) nucleotides, for the three dose groups, respectively. The adduct co-chromatographed with the one formed in the liver of rats after oral gavage of MDA. The results are discussed in terms of the importance of genotoxic versus nongenotoxic aspects of carcinogenesis.

Administration, Inhalation↗

PubMed1985

The results of microbial mutation test for forty-three industrial chemicals.

The mutagenicity of 43 industrial chemicals in Salmonella typhimurium (TA98, TA100, TA1535, TA1537, and TA1538) and Escherichia coli (WP2uvrA) was examined. The output of these chemicals in Japan is more than a million kilograms per year. The mutation test was carried out under the condition of absence and presence of rat microsomal activation. Two chemicals, hexamethylenetetramine and 4,4'-methylenediphenyldiisocyanate, showed mutagenic activity in S. typhimurium TA98 and TA100 by metabolic activation. Hexamethylenetetramine also showed mutagenic activity in TA98 without microsomal activation. No mutagenic activity was observed in the 41 chemicals including 4 volatile and gaseous compounds.

Cyanates↗

PubMed2005

[Bromophenols from the brown alga Leathesia nana].

OBJECTIVE: To investigate the chemical constituents of the brown alga Leathesia nana. METHOD: Compounds were isolated by normal phase silica gel, Sephadex LH-20 chromatography and reverse phase HPLC techniques. Their structures were elucidated with spectroscopic methods including IR, MS and NMR. RESULT: Six compounds were isolated from ethanolic extract of the brown alga L. nana and their structures were identified as 2,2',3,3'-tetrabromo-4,4',5,5'-tetrahydroxydiphenyl methane, 2,2',3-tribromo-3', 4,4', 5-tetrahydroxy-6'-ethyloxymethyldiphenyl methane, 2,3-dibromo-4,5-dihydroxybenzyl alcohol, 2,3-dibromo-4,5-dihydroxybenzyl methyl ether, 3-bromo-4-hydroxybenzoic acid and 2-bromo-4,5-dihydroxybenzaldehyde. CONCLUSION: All these compounds were obtained from this species for the first time.

Benzhydryl Compounds↗

PubMed2006

Activation of kinase pathways in MCF-7 cells by 17beta-estradiol and structurally diverse estrogenic compounds.

17beta-Estradiol (E2) activates non-genomic pathways in MCF-7 cells, and this study investigates the effects of structurally-diverse estrogenic compounds on activation of mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3-K), protein kinase C (PKC), PKA, and calcium calmodulin-dependent kinase IV (CaMKIV). Activation of kinases was determined by specific substrate phosphorylation and transactivation assays that were diagnostic for individual kinases. The compounds investigated in this study include E2, diethylstilbestrol (DES), the phytoestrogen resveratrol, and the following synthetic xenoestrogens, bisphenol-A (BPA), nonylphenol, octylphenol, endosulfan, kepone, 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), and 2',3',4',5'-tetrachloro-4-biphenylol (HO-PCB-Cl(4)). With the exception of resveratrol, all the compounds activated PI3-K and MAPK. Activation of PKC by the xenoestrogens was structure-dependent since resveratrol, kepone and HO-PCB-Cl(4) were inactive and only minimal activation of PKA was observed. CaMKIV was activated only by E2 and DES, and HO-PCB-Cl(4) was a potent inhibitor of CaMKIV-dependent activity. These results demonstrate that activation of estrogen receptor-alpha-mediated non-genomic pathways by estrogenic compounds in MCF-7 cells is structure-dependent and can result in activation or inhibition of kinase activities.

Benzhydryl Compounds↗

PubMed1996

Synthesis and phospholipase A2 inhibitory activity of thielocin B3 derivatives.

We prepared several types of derivatives of thielocin B3, a very potent naturally occurring inhibitor for human nonpancreatic secretory PLA2 (sPLA2-II), and conducted a structure-activity relationship study to identify potent sPLA2-II inhibitors with the aim of developing antiinflammatory drugs. The total number of aromatic rings is critical for sPLA2-II inhibition, and the best result was obtained in the case of six rings. The structure of the central part of the inhibitors was not specific, and potent inhibitors were found among the sulfide, sulfone, ether, methylene, and amino derivatives. Although a diester of the terminal carboxylic acid lost its inhibitory activity, having both of the carboxylic acids was not necessary for expression of activity, as illustrated by a glycine derivative with the benzyl ester group 36. Among the newly synthesized derivatives, 18, 20, 29, and 36 showed very potent human sPLA2-II inhibitory activity comparable to that of natural thielocin B3. Their IC50 values are in the range 0.069-0.14 microM, and they are a class of compounds showing the most potent sPLA2-II inhibition to date.

