Abstract  A variety of so-called innocuous chemicals can have insidious and long lasting effects on the developing male reproductive system. Developmental exposures of male rabbits to common industrial contaminants in drinking water (a mixture of arsenic, chromium, lead, benzene, chloroform, phenol, and trichloroethylene); alkyl phenols (e.g. octylphenol); water disinfection by-products (e.g. dibromoacetic acid); anti-androgenic pesticides (e.g. pp'-DDT and vinclozolin); and plasticizers (e.g. dibutyl phthalate) produce testicular dysgenesis. The lesions include testicular carcinoma in situ, also called intratubular germ cell neoplasia - the precursor lesion of germ cell tumors in men, and acrosomal dysgenesis - characterized by sharing of a dysplastic acrosome by two or more spermatids resulting in characteristic sperm acrosomal-nuclear malformations. Certain manifestations of testicular dysgenesis arch across environmental agents, and sequelae of intentional developmental exposures of rabbits duplicate what has been encountered in deer, horses, and humans for which the etiology is uncertain. (C) 2007 Elsevier B.V. All rights reserved.

Abstract  Trace contaminants generated in closed facilities can cause abnormal plant growth. We present measurement data of trace contaminants released from soils, plants, and construction materials. We mainly used two closed chambers, a Closed-type Plant and Mushroom Cultivation Chamber (PMCC) and Closed-type Plant Cultivation Equipment (CPCE). Although trace gas budgets from soils obtained in this experiment are only one example, the results indicate that the budgets of trace gases, as well as CO2 and O2, change greatly with the degree of soil maturation and are dependent on the kind of substances in the soil. Both in the PMCC and in the CPCE, trace gases such as dioctyl phthalate (DOP), dibutyl phthalate (DBP), toluene and xylene were detected. These gases seemed to be released from various materials used in the construction of these chambers. The degree of increase in these trace gas levels was dependent on the relationship between chamber capacity and plant quantity. Results of trace gas measurement in the PMCC, in which lettuce and shiitake mushroom were cultivated, showed that ethylene was released both from lettuce and from the mushroom culture bed. The release rates were about 90 ng bed-1 h-1 for the shiitake mushroom culture bed (volume is 1700 cm3) and 4.1 approximately 17.3 ng dm-2 h-1 (leaf area basis) for lettuce. Higher ethylene release rates per plant and per unit leaf area were observed in mature plants than in young plants

Abstract  In this study, we hypothesized that many of the reported effects of phthalate esters and other peroxisome proliferators (PPs) in the testis are mediated by members of the PP- activated receptor (PPAR) family of transcription factors through alterations in proteins involved in steroidogenesis. Exposure of Leydig cells to PPs prevented cholesterol transport into the mitochondria after hormonal stimulation and inhibited steroid synthesis, without altering total cell protein synthesis or mitochondrial and DNA integrity. PPs also reduced the levels of the cholesterol-binding protein peripheral-type benzodiazepine receptor (PBR) because of a direct transcriptional inhibition of PBR gene expression in MA-10 Leydig cells. MA-10 cells contain mRNAs for PPARalpha and PPARbeta/delta, but not for PPARgamma. In vivo treatment of mice with PPs resulted in the reduction of both testis PBR mRNA and circulating testosterone levels, in agreement with the proposed role of PBR in steroidogenesis. By contrast, liver PBR mRNA levels were increased, in agreement with the proposed role