[Toxicity of orally ingested asbestos].
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Administration, Oral↗
Biomedical subjects
Chikako Uneyama
Publications and source records attributed to Chikako Uneyama.
Limited tumor-initiating activity of phenylethyl isothiocyanate by promotion with sodium L-ascorbate in a rat two-stage urinary bladder carcinogenesis model.
Initiation activity of phenylethyl isothiocyanate (PEITC) was examined in a two-stage urinary bladder carcinogenesis model. Male 6-week-old Fischer 344 rats were fed diet containing 0.1% PEITC for 12 or 24 weeks, with or without subsequent administration of 5% sodium l-ascorbate (Na-AsA) in diet until week 48, or for the entire experimental period. After 12 weeks of PEITC-treatment, both simple hyperplasia and papillary or nodular (PN) hyperplasia had developed in all animals, but the majority of these lesions had disappeared at week 48, irrespective of the Na-AsA-treatment. The same lesions after 24 weeks of PEITC-treatment had progressed to dysplasia and carcinoma, in a small number of cases by week 48 (6% in incidence for each lesion), but enhancement by the Na-AsA-treatment was evident only with simple hyperplasias (from 56 to 100% in incidence) and PN hyperplasias (from 19 to 56%). The results suggest a limited initiation activity of PEITC with induction of irreversible lesions by 24 weeks of exposure.
Animals↗
Down-regulation of GAT-1 mRNA expression in the microdissected hypothalamic medial preoptic area of rat offspring exposed maternally to ethinylestradiol.
Steroid hormones are powerful regulators of gene transcription in the brain and have the potential to permanently alter the structure and function of the developing brain. Steroid-mediated altered gene expression may thus be responsible for the molecular cascade for sexual differentiation. In this study, to assess effects of maternal exposure to ethinylestradiol (EE) on brain sexual differentiation of offspring, region-specific mRNA expression of two estrogen-responsive genes, gamma-aminobutyric acid transporter type 1 (GAT-1) and anti-apoptotic bcl-xL was measured in the medial preoptic area (MPOA), including sexually dimorphic nucleus (SDN), at the late stage of brain sexual differentiation in rats. Pregnant Sprague-Dawley animals were fed diets containing EE at concentrations of 0, 0.02, 0.1, and 0.5 ppm from day 15 of pregnancy to day 9 after delivery. In another group, neonates were directly injected with estradiol benzoate (EB: 10 microg/pup, sc) on postnatal day (PND) 2. The MPOA on PND 9 was microdissected from methacarn-fixed paraffin-embedded brain sections to measure mRNA levels by competitive RT-PCR, followed by plate hybridization. EE-exposure decreased GAT-1 expression dose-dependently from 0.02 ppm in females and at 0.5 ppm in males, while EB-treatment caused reduction only in females. EE-exposure did not alter Bcl-xL levels. At week 11, EE-exposed females exhibited a similar spectrum of histopathological changes in endocrine-linked organs as with EB, evident from 0.1 ppm, while in males EE-exposure did not cause histopathological alteration despite clear change with EB-treatment. Measurement of SDN-POA dimensions at week 11 revealed volume reduction in males exposed to 0.5 ppm EE or EB. The results suggest that GAT-1 expression in the developing MPOA is a sensitive measure for the level of disruption of brain sexual differentiation due to maternal dietary exposure to estrogens, despite definite reproductive abnormalities may not be detectable in males with this exposure protocol.
Animals↗
Methacarn fixation for genomic DNA analysis in microdissected cells.
We have found methacarn, a non-crosslinking protein-precipitating fixative, to be useful for the analysis of DNA from microdissected specimens of wax-embedded tissue. In this chapter, we present the procedure regarding genomic DNA analysis in methacarn-fixed wax-embedded microdissected rat tissue. Using nested polymerase chain reaction (PCR), and a rapid extraction procedure, fragments of DNA up to 2.8 kb in size can be amplified from a 1 x 1 mm area of a 10-microm-thick tissue section. Target fragments of about 500 bp can be amplified from a single cell, but 10-20 cells are necessary for practical detection by nested PCR. Although tissue staining with hematoxylin and eosin inhibits the PCR, amplification of about 500-bp fragments is successful with 150-270 cells by single-step PCR. Immunostaining results in a substantial decrease of yield and degradation of extracted DNA. However, even after immunostaining, fragments of about 180 bp can be amplified with 150-270 cells by single-step PCR. These features demonstrate the suitability of methacarn-fixed wax-embedded tissue for practical genomic DNA analysis in terms of tissue handling, extraction efficiency, and satisfactory PCR results.
Acetic Acid↗
[Global trends of food safety information associated with chemicals in food].
Recently, a number of food safety problems have frequently arisen and consumer concerns have drastically increased. In order to meet these concerns, we have been publishing a biweekly bulletin called "Food Safety Information" since April 2003, monitoring the latest information from overseas on food safety. In this paper, we analyze the recent trends of information on food chemicals in the bulletin published between April 2003 and March 2005 in order to clarify the problems that need to be followed up. Among the 1,199 entries on food chemicals included in the bulletin, about 50% were from the EU and European organizations such as the FSA (UK). Approximately 20% of the total information focused on food contaminants such as heavy metals, dioxins, PCBs and mycotoxins. Scientific evidence-based information on dietary supplements and herb products was also suggested to be important to protect public health as well as food contaminants. We monitor the latest information on food safety constantly and continuously, which is important for long-term follow up of food safety issues of concern. We also provide the bulletin to the general public through the website as well as to researchers and risk managers.
Consumer Product Safety↗
[Recent trends in evaluating risk associated with acrylamide in foods. --Focus on a new approach (MOE) to risk assessment by JECFA--].
The safety of acrylamide in foods was evaluated in the 64th meeting (2005) of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). Acrylamide is classified as "probably carcinogenic to humans (Group 2A)" by the International Agency for Research on Cancer (IARC) from evidence of carcinogenicity in experimental animals and from evidence that acrylamide is metabolized to a genotoxic compound, glycidamide, in both rodents and humans. Acrylamide is also known to have genotoxicity, neurotoxicity, reproductive and developmental toxicity. In this meeting, the Committee used "Margin of Exposure (MOE)" as a new approach to risk assessment for compounds that were both genotoxic and carcinogenic, the lower the MOE the greater the health concern. JECFA calculated MOE values of 300 for the general population and 75 for consumers of large quantities of food containing high acrylamide. These MOEs were considered low and a potential human health concern. Therefore, appropriate efforts to reduce acrylamide concentrations in foodstuffs should continue. This report discusses how JECFA applied the MOE concept to the risk assessment of acrylamide in foods.
Acrylamide↗
Diverse developmental toxicity of di-n-butyl phthalate in both sexes of rat offspring after maternal exposure during the period from late gestation through lactation.
To evaluate developmental toxicity of di-n-butyl phthalate (DBP) with exposure during the period from late gestation to following lactation, maternal rats were given DBP at dietary concentrations of 0, 20, 200, 2000 and 10,000 ppm from gestational day 15 to postnatal day (PND) 21. At 10,000 ppm, male offspring showed a decreased neonatal anogenital distance and retention of nipples (PND 14), while females showed a slight non-significant delay in the onset of puberty. At PND 21, reduction of testicular spermatocyte development was evident from 20 ppm, as well as mammary gland changes at low incidence in both sexes. At this time point, population changes of pituitary hormone-immunoreactive cells were observed at 10,000 ppm with a similar pattern of increase in the percentages of luteinizing hormone (LH)-positive and decrease in follicle-stimulating hormone (FSH) and prolactin producing cells in both sexes, effects also being evident on FSH from 200 ppm and LH from 2000 ppm in females. During postnatal week (PNW) 8-11, marginal increase of the number of cases with extended diestrus was found at 10,000 ppm. At adult stage necropsy, testicular lesions appeared to be very faint in most cases, but degeneration and atrophy of mammary gland alveoli were observed in males from 20 ppm. Although without clear monotonic dose-dependence, relative pituitary weights were increased with the intermediate doses in males at PNW 11. In females, relative pituitary weights were decreased after 10,000 ppm at PNW 11, and from 200 ppm at PNW 20. The proportion of FSH-positive cells in the pituitaries at PNW 11 was increased in both sexes at 10,000 ppm. Thus, developmental exposure to DBP affected female sexual development involving pituitary function, while in males testicular toxicity was mostly reversible but mammary gland toxicity was persistent at a dose level as low as 20 ppm.
Animals↗
Gene expression profile in the livers of rats orally administered ethinylestradiol for 28 days using a microarray technique.
To identify genes showing responses to estrogen exposure in the livers of animals in a repeated oral dose toxicity study, dose-dependent gene expression profiles were analyzed using high-density oligonucleotide microarrays in Sprague-Dawley rats of both sexes administered ethinylestradiol (EE) for 28 days at concentrations of 0, 0.01, 0.1, and 1.0 ppm in the diet. Among 3776 genes examined, examples showing increased expression on EE-treatment were detected predominantly in females. Genes showing dose-dependent up-regulation with greater than five-fold change at 1.0 ppm from the control levels were found to, respectively, number 4 in males, and 24 in females. Most of the latter exhibited relatively high basal expression as well as low variability, and many exhibited clear dose-dependence. Genes showing dose-dependent down-regulation were rather few, and many of those affected exhibited relatively low expression levels with large variation between animals, like genes showing dose-unrelated expression patterns in both sexes or dose-dependent up-regulation in males. Considering that detection of changes in endocrine-linked organs and estrous cyclicity is only possible at the high dose of 1.0 ppm, up-regulation of genes dose-dependently in females provides a sensitive tool to detect estrogenic effects in the rat liver in the framework of the 28-day toxicity study.
Animals↗
Subchronic toxicity study of dietary N-acetylglucosamine in F344 rats.
A subchronic toxicity study of N-acetylglucosamine (GlcNAc), a monomeric form of chitin, was conducted in groups of 10 male and 10 female F344 rats fed pelleted diets containing 0, 0.625, 1.25, 2.5 or 5% concentrations for 13 weeks. All animals survived until the end of the experiment. Slight, non-significant increase in body weights was observed in males receiving 0.625, 1.25 or 2.5% from week 4 until the end of the experiment, when significant elevation was found for the males receiving 0.625, 1.25 or 2.5% at the terminal sacrifice to result in decreased relative weights of many organs in these cases. However, there were no obvious indications of toxicity in any group receiving GlcNAc in terms of clinical signs, food intake, hematology, serum biochemistry, and histopathological findings. Thus, it was concluded that orally administered GlcNAc exerts no obvious toxicity to F344 rats at concentrations up to 5% in the diet for 13 weeks. Based on the present toxicity data, > or =5% was determined to be a no-observed-adverse-effect level, translated into 2476 and 2834 mg/kg/day for male and female rats, respectively.
Acetylglucosamine↗
Lack of modifying effects of genistein on disruption of the reproductive system by perinatal dietary exposure to ethinylestradiol in rats.
We previously found that effects of perinatal dietary exposure to ethinylestradiol (EE) on the rat reproductive system differ depending on the diet used, with a more pronounced estrogenic impact with a regular diet that includes soy-derived proteins than with a soy-free (SF) diet. The present study was performed to examine whether genistein (GEN), a soy-derived major phytoestrogen, acts synergistically with EE. Maternal rats were fed SF diet without chemical (control) or containing 0.5-ppm EE, 0.5-ppm EE + 100-ppm GEN, 0.5-ppm EE + 1250-ppm GEN, or 1250-ppm GEN, from gestational day 15 to postnatal day (PND) 11. EE reduced serum testosterone in males at PND 3, and affected the onset of puberty of both sexes and estrous cyclicity and reproductive system in females, irrespective of co-administration of GEN. GEN alone also affected estrous cyclicity and the reproductive system in females. However, no combination effects of GEN with EE were evident, suggesting no synergism between the two.
Administration, Oral↗
Impact of dietary exposure to methoxychlor, genistein, or diisononyl phthalate during the perinatal period on the development of the rat endocrine/reproductive systems in later life.
To evaluate the impact of dietary exposure to endocrine disrupting chemicals (EDCs) during the sensitive period of brain sexual differentiation, maternal Sprague-Dawley rats were fed three representative chemicals, methoxychlor (MXC; 24, 240, and 1200 ppm), genistein (GEN; 20, 200, and 1000 ppm), or diisononyl phthalate (DINP; 400, 4000, and 20,000 ppm), from gestational day 15 to postnatal day 10. Soy-free diet was used as a basal diet to eliminate possible estrogenic effects from the standard diet. Offspring were examined in terms of anogenital distances, prepubertal organ weights, onset of puberty, estrous cyclicity, and organ weights and histopathology of endocrine organs at adult stage (week 11) as well as the volumes of sexually dimorphic nucleus of preoptic area (SDN-POA). All chemicals caused signs of maternal toxicity at high doses. MXC, at 1200 ppm, facilitated and delayed the onset of puberty in females and males, respectively, females also showing endocrine disrupting effects thereafter, such as irregular estrous cyclicity and histopathological alterations in the reproductive tract and anterior pituitary. GEN, at all doses, reduced body weight (BW) at week 11, but did not affect endocrine parameters. Treatment with DINP at 20,000 ppm resulted in degeneration of meiotic spermatocytes and Sertoli cells in the testis and decrease of corpora lutea in the ovary at week 11, although changes remained minimal or slight. The SDN-POA volume remained unchanged with all three chemicals. The results demonstrated that perinatal dietary exposure to EDCs for a limited period causes endocrine disruption in offspring only at high doses.
Administration, Oral↗
Alteration of pituitary hormone-immunoreactive cell populations in rat offspring after maternal dietary exposure to endocrine-active chemicals.
We previously performed dose-response studies of genistein, diisononyl phthalate, 4-nonylphenol, methoxychlor (MXC), and bisphenol A to examine the impact of maternal dietary exposure from gestational day 15 to postnatal day 10 on the development of rat reproductive system in later life. Among the chemicals MXC alone showed typical estrogenic effects only at the maternally toxic 1200 ppm. The present study was performed to examine the sensitivity of immunohistochemical analysis of pituitary cells of offspring similarly exposed to each chemical for detection of endocrine-disrupting effects. For this purpose, ratios of pituitary cells expressing luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (PRL), were measured at 3 and 11 weeks of age. Ethinylestradiol (EE) at 0.5 ppm was used as a reference chemical. At week 3, decrease in the relative proportions of LH, FSH, and PRL cells in males and LH cells in females was evident with MXC at 1200 ppm. At week 11, increase was found for PRL cells from 240 ppm MXC, and FSH cells at 1200 ppm in females. On the other hand, EE increased the PRL cell percentage in females at week 3 but no effects were apparent at week 11. The other chemicals were without influence at either time point. The results suggest that the assessment of the pituitary cell populations might be a more sensitive approach to detect perinatal endocrine-disrupting effects than other methods. The difference in the pituitary effect between MXC and EE is discussed.
Administration, Oral↗
Lack of maternal dietary exposure effects of bisphenol A and nonylphenol during the critical period for brain sexual differentiation on the reproductive/endocrine systems in later life.
Two potential endocrine-disrupting chemicals, bisphenol A (BPA) and nonylphenol (NP), were assessed for their long-lasting effects on endocrine/reproductive systems following transplacental and lactational exposure to rat offspring during a time-window that included the critical period for brain sexual differentiation. Each chemical was mixed with diet at concentrations of 60, 600 and 3000 ppm and was provided to maternal Sprague-Dawley rats from gestational day (GD) 15 to postnatal day (PND) 10. Ethinylestradiol (EE) at 0.5 ppm was used as an estrogenic reference drug. During pregnancy and lactation, including the exposure period, a soy-free rodent diet was provided to eliminate possible modification of the study results by plant-derived phytoestrogens. Effects on endocrine/reproductive systems were evaluated by examining the anogenital distance, organ weights before puberty, onset of puberty, estrous cyclicity, and organ weights and histopathology of adult endocrine organs (at 11 weeks of age), as well as the volume of the sexually dimorphic nucleus of preoptic area. Both NP and BPA, at high doses, caused decreases in maternal body weights and retardation of offspring growth, but neither affected any of the endocrine/reproductive endpoints of offspring, whereas EE induced irreversible changes in estrous cyclicity and histopathology of ovaries and uterus of adult females. The results indicated that maternal dietary exposure to NP or BPA at concentrations up to 3000 ppm from GD 15 through PND 10 do not exert any apparent adverse effects on the endocrine/reproductive systems of offspring.
Administration, Oral↗
Methacarn: a fixation tool for multipurpose genetic analysis from paraffin-embedded tissues.
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Acetic Acid↗
Molecular profiling of genes up-regulated during promotion by phenobarbital treatment in a medium-term rat liver bioassay.
In search of genes that are steadily up-regulated during the promotion stage in carcinogenesis, suppression PCR subtractive hybridization and following northern blot screening were performed using a phenobarbital (PB)-promotion model based on a medium-term liver bioassay. Two weeks after a single injection of diethylnitrosamine (DEN; 200 mg/kg body wt, i.p.), rats were given 600 p.p.m. PB in the drinking water for up to 64 weeks. For comparison, animals fed 1 p.p.m. ethinylestradiol (EE) or 3000 p.p.m. butylated hydroxytoluene (BHT) in the diet at promotion stage were also included. Rats were subjected to partial hepatectomy (PH) at week 3. In addition, dose-dependence of PB at week 8 of promotion and responsiveness to representative non-genotoxic carcinogens without DEN initiation were examined. Fragments of a total of 67 different genes were isolated from the up-regulated gene population in the liver at day 10 of PB treatment by subtracting from basal expression of DEN + PH alone. Using northern blot screening for signal-detectable 48 genes, 16 genes showed up-regulation in the livers at week 8 of promotion, common to the PB and EE treatments with the levels being three times or more than the basal expression of unpromoted liver. The majority of these genes were also up-regulated at week 8 by BHT treatment, and were also constitutively expressed in the DEN(-), PH(-) untreated rat livers. Among the up-regulated genes common to the PB and EE promotion, and not responding to the non-genotoxic carcinogens in uninitiated liver, the following six genes showed overexpression in PB-promoted hepatocellular carcinomas at week 64, with the levels three times or more than untreated rat liver: ubiquitously expressed mammalian ABC half transporter, apolipoprotein A4, nuclear receptor binding factor-2, CD81, hypothetical protein (HSPC014) and one unidentified gene. These genes might be candidates for biomarkers in screening of non-genotoxic hepatocarcinogens by analysis in two-stage carcinogenesis models.
Animals↗
Methacarn fixation for genomic DNA analysis in microdissected, paraffin-embedded tissue specimens.
We recently found methacarn to be a versatile fixative for analysis of RNA and protein applicable for microdissected specimens from paraffin-embedded tissue (PET). In this study we investigated the performance of methacarn for genomic DNA analysis using microdissected rat tissues. We found that extensive portions of DNA up to 2.8 kb could be amplified by nested PCR using DNA templates extracted by a simple and rapid extraction procedure from a 1 x 1-mm area of cerebral cortex of a 10-microm-thick section. By nested PCR, a 522-bp fragment from a single cell could be amplified in 20% of cresyl violet-stained Purkinje cells, and the minimal number of cells required, as estimated using hippocampal neurons, was on the order of 10-20. Although tissue staining with hematoxylin and eosin affected the PCR, amplification of a 522-bp fragment was successful, with 150-270 cells by 35 cycles of single-step PCR. Immunostaining resulted in a substantial decrease of yield and degradation of extracted DNA. However, even after immunostaining, a 184-bp DNA fragment could be amplified with 150-270 cells by 35 cycles of PCR. The results thus demonstrate the superior performance of methacarn to that reported with formalin in genomic DNA analysis using microdissected PET specimens.
Acetic Acid↗