Benzhydryl Compounds↗

PubMed2000

Metabolic inactivation of five glycidyl ethers in lung and liver of humans, rats and mice in vitro.

1. Some glycidyl ethers (GE) have been shown to be direct mutagens in short-term in vitro tests and consequently GE are considered to be potentially mutagenic in vivo. However, GE may be metabolically inactivated in the body by two different enzymatic routes: conjugation of the epoxide moiety with the endogenous tripeptide glutathione (GSH) catalysed by glutathione S-transferase (GST) or hydrolysis of the epoxide moiety catalysed by epoxide hydrolase (EH). 2. The metabolic inactivation of five different GE, the diglycidyl ethers of bisphenol A (BADGE), 4,4'-dihydroxy-3,3',5,5'-tetramethylbiphenyl (Epikote YX4000) and 1,6-hexanediol (HDDGE) and the GE of 1-dodecanol (C12GE) and o-cresol (o-CGE), has been studied in subcellular fractions of human, C3H mouse and F344 rat liver and lung. 3. All GE were chemically very stable and resistant to aqueous hydrolysis, but were rapidly hydrolysed by EH in cytosolic and microsomal fractions of liver and lung. The aromatic GE were very good substrates for EH. In general, microsomal EH is more efficient than cytosolic EH in hydrolysis of GE, and human microsomes are more efficient than rodent microsomes. 4. The more water-soluble GE, o-CGE and HDDGE, were good substrates for GST whereas the more lipophilic GE, YX4000 and C12GE, were poor substrates for GST. In general, rodents are more efficient in GSH conjugation of GE than humans. 5. In general, the epoxide groups of YX4000 are the most and those of HDDGE the least efficiently inactivated of the five GE under study. For the other three GE no general trend was observed: the relative efficiency of inactivation varied with organ and species. 6. The large variation in metabolism observed with five representative GE indicate that GE have variable individual properties and should not be considered as a single, homogenous class of compounds.

Adolescent↗

PubMed1998

Effect of tropine derivatives, antimuscarinic agents, on the growth of Bombyx mori larvae.

A number of atropine analogs were synthesized and their effects on larval growth of the silkworm, Bombyx mori, were investigated by both topical application and dietary administration. Among the tested compounds, 8-methyl-8-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (5), an antagonist of the muscarinic acetylcholine receptor in mammals, significantly prolonged the duration of the instar. When fed on compound 5 at 30 ppm, some of the larvae failed to molt. A 2,2-diphenylpropionate moiety was indispensable for this activity. Compound 5 had more potent activity than atropine which is known to inhibit PTTH release in vitro.

Animals↗

PubMed2002

The quantification and characterization of endocrine disruptor bisphenol-A leaching from epoxy resin.

Bisphenol-A (BPA), a known endocrine disruptor, is a main building block of epoxy resin which has been widely used as a surface coating agent on residential water storage tanks. Therefore, BPA leaching from the epoxy resin can adversely affect human health. In this study, BPA leaching from three epoxy resins were quantified at 20, 50, 75 and 100 degrees C both in deionized water and the specified test water, respectively. BPA leached to the test water was identified using GC-MS and quantified with GC-FID after a sequential extraction and concentration. The results showed that BPA leaching has occurred in all three samples tested. The quantity of BPA from unit area of epoxy resin coating was in the range of 01.68-273. 12 microg/m2 for sample A, 29.74-1734.05 microg/m2 for sample B and 52.86-548.78 microg/m2 for sample C depending on the test temperature, respectively. In general, the amount of BPA leashing increased as the water temperature increases. This result implies a higher risk of BPA leaching to drinking water during a summer season. In addition, microbial growth, measured by colony forming units, in epoxy coated water tanks was higher than that in a stainless steel tank. The results suggest that compounds leaching from epoxy resin may support the growth of microorganisms in a residential water holding tank.

Benzhydryl Compounds↗

PubMed1977

[Isolation and identification of some metabolites of clofedanol from human urine (author's transl].

10 excretory products of Clofedanol (1-(o-chlorphenyl)-1-phenyl-3-dimethylaminopropanol) were identified in human urine. The following five products were extracted with chloroform at pH 1--2: o-(chlorphenyl)-phenylmethane (I), benzophenone (II), o-chlorbenzophenone (III), benzhydrol (IV), and o-(chlorphenyl)-beta-phenylacrolein (V). Two compounds were extracted with chloroform at pH 13--14: unchanged Clofedanol and 1-(o-chlorphenyl)-1-phenyl-3-dimethylaminopropene-1 (VI). N,N-dimethylamino-acetic acid (VII) was also identified in urine. Clofedanol and metabolite IV were present as free compounds, and they were also found after hydrolysis of metabolites VIII and IX with beta-glucuronidase.

Antitussive Agents↗