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PubMed1994

Methylene dianiline hepatotoxicity is not leukocyte-dependent.

Methylene dianiline (DDM) causes a dose- and time-dependent cholestasis, bile ductular epithelial injury, and hepatic parenchymal insult in rats. The mechanism of toxicity is unknown. Since hepatic leukocyte infiltration is a prominent feature of DDM-induced liver injury, and because leukocytes play a causal role in hepatic and extrahepatic tissue injury, we tested the hypothesis that toxicity caused by DDM is dependent on neutrophils or other circulating inflammatory cells. A polyclonal antibody (NAb) against rat neutrophils was used to address the role of the neutrophil in DDM-induced liver injury. NAb administration caused a significant reduction in circulating neutrophils without altering other leukocyte numbers. Moreover, NAb pretreatment prevented hepatic neutrophil infiltration after administration of DDM. However, neutrophil depletion did not afford protection from DDM-induced liver injury. This result was confirmed and the role of other circulating leukocytes was evaluated by inducing systemic leukopenia using cyclophosphamide (CYCLO). Administration of CYCLO diminished the number of circulating leukocytes within 4 days after treatment. Depletion of leukocytes by CYCLO prevented the hepatic accumulation of leukocytes but did not protect rats from DDM hepatotoxicity. These results suggest that the large numbers of leukocytes that infiltrate the liver after DDM administration do not contribute to hepatic injury.

Aniline Compounds↗

PubMed1982

Mutagenicity of 4,4'-methylenedianiline derivatives in the Salmonella histidine reversion assay.

4,4'-Methylenedianiline and its derivatives were assayed for mutagenicity in the Salmonella/microsomal mutagenicity assay develop by Ames. A specificity to revert strain TA98 suggests a mechanism of frameshift mutagenesis. Liver microsomal preparations (S-9) from rats induced with phenobarbital were most effective for metabolic activation. Alkyl substitution of 4,4'-methylenedianiline did not alter its mutagenic activity; however, substitution of both positions ortho to the amino group eliminated mutagenic activity. Substitution with alkoxy-carbonyl groups eliminated mutagenic activity, whereas halogen substitution (chlorine, fluorine) enhanced the mutagenic activity. The results presented here show the use of structure-activity studies as predictive tools for the assessment of genotoxic properties of industrial chemicals.

Aniline Compounds↗

PubMed1995

Infusion of bile from methylene dianiline-treated rats into the common bile duct injures biliary epithelial cells of recipient rats.

Methylene dianiline (4,4'-diaminodiphenylmethane, DAPM) rapidly causes cholestasis and injury to biliary epithelial cells (BEC) in the liver and common bile duct of rats. Our objective was to determine if the proximate toxicant(s) was present in bile. Bile from DAPM-treated or control rats was infused through the common bile duct of untreated rats via inflow and outflow cannulas for 4 h. Cholestasis, increases in serum constituents, and intrahepatic BEC injury in the livers of DAPM-treated donor rats at 4 h were comparable to previous studies (Kanz et al., Toxicol. Appl. Pharmacol. 117 (1992) 88-97). BEC injury in the common bile duct of rats receiving DAPM bile or control bile was assessed by point counting. Percent necrosis was > 28% in the common bile duct of rats receiving DAPM bile compared to < 5% in rats receiving control bile. These results indicate that bile is a major route of BEC exposure to DAPM proximate toxicant(s) and demonstrate the utility of a new method for investigating mechanisms of biliary toxicants.

Aniline Compounds↗

PubMed1998

Characterization of hemoglobin adducts from a 4, 4'-methylenedianiline metabolite evidently produced by peroxidative oxidation in vivo.

