[Safety evaluation of chemicals using bibliographic databases for their effects on gene expression profiles].
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Animals↗
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Dynamic changes in dopaminergic neurotransmission induced by a low concentration of bisphenol-A in neurones and astrocytes.
One of the most common chemicals that behaves as an endocrine disruptor is the compound 4,4'-isopronylidenediphenol, called bisphenol-A (BPA). We previously reported that prenatal and postnatal exposure to BPA potentiated central dopaminergic neurotransmission, resulting in supersensitivity to psychostimulant-induced pharmacological actions. Many recent findings have supported the idea that astrocytes, which are a subpopulation of glial cells, play a critical role in neuronal transmission in the central nervous system. The present study aimed to investigate the role of neurone-astrocyte communication in the enhancement of dopaminergic neurotransmission induced by BPA. We found that treatment of mouse purified astrocytes and neurone/glia cocultures with BPA in vitro caused the activation of astrocytes, as detected by a stellate morphology and an increase in levels of glial fibrillary acidic protein. A low concentration of BPA significantly enhanced the Ca2+ responses to dopamine in both neurones and astrocytes. Furthermore, a high concentration of BPA markedly induced the activation of caspase-3, which is a marker of neuronal apoptotic cell death in mouse midbrain neurone/glia cocultures. By contrast, treatment with 17beta-oestradiol (E2) had no such effects. Prenatal and neonatal exposure to BPA led to an enhancement of the dopamine-dependent rewarding effect induced by morphine. These findings provide evidence that BPA alters dopamine responsiveness in neurones and astrocytes and that, at least in part, it may contribute to potentiate the development of psychological dependence on drugs of abuse.
Analgesics, Opioid↗
[The molecular mechanisms of estrogens. Clinical aspects, industrial estrogens and phytoestrogens].
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Animals↗
[Experimental behavioral tests using monkey and rat offspring born from mothers exposed perinatally to EDCs].
Purpose of this study is to conduct risk assessment of EDCs for the development of CNS in humans by extrapolation from the results of behavioral tests in rats and monkeys. Our hypotheses on the mechanism which gives an adverse effect of EDCs to the developing neural systems are as follows. Thyroid hormone (TH) disrupting chemicals induce deterioration of neural development and estrogen (E2) agonistic chemicals may disturb apoptosis of fetal neural cells resulting in injury of normal neural circuit. The strategy of this study is a bottom up system; for example, basic information was obtained by an experiment using rats and then an experiment using monkey was designed to adapt the results from rats. The monkey experiment data will be assessed in comparison with human behavior. The tactics of this study are, however, a top down system. It is neural behaviors which are an end point evaluation that are primarily performed. They are mother-infant interactions, social behaviors, open field test, memory and learning tests, etc. As for analysis of the mechanism of EDCs' adverse effect, we tried two methods: one is an in vivo drug biased test which interferes with the monoamine oxidase (MAO) system and the other is an in vitro primary neural cell culture. EDCs including BPA, NP, propylthiouracil (PTU) and PCB-OH are injected orally to pregnant rats from gestation day 3 (GD3) to post natal day 21 (PND21) at weaning and their offspring were tested. On the other hand TCDD, BPA and PCB effect are assessed in rhesus monkey or cynomolgus monkey offspring. The study is still continuing and we will present the results obtained to date.
Animals↗
Synthesis and estrogenic activity of bisphenol a mono- and di-beta-D-glucopyranosides, plant metabolites of bisphenol A.
The syntheses and characterization of bisphenol A mono- and di-beta-D-glucopyranosides were undertaken to confirm that these compounds are major plant metabolities of bisphenol A (BPA) and to allow an assessment of their estrogenicity. Synthesis involved the glucosidation of unprotected BPA with glucose penta-acetate with phosphorus oxychloride as catalyst. The estrogenic activity of BPA and its mono- and di-beta-D-glucopyranosides were measured with an enzyme-linked immunosorbent assay (ELISA)-based estrogen receptor competitive binding assay and with a yeast two-hybrid assay adapted to a chemiluminescent reporter gene (for beta-galactosidase). Both methods showed that the estrogenicity of BPA was eliminated by formation of the di-glucoside, but whereas the ELISA-based method indicated that reduced activity remained in the monoglucoside, the yeast two-hybrid method showed the monoglucoside to be inactive. Presumably these results reflect the more complex interactions of test compound and cellular components required to demonstrate estrogenicity in the yeast two-hybrid assay. As these processes parallel those in mammalian cells, the yeast two-hybrid method is likely to be the more realistic assay. The uptake and metabolism of BPA by plants offers the possibility of phytoremediation of contaminated water, but also provides an additional route for the compound to enter the human food chain.
Benzhydryl Compounds↗
Sensitivity of expression of perivitelline membrane glycoprotein ZP1 mRNA in the liver of Japanese quail (Coturnix japonica) to estrogenic compounds.
Avian perivitelline membrane protein, ZP1, is synthesized and secreted by the liver with the stimulation of estrogens. In the present study, we measured the expression of ZP1 gene in the liver of immature male quail treated with various estrogenic compounds and in the liver of male quail embryos that were developed in the fertilized eggs laid by mother quail injected with various estrogenic compounds during vitellogenesis. Total RNA extracted from the liver was reverse-transcribed and cDNA was subjected to real-time PCR. Both diethylstilbestrol and ethinyl estradiol caused significant effect on the increase in mRNA in immature male quail. In contrast, diethylstilbestrol administered via the route of maternal injection was not effective for induction of embryonic mRNA, although the effect of ethinyl estradiol administered via the same route was prominent. These results showed that direct administration of estrogenic compounds, diethylstilbestrol and ethinyl estradiol, stimulates the induction of ZP1 gene, but the rate of accumulation of these compounds in the yolk is different during vitellogenesis. The present studies suggest that although ZP1 gene is a sensitive biomarker to evaluate the effects of endocrine disruptors, the route of administration is an important factor to compare the effectiveness.
Animals↗
Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro.
BACKGROUND & AIMS: The ligand-dependent transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in hepatic stellate cells (HSC), and its transcriptional activity is reduced during cell transdifferentiation in culture. PPARgamma transcriptional activation decreases platelet-derived growth factor-induced proliferation and inhibits alpha-smooth muscle actin expression in cultured HSC. The aim of our study was to evaluate whether oral administration of synthetic PPARgamma ligands, thiazolidinediones (TZD), might affect collagen deposition in animal models of liver fibrosis. METHODS: The effect of 2 TZD (pioglitazone or rosiglitazone) was tested on liver fibrosis induced in rats by either toxin administration (dimethylnitrosamine or carbon tetrachloride) or bile duct ligation. In vivo PPARgamma activation was evaluated by gel shift assay using nuclear extracts from HSC isolated from control and treated rats. RESULTS: Oral administration of TZD reduced extracellular matrix deposition and HSC activation in both toxic and cholestatic models of liver fibrosis. PPARgamma-specific DNA binding was significantly impaired in nuclear extracts of HSC isolated from fibrotic rats compared with HSC from control rats. TZD administration restored PPARgamma DNA binding in HSC nuclei. In vitro, TZD-induced PPARgamma activation inhibited collagen and fibronectin synthesis induced by transforming growth factor (TGF)-beta1 in human HSC, as measured by enzyme-linked immunosorbent assay and Northen blotting. TZD also reduced the TGF-beta1-induced activity of a 3.5-kilobase procollagen type I promoter transfected in human HSC. CONCLUSIONS: These findings indicate that PPARgamma activation in HSC retards fibrosis in vivo and suggest the use of TZD for the treatment of liver fibrosis.
Animals↗
Characterization of diethylstilbestrol-induced hypospadias in female mice.
The urethral duct and vagina are formed from the urogenital sinus (UGS) during the early neonatal period in mice. Neonatal estrogen exposure results in hypospadias, or the malpositioning of vaginal and urethral openings, with wide cleft clitoris. We sought to characterize diethylstilbestrol (DES) influence on UGS morphogenesis and hypospadias formation. Newborn (day 0) and 1-4-day-old female mice (ICR/Jcl) were given (s.c.) oil or 3.0 microg DES. Animals were killed 24 hr later; then hypospadias formation and epithelial apoptosis and proliferation within the developing UGS were assessed. DES did not alter normal UGS morphogenesis by day 1, in comparison with controls. However, hypospadias formation was observed in DES-treated mice by day 3. In these mice, the distal dorsal urethral duct appeared to fuse with and open into the lower vaginal solid cord region. Further, DES treatment produced a gradual significant increase in dorsal urethral epithelial apoptosis (P < 0.05) just prior to and during fusion and hypospadias formation. DES-induced urethral epithelial and sinus cord proliferation appeared significantly increased (P < 0.05) and unchanged, respectively, just prior to fusion. By day 5, DES-treated mice exhibited wide cleft clitoris. In addition, if DES was given on day 3 or 5, a gradual, distinct caudal shift in the vaginal-urethral junction was observed compared to mice treated on days 0-2. Although hypospadias was not induced when neonates were given DES on day 7, these mice continued to display early vaginal opening. Dose-response analysis indicated that 0.03 microg DES for 5 days is the lowest known critical dose for hypospadias induction. We have shown for the first time that DES-induced hypospadias onset may primarily be the result of changes in developing dorsal urethral epithelial cell apoptotic and proliferative activity, and that the location of DES-induced hypospadias formation is dependent on age at time of exposure.
Animals↗
Summary of the National Toxicology Program's report of the endocrine disruptors low-dose peer review.
At the request of the U.S. Environmental Protection Agency (U.S. EPA), the National Toxicology Program organized an independent and open peer review to evaluate the scientific evidence on low-dose effects and nonmonotonic dose-response relationships for endocrine-disrupting chemicals in mammalian species. For this peer review, "low-dose effects" referred to biologic changes that occur in the range of human exposures or at doses lower than those typically used in the standard testing paradigm of the U.S. EPA for evaluating reproductive and developmental toxicity. The demonstration that an effect is adverse was not required because in many cases the long-term health consequences of altered endocrine function during development have not been fully characterized. A unique aspect of this peer review was the willing submission of individual animal data by principal investigators of primary research groups active in this field and the independent statistical reanalyses of selected parameters prior to the peer review meeting by a subpanel of statisticians. The expert peer-review panel (the panel) also considered mechanistic data that might influence the plausibility of low-dose effects and identified study design issues or other biologic factors that might account for differences in reported outcomes among studies. The panel found that low-dose effects, as defined for this review, have been demonstrated in laboratory animals exposed to certain endocrine-active agents. In some cases where low-dose effects have been reported, the findings have not been replicated. The shape of the dose-response curves for reported effects varied with the end point and dosing regimen and were low-dose linear, threshold-appearing, or nonmonotonic. The findings of the panel indicate that the current testing paradigm used for assessments of reproductive and developmental toxicity should be revisited to see whether changes are needed regarding dose selection, animal-model selection, age when animals are evaluated, and the end points being measured following exposure to endocrine-active agents.
Androgens↗
The endocrine and reproductive system: adverse effects of hormonally active substances?
Chemicals that have the intrinsic property to modulate or even disrupt the endocrine system are present in the human environment. Because it is the potency of such chemicals that determines the toxicologic relevance, assessment of the risk to human health must consider both the endocrine disrupting potential and the potency. Usually in vitro assays are applied to detect the potential of a hormone-like effect, and such data are considered useful to set priorities for additional testing and for mechanistic studies. However, such data allow only determination of relative potency of a chemical as compared with other xenobiotics, natural compounds, or endogenous hormones. Relevant information on the endocrine-disrupting potency can be taken only from in vivo assays, eg, the Hershberger (male reproductive organs) and uterotrophic (female reproductive organs) assays, the updated versions of the 28- and 90-day toxicity studies in rodents, and the 2-generation studies in rodents. With the use of this information and the concentration of these chemicals in humans, the potency of the effect as compared with endogenous hormone activity can be estimated. So far, the relative potencies of chemicals tested in in vitro systems as compared with estradiol are several orders of magnitude smaller, whereas potency of the phytoestrogen, eg, isoflavones such as genistein or daidzein, can even exceed that of estradiol, especially in infants who are fed soy-based formula as a sole source of nutrition. Although there are still open questions regarding in utero or early postnatal exposure, the low potencies and concentrations of manmade chemicals as compared with the endogenous hormones in humans make it unlikely that adverse effects occur at common exposure.
Animals↗
The food contaminants bisphenol A and 4-nonylphenol act as agonists for estrogen receptor alpha in MCF7 breast cancer cells.
Xenoestrogens are chemically distinct industrial products potentially able to disrupt the endocrine system by mimicking the action of endogenous steroid hormones. Among such compounds, the ubiquitous environmental contaminants bisphenol A (BPA) and 4-nonylphenol (NPH) may promote adverse effects in humans triggering estrogenic signals in target tissues. Following a research program on human exposure to endocrine disruptors, we found contamination of fresh food by BPA and NPH. More important, these contaminants were found to display estrogen-like activity using as a model system the estrogen-dependent MCF7 breast cancer cells (MCF7wt); its variant named MCF7SH, which is hormone-independent but still ERalpha-positive, and the steroid receptor-negative human cervical carcinoma HeLa cells. In transfection experiments BPA and NPH activated in a direct manner the endogenous ERalpha in MCF7wt and MCF7SH cells, as the antiestrogen hydroxytamoxifen was able to reverse both responses. Moreover, only the hormone-binding domains of ERalpha and ERbeta expressed by chimeric proteins in HeLa cells were sufficient to elicit the transcriptional activity upon BPA and NPH treatments. Transfecting the same cell line with ERalpha mutants, both contaminants triggered an estrogen-like response. These transactivation properties were interestingly supported in MCF7wt cells by the autoregulation of ERalpha which was assessed by RT-PCR for the mRNA evaluation and by immunoblotting and immunocytochemistry for the determination of protein levels. The ability of BPA and NPH to modulate gene expression was further confirmed by the upregulation of an estrogen target gene like pS2. As a biological counterpart, concentrations of xenoestrogens eliciting transcriptional activity were able to stimulate the proliferation of MCF7wt and MCFSH cells. Only NPH at a dose likely too high to be of any physiological relevance induced a severe cytotoxicity in an ERalpha-independent manner as ascertained in HeLa cells. The estrogenic effects of such industrial agents together with an increasing widespread human exposure should be taken into account for the potential influence also on hormone-dependent breast cancer disease.
Benzhydryl Compounds↗
Development and characterization of a biodegradable polyphosphate.
A biodegradable polyphosphate polymer (Mn = 18,000, Mw/Mn = 3.2) matrix system was developed as a potential delivery vehicle for growth factors. As a model system, release of recombinant human osteogenic protein-1 (OP-1) from this polymer was evaluated. The polyphosphate was synthesized using a triethylamine catalyst in an argon environment, and characterized using elemental analysis, gel permeation chromatography (GPC), and Fourier transform infrared spectroscopy (FTIR). Degradation kinetics of the polyphosphate polymer in phosphate-buffered saline (PBS) were represented by a second-order polynomial while degradation in bovine serum was linear with time. The polymer degraded faster in PBS than in bovine serum. In vitro release of OP-1 was also faster in PBS than in serum. Release kinetics of OP-1 in PBS and serum were represented by second-order polynomials. The OP-1 release from this physically dispersed polymeric matrix may be described by several possible mechanisms: diffusion, bulk polymer degradation, ion complexation, and interactions among the protein (OP-1), polymer, proteins, and enzymes in the media. This polyphosphate may be an effective carrier for morphogens, growth factors, or other classes of bioactive molecules.
Animals↗
Effects of resin hydrophilicity on water sorption and changes in modulus of elasticity.
UNLABELLED: As acidic monomers of self-etching adhesives are incorporated into dental adhesives at high concentrations, the adhesive becomes more hydrophilic. Water sorption by polymers causes plasticization and lowers mechanical properties. The purpose of this study was to compare the water sorption and modulus of elasticity (E) of five experimental neat resins (EX) of increasing hydrophilicity, as ranked by their Hoy's solubility parameters and five commercial resins. METHODS: After measuring the initial modulus of all resin disks by biaxial flexure, half the specimens were stored in hexadecane and the rest were stored in water. Repeated measurements of stiffness were made for 3 days. Water sorption and solubility measurements were made in a parallel experiment. RESULTS: None of the specimens stored in oil showed any significant decrease in modulus. All resins stored in water exhibited a time-dependent decrease in modulus that was proportional to their degree of water sorption. Water sorption of EX was proportional to Hoy's solubility parameter for polar forces (delta(p)) with increasing polarity resulting in higher sorption. The least hydrophilic resin absorbed 0.55 wt% water and showed a 15% decrease in modulus after 3 days. The most hydrophilic experimental resin absorbed 12.8 wt% water and showed a 73% modulus decrease during the same period. The commercial resins absorbed between 5% and 12% water that was associated with a 19-42% reduction in modulus over 3 days.
Absorption↗
Bioassay-derived androgenic and estrogenic activity in municipal sewage in Australia and New Zealand.
Raw sewage and sewage at various stages of treatment were sampled from 15 municipal sewage treatment plants in south Queensland (Australia) and Canterbury (New Zealand). Estrogenic and androgenic activities were determined with sheep estrogen receptor and rainbow trout androgen receptor binding assays, respectively. Selected estrogenic chemicals were also analyzed by gas chromatography-mass spectrometry. The raw sewage influents contained significant levels of both estrogenic (<4-185 ng/L estradiol equivalents) and androgenic (1920-9330 ng/L testosterone equivalents) activity. Subsequent treatment of raw sewage successfully removed most of the activity so that the estrogenicity and androgenicity associated with the final effluents were very low (<1-4.2 ng/L estradiol equivalents and <6.5-736 ng/L testosterone equivalents, respectively). Secondary treatment was the most effective treatment step to remove estrogenic and androgenic activity from sewage water. Activated sludge treatment in particular removed 92% to >99% of the estrogenic activity and 82% to >99% of the androgenic activity in sewage.
Androgens↗
The effect of AH 26 and AH Plus on MCF-7 breast cancer cell proliferation in vitro.
AIM: The purpose of this study was to determine whether AH 26 and AH Plus have in vitro oestrogenic effects. METHODOLOGY: MCF-7 breast cancer cells were trypsinized and plated in 24-well plates at initial concentrations of 10,000 cells per well in 5% FBS in DME. Cells were allowed to attach for 24 h; then the seeding medium was replaced with 10% CDHuS-supplemented phenol red-free DME. Different concentrations of the test compound were added to sample wells (AH 26 and AH Plus at 1/100 to 1/1,000,000 dilutions), 10 pM estradiol-17beta to positive controL and no sub-stance to negative control (hormone-free control cells). The assay was stopped after 144 h. RESULTS: AH 26-powder induced MCF-7 cell proliferation in a dose-dependent manner. The cell yield obtained with AH 26-powder at 1/100 dilution sample was 2.5-fold greater than in control cultures. The sam-ple prepared with mixed AH 26 paste/powder 1:1 also induced MCF-7 cell proliferation, but showed less potency than AH 26-powder alone. The cell yield obtained with AH 26 paste/powder at 1/100 dilution sample was 1.9-fold greater than in control cultures. AH Plus did not show in vitro oestrogenic effect. CONCLUSIONS: AH 26 showed in vitro oestrogenic effect, but not AH Plus. The endodontist must consider the possible oestrogenic effect of AH 26, as well as the cytotoxic effects of root filling materials, and avoid the leakage of sealer through the apex during root canal treatment.
Benzhydryl Compounds↗
A novel flexible approach for evaluating fixed ratio mixtures of full and partial agonists.
Assessing for interactions among chemicals in a mixture involves the comparison of actual mixture responses to those predicted under the assumption of zero interaction (additivity), based on individual chemical dose-response data. However, current statistical methods do not adequately account for differences in the shapes of the dose-response curves of the individual mixture components, as occurs with mixtures of full and partial receptor agonists. We present here a novel extension of current methods, which overcomes some of these limitations. Flexible single chemical concentration-effect curves combined with a common background parameter are used to describe an additivity surface along each axis. The predicted mixture response under the assumption of additivity is based on the constraint of Berenbaum's definition of additivity. Iterative algorithms are used to estimate mean responses at observed mixture combinations using only single chemical parameters. A full model allowing for different maximum response levels, different thresholds, and different slope parameters for each mixture component is compared to a reduced model under the assumption of additivity. A likelihood-ratio test is used to test the hypothesis of additivity by utilizing the full and reduced model predictions. This approach is useful for mixtures of chemicals with threshold regions and whose component chemicals exhibit differing response maxima (e.g., mixtures of full and partial agonists). The methods are illustrated with a combination of six chemicals in an estrogen receptor-alpha (ER-alpha) reporter gene assay.
Algorithms↗
Endocrine disrupters. Panel cautiously confirms low-dose effects.
Faced with conflicting results from studies of the effects of small amounts of hormonelike chemicals in the environment, the Environmental Protection Agency enlisted the help of an expert panel, which met earlier this month to conduct an extensive review of the data. The panel concluded that estrogenic chemicals can cause biological effects in lab animals at levels below those normally found to be safe--which runs counter to the conventional wisdom in toxicology. But the implications for human health are unclear.
Animals↗