4,4'-Methylenedianiline (MDA) is a widely used mutagenic and carcinogenic industrial chemical. It is also a metabolite of 4, 4'-methylenediphenyl diisocyanate (MDI), which is used in the manufacturing of polyurethane foams. Biomonitoring of MDA, like other aromatic amines, is mainly carried out by GC/MS measurement of cysteine adducts in Hb from the nitroso metabolite, released by alkaline hydrolysis. In the present study it was investigated whether the formation of Hb adducts from non-nitroso metabolites of MDA can be used for the dosimetry of MDA. The study was carried out by treatment of mice with MDA and tritiated MDA or deuterated MDA and by identification of their products of reaction with Hb, after enzymatic hydrolysis of the globin and enrichment of the adducts. The main adduct, about 50% of the total amount of MDA associated with Hb, was characterized by MS and was shown to be a reaction product of MDA and the amino group of N-terminal valine in Hb, the derived structure being 1-[(4-imino-2, 5-cyclohexadien-1-ylidene)methyl]benzene-4-azo-2-isovaleric acid. It is likely that this quinonoid MDA imine adduct to valine was formed by an attack of a metabolite formed through peroxidative oxidation of MDA, in analogy with earlier observed oxidation of some other aromatic amines, e.g., benzidine. The reactive intermediate is suggested to be [(4-imino-2, 5-cyclohexadien-1-ylidene)methyl]-4-aminobenzene. The formation of the adduct was confirmed by incubating MDA with valine methyl ester in vitro in the presence of H2O2 and lactoperoxidase. Further, the same adduct was detected in MDI-exposed and control rats, the level in the exposed animals being about 60 times higher than in the controls. This study indicates that, at least in the mouse, extrahepatic peroxidative metabolism is an important pathway for the bioactivation of MDA, possibly leading to a genotoxic reactive intermediate. This study also demonstrates the usefulness of Hb adduct analysis for the identification of reactive intermediates in vivo.

Aniline Compounds↗

PubMed1987

Inhibition of neoplastic development in rat liver, kidney, oesophagus and forestomach by 4,4'-diaminodiphenylmethane administration.

The modifying effects of 4,4'-diaminodiphenylmethane (DDPM) (0.1% in diet) administration on liver carcinogenesis induced by 2-acetylaminofluorene (2-AAF) (0.02% in diet), 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) ( 0.06% in diet), diethylnitrosamine (DEN) (0.001% in drinking water) and N-ethyl-N-hydroxyethylnitrosamine (EHEN) (0.1% in drinking water), EHEN-induced oesophagus and kidney carcinogenesis and forestomach carcinogenesis induced by butylated hydroxyanisole (1.0% in diet) were examined in F344 male rats. Mean survival time tended to be longer in DDPM-supplemented groups, the difference being significant in DEN + DDPM and EHEN + DDPM groups. Intake of carcinogens was slightly but not significantly reduced by DDPM. The incidences of hyperplastic nodules and hepatocellular carcinomas were significantly decreased in 2-AAF or 3'-Me-DAB + DDPM groups. Pulmonary metastases were also less common in 3'-Me-DAB or EHEN + DDPM groups. Development of papillomas in the oesophagus but not in tumours in the forestomach was also inhibited by DDPM. Inhibition in the different organs was not significantly related to decrease in body weight or carcinogen intake, indicating a mechanism independent of non-specific toxic effects or reduction in food consumption. Some other factors possibly related to its ability to cause bile duct proliferation and/or altered activity of enzymes relevant to drug metabolism may be involved.

2-Acetylaminofluorene↗

PubMed2004

Co-culture of primary human mammary fibroblasts and MCF-7 cells as an in vitro breast cancer model.

Approximately 60% of all breast tumors are estrogen-responsive and chemicals that show estrogenic or anti-estrogenic properties are able to interact with breast tumor growth. In a breast tumor, adipose stromal cells (fibroblasts) surrounding the epithelial tumor contain the aromatase enzyme, which converts androgens into estrogens. Exposure to aromatase inducers can therefore lead to increased estrogen levels and possibly to accelerated breast tumor growth. Subsequently, breast tumor cells synthesize and secrete elevated levels of factors such as prostaglandin E2 (PGE2), interleukin-6 (IL-6), and IL-6 soluble receptor (IL-6sR), which in turn have the ability to stimulate aromatase gene transcription in fibroblasts, establishing a positive feedback loop. In this study, a technique that allows for culturing MCF-7 epithelial breast tumor cells and healthy primary human mammary fibroblasts together in one compartment was developed. To establish the positive feedback loop, the co-culture was exposed to estrogenic compounds. RNA was isolated and reverse-transcriptase polymerase chain reaction (RT-PCR) was performed on the aromatase and pS2 genes. Exposure of the co-culture to estradiol (E2), diethylstilbestrol (DES), and bisphenol-A (BPA), resulted in a three- to seven-fold increase of pS2 transcription levels. Furthermore, pS2 transcription levels increased even more when the aromatase substrate testosterone (20 nM) was present in the co-culture medium. Exposure of the co-culture to the aromatase inducer dexamethasone (DEX) resulted in increased pS2 transcription levels, as well as increased aromatase transcription levels. Simultaneous exposure to DEX and the synthetic anti-estrogen ICI 182,780 almost completely blocked the pS2 response. The aromatase induction response was not altered by ICI 182,780 treatment. Simultaneous exposure to DEX and the non-steroidal aromatase inhibitor fadrozole, abolished the effect of the presence of testosterone in the co-culture medium, but did not result in pS2 gene transcription levels as low as seen after exposure to ICI 182,780. These observations indicate the presence of a positive feedback loop in our co-culture system. This co-culture provides a more sophisticated and sensitive system to detect direct and indirect estrogenic effects of compounds and their possible effects on breast tumor promotion.

Aromatase↗

PubMedDate not supplied

Mutagenicity of N-acetyl and N,N'-diacetyl derivatives of 3 aromatic amines used as epoxy-resin hardeners.

3 epoxy-resin hardeners, 4,4'-diaminodiphenyl ether (DDE), 4,4'-diaminodiphenylmethane (DDM), and 4,4'-diaminodiphenylsulfone (DDS), and their N-acetyl and N,N'-diacetyl derivatives were examined for their mutagenicity using Salmonella typhimurium TA98 and TA100 as the tester stains and an S9 mix containing a rat-liver 9000 X g supernatant fraction as the metabolic activation system. DDE and DDM were mutagenic towards TA98 and TA100 in the presence of S9 mix while DDS exhibited no significant mutagenic activity towards these tester strains. These epoxy-resin hardeners were metabolized in vivo and their N-acetyl and N,N'-diacetyl metabolites were found in the urine. Among these acetyl metabolites, only N-acetyl-DDE was found to be mutagenic towards TA98 and TA100 in the presence of S9 mix. None of these acetyl metabolites exhibited significant mutagenic activity towards these tester strains in the absence of S9 mix.

Aniline Compounds↗

PubMed1985

Methylene dianilene: a new toxic cause of visual failure with hepatitis.

A 28-year-old man ingested methylene dianilene in potassium carbonate and gamma-butyrolactone. He developed toxic optic neuritis, with severe visual dysfunction (not previously reported in humans), prolonged toxic hepatitis, with disturbed liver-function tests 18 months after the incident, and other more transient effects. The course of his illness is described and the literature on methylene dianilene toxicity is reviewed.

Adult↗

PubMed2006

Endocrine disrupting chemicals (bisphenol A, 4-nonylphenol, 4-tert-octylphenol) modulate expression of two distinct cytochrome P450 aromatase genes differently in gender types of the hermaphroditic fish Rivulus marmoratus.

To understand the effect of endocrine-disrupting chemicals (EDCs) on cytochrome P450 aromatase (rm-cyp19) gene expression between gender types in the hermaphroditic fish Rivulus marmoratus, we cloned two distinct rm-cyp19 genes using RT-PCR with degenerative primers, obtained full-length cDNAs using 5'- and 3'-RACE-PCR methods, and completely sequenced them. The brain aromatase (rm-cyp19b) cDNA consisted of 2,124 bp including the open reading frame (ORF), which encoded a putative protein of 505 amino acids. The ovarian aromatase (rm-cyp19a) cDNA consisted of 2,075 bp, including the ORF encoding a putative protein of 516 amino acids. Expression patterns of rm-cyp19b and rm-cyp19a mRNAs were investigated in embryos of different developmental stages and in seven different tissues of adult fish. The rm-cyp19b gene in hermaphrodite and secondary male R. marmoratus was predominantly expressed in the brain, while the rm-cyp19a gene was expressed gender-specifically in the gonad. The expression of rm-cyp19b mRNA increased from stage 1 (2 d post fertilization) to stage 4 (12 d post fertilization) in a developmental stage-dependent manner but steeply decreased in the hatching stage. Compared to the rm-cyp19b gene, the abundance of ovarian aromatase rm-cyp19a transcripts was very low, and its expression was first detected at stage 3 and then decreased gradually to the hatching stage. Alteration of rm-cyp19b and rm-cyp19a gene expression was further analyzed in the brain and gonad by real-time RT-PCR 96 h after EDC exposure in hermaphrodites and secondary males. The brain aromatase rm-cyp19b gene was up-regulated in the brain after 4-nonylphenol (4-NP)-exposure, while the ovarian aromatase rm-cyp19a gene was significantly down-regulated in the gonad. In 300 microg/L 4-tert octylphenol (4-tert-OP), or 600 microg/L bisphenol A-exposed brain and gonad, both rm-cyp19b and rm-cyp19a genes were up-regulated. In the case of secondary males, the rm-cyp19b gene was highly expressed in the 4-NP-exposed brain, while expression of the rm-cyp19a gene was not detected in the gonad. These results indicate that the expression of rm-cyp19a and rm-cyp19b genes is differently modulated according to estrogenic compounds and gender type of R. marmoratus.

Animals↗

PubMed2004

Study on anti-androgenic effects of bisphenol a diglycidyl ether (BADGE), bisphenol F diglycidyl ether (BFDGE) and their derivatives using cells stably transfected with human androgen receptor, AR-EcoScreen.

We studied in vitro hormonal activity of bisphenol A diglycidyl ether (BADGE) and bisphenol F diglycidyl ether (BFDGE), which are used as a material of interior coating for food cans. We also examined related compounds such as 2,2-bis[4-(3-chloro-2-hydroxypropoxy)phenyl]propane (BADGE.2HCl), and bis[4-(3-chloro-2-hydroxypropoxy)phenyl]methane (BFDGE.2HCl) etc. For this purpose, we constructed two stably transfected CHO-K1 cell lines (AR-EcoScreen for androgenic activity and c-luc for cell toxicity evaluation). One stably expresses luciferase with induction of androgen. The other stably expresses luciferase without androgen induction. Also, we have determined the androgenic and anti-androgenic effects of the test chemicals by reporter gene assay with these cell lines. None of the chemicals tested by this assay exhibited androgen agonistic activity. However, BADGE.2HCl and BFDGE.2HCl had the conspicuous antagonistic activity for androgen. These compounds had a high binding affinity for androgen receptor. Furthermore, these two compounds did not show the estrogenic activity in vitro assays. On the contrary, bisphenol A and bisphenol F exhibited anti-androgenic activity in vitro in addition to the estrogenic activity. These results suggest that these chlorohydroxy compounds of BADGE and BFDGE act as androgen antagonist through the process of binding to androgen receptor.

Androgen Antagonists↗

PubMedDate not supplied

Novel Calbindin-D(9k) protein as a useful biomarker for environmental estrogenic compounds in the uterus of immature rats.

The compounds that bind the estrogen receptors (ER) and induce or modulate an ER-mediated response can be defined as estrogenic endocrine disruptors (EDs). We demonstrated that environmental estrogens induced the uterine CaBP-9k mRNA in rats using Northern blot assay suggesting that CaBP-9k gene could be a biomarker for the estrogenicity of chemicals in the previous studies. In the present studies, we further collaborated this idea by investigating the regulation and localization of CaBP-9k protein in response to estrogenic compounds. Immature rats were injected with estrogenic chemicals, 4-tert-octylphenol (OP), nonylphenol (NP) and bisphenol A (BPA) or 17beta-estradiol (E2). After treatment with these estrogenic compounds, the effects on the accumulation of CaBP-9k protein and uterine localization were examined by Western blot analysis and immunohistochemical staining (IHC), respectively. A dose- and time-dependent increase in CaBP-9k protein was observed in the uterus of immature rats when treated with OP and NP. In addition, treatment with BPA resulted in a significant increase in CaBP-9k protein at dose of 500mg/kg BW/day. Taken together, CaBP-9k protein is strongly up-regulated by estrogenic compounds (OP, NP and BPA) and E2 itself in the uterus of immature rats. These results indicate that CaBP-9k protein can be a useful biomarker for detection of the estrogenicity of putative estrogenic compounds. Thus, regarding to risk assessment, we propose that CaBP-9k protein assay in the immature rat uterus can be a very sensitive and powerful tool to identify compounds with estrogenic activity when used in combination with classical assays.

Animals↗

PubMed2005

Fatigue in military aviation: an overview of US military-approved pharmacological countermeasures.

Uncomfortable working and sleeping environments, high operational tempos, sustained operations, and insufficient staffing make fatigue a growing concern. In aviation, where a single mistake can cost millions of dollars, it is essential to optimize operator alertness. Although behavioral and administrative fatigue countermeasures should comprise the "first line" approach for sustaining aircrew performance, pharmacological fatigue countermeasures are often required. Various components of the U.S. military have authorized the use of specific compounds for this purpose. Hypnotics such as temazepam, zolpidem, or zaleplon can mitigate the fatigue associated with insufficient or disturbed sleep. Alertness-enhancing compounds such as caffeine, modafinil, or dextroamphetamine can temporarily bridge the gap between widely spaced sleep periods. Each of these medications has a role in sustaining the safety and effectiveness of military aircrews. The present paper provides a short overview of these compounds as well as factors to be considered before choosing one or more to help manage fatigue.

Acetamides↗

PubMed1993

Modifying influence of prior treatment with toxic agents on induction of preneoplastic and neoplastic lesions in a medium-term multi-organ carcinogenesis bioassay.

The modifying potential of prior administration of toxic agents was investigated in our multi-organ carcinogenesis model using male F344/DuCrj rats with the aim of assessing the link between tissue damage and initiation. Animals were administered one of four toxic agents for 8 wk, and then treated with N-diethylnitrosamine (DEN, 100 mg/kg body weight (b.w.), intraperitoneally (i.p.), single injection), N-methylnitrosourea (MNU, 20 mg/kg b.w., i.p., four times during wk 9 and 10), and dihydroxy-di-N-propylnitrosamine (DHPN, 0.1% in drinking water, during wk 11 and 12) for multi-organ carcinogenesis. All surviving rats were killed at the end of wk 36, and the major organs carefully examined for preneoplastic and neoplastic lesion development. Immunohistochemical demonstration of glutathione S-transferase placental form (GST-P) positive foci was also performed to facilitate quantitative assessment of liver lesion development. D-galactosamine (300 mg/kg b.w., i.p., once a week), a hepatotoxin, significantly inhibited the induction of GST-P positive foci, while 4,4'-diaminodiphenylmethane (DDPM, 0.1% in diet), a bile duct proliferator which is itself a hepatocarcinogen, possessed enhancing activity. DDPM, also a goitrogen, clearly inhibited the development of follicular cell tumors in the thyroid. Uracil (3.0% in diet), which is an inducer of papillomatosis in the urinary bladder, did not exert any enhancing potential on bladder carcinogenesis. Bleomycin (2 mg/kg b.w., i.p., twice a week), which is an alveolar epithelium injuring agent, also did not modify the induction of alveolar epithelium proliferative lesions. These results indicate that prior organ injury by toxic agents does not always act to enhance sensitivity to carcinogenesis.

Aniline Compounds↗

PubMed1986

Inhibitory effects of ethoxyquin, 4,4'-diaminodiphenylmethane and acetaminophen on rat hepatocarcinogenesis.

Four antioxidant species, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethoxyquin and alpha-tocopherol, and three other compounds, 4,4'-diaminodiphenylmethane (DDPM), acetaminophen and glutathione, were tested for inhibitory effect on hepatocarcinogenesis in male F344 rats. Rats were initially given a single ip injection of diethylnitrosamine (200 mg/kg body weight) and fed basal diet containing 0.02% 2-acetylaminofluorene from week 2 to week 8. Animals were subjected to partial hepatectomy at the end of week 3. From week 12 to week 36, they were given basal diet containing 2% BHA, 1% BHT, 0.8% ethoxyquin, 1% alpha-tocopherol, 0.1% DDPM, 1% acetaminophen, or 1% glutathione, then killed at week 40, 4 weeks after cessation of treatment with the test chemicals. The incidence of hepatocellular carcinoma (HCC) was significantly decreased in the groups given ethoxyquin or DDPM. Quantitative analysis of the number and area of HCC per unit liver area revealed a significant decrease in the area of HCC in the groups given ethoxyquin, DDPM or acetaminophen. The results suggest that ethoxyquin, DDPM and acetaminophen exerted an inhibitory effect on the development of HCC, while BHA, BHT, alpha-tocopherol and glutathione had no significant effect.

2-Acetylaminofluorene↗

PubMed2004

Oxidation of bisphenol A, 17beta-estradiol, and 17alpha-ethynyl estradiol and byproduct estrogenicity.

A human breast cancer cell line (MCF-7) was used to investigate the cumulative estrogenicity profiles elicited during the oxidation of three estrogenic compounds [bisphenol A (BPA), 17beta-estradiol (E2), and 17alpha-ethynyl estradiol (EE2)]. High-performance liquid chromatography (HPLC) with a method detection limit (MDL) of approximately 1 nM was used to measure the initial and final concentrations of test compounds during oxidation. Both chlorination and ozonation removed from 75% to >99% of the test compounds in distilled water. Increasing contact time and chlorination dose improved compound removal. Chlorination byproducts of BPA, E2, and EE2 elicited low levels of estrogenicity over an extended period of time. For equivalent molar oxidant dosages, ozone and chlorine had comparable residual proliferative effect values and >99% loss of the parent compounds. For oxidation studies of estrogenic chemicals, ammonium chloride was found to adequately quench residual chlorine without interfering with cell culture assay. Oxidation of test compounds with chlorine and ozone resulted in a similar estrogenicity trend, with a relative higher level of estrogenicity elicited during the early phases of oxidation, which gradually dissipated over the extended exposure time to a stable point. Oxidation with ozone resulted in the rapid transformation of test compounds, reaching a stabilized estrogenic level in 10 min, whereas for chlorination it took more than 120 min for elicited estrogenicity to stabilize.

Benzhydryl Compounds↗

PubMed2001

Distribution of bisphenol A and tetrabromobisphenol A in quail eggs, embryos and laying birds and studies on reproduction variables in adults following in ovo exposure.

In a previous study, we showed that bisphenol A (BPA) had oestrogen-like effects in bird embryos, causing malformations of the oviducts in Japanese quail (Coturnix japonica) and feminisation of the left testis in chicken (Gallus domesticus). In this study, uptake and distribution of BPA and tetrabromobisphenol A (TBBPA) in embryos and laying quail were examined as well as variables related to reproduction in adult quail following administration of the compounds into the yolk of embryonated eggs. The uptake of radiolabelled BPA, TBBPA and the reference compound diethylstilboestrol (DES) was studied in the embryos using beta-spectrometry. Autoradiography was employed to examine distribution in egg and embryo after yolk sac injection of BPA or TBBPA and in laying birds, following intravenous and oral administration. Following embryonic exposure to BPA or TBBPA, sexually mature male birds were examined for reproductive behaviour and testis morphology, and females were examined for egg laying and oviduct morphology. Neither BPA (200 microg/g egg) nor TBBPA (15 microg/g egg) caused any significant oestrogen-like effects on the variables studied, although effects on the female oviducts after BPA exposure were indicated. Embryonic exposure to DES is known to cause profound effects on male sexual behaviour and female oviduct morphology at doses 3-5 orders of magnitude lower than the BPA and TBBPA doses used in the present study. The proportions of BPA and TBBPA taken up by the embryos after yolk sac injection were similar to the proportion of DES taken up. Differences in bioavailability, therefore do not account for any major part of the potency differences between DES and the two bisphenol A compounds. The concentration of radioactivity in the embryo, as revealed by autoradiography, was low compared with that in the yolk at all stages studied (days 6, 10 and 15). Pronounced labelling of the bile and the allantoic fluid was observed, however, indicating that both compounds were readily metabolised and excreted. Radiolabelled BPA and TBBPA administered to laying quail were largely excreted via the bile and 9 days after oral dosing, only small amounts of the labelled compound remained within the body. Maternal transfer of labelled BPA and TBBPA to the egg was low.

Administration, Oral↗

PubMed1983

A gas chromatographic procedure for the determination of airborne MDI and TDI.

A method is described for the analysis of airborne diphenylmethane diisocyanate (MDI) and toluene diisocyanate (TDI) using gas-liquid chromatography. The diisocyanates are collected in acidic absorbing solution where they undergo hydrolysis, converted to the free diamines with caustic, and extracted into toluene. The diamines are derivatized in the toluene with heptafluorobutyric anhydride (HFBA). These derivatives are analyzed by GLC using an electron capture detector. The method has the advantages of specificity for the two diisocyanates, while demonstrating excellent accuracy and precision. A value one-tenth of the NIOSH recommended Occupational Health Standard for either compound may easily be detected in a 40 liter air sample.

Air↗

PubMed2005

Inhibitory effects of environmental chemicals on protein disulfide isomerase in vitro.

BACKGROUND: The influence of endocrine disrupting chemicals (EDCs) upon physiological functions and their mechanisms is of concern. We have previously demonstrated that protein disulfide isomerase (PDI) was a target molecule of bisphenol A (BPA), which is considered to be EDC. PDI plays a key role in protein folding as an isomerase and also possesses a 3,3',5-triiodo-L-thyronine (T3)-binding activity. Since PDI activities were inhibited by BPA in our previous study, BPA might have adverse effects on physiological functions via the inhibition of PDI activities. We conducted this study to identify the compounds which disturb PDI activities as well as BPA, and to discuss their structural characteristics. METHODS: We examined the effects of 22 suspected EDC on both the T3-binding activity and isomerase activity of rat recombinant PDI. RESULTS: Among the 22 compounds, only phenolic compounds, namely BPA, p-octylphenol, p-nonylphenol, 2,4-dichlorophenol, pentachlorophenol, tetrabromobisphenol A, and tetrachlorobisphenol A, inhibited T3 binding to PDI. Furthermore non-halogenated compounds among these phenolic compounds, such as BPA, p-octylphenol, and p-nonylphenol, showed inhibitory effects on the isomerase activity of PDI. CONCLUSIONS: Our results suggest that phenolic groups might have important inhibitory effects on the T3-binding activity of PDI, and that compounds with phenolic groups might have the same effects on PDI. Furthermore, non-halogenated phenolic compounds had inhibitory effects on the isomerase activities of PDI in addition to T3-binding activity, indicating that these compounds might also have adverse effects on protein folding, which PDI participates in by catalyzing rearrangements of disulfide bonds as an isomerase.

Animals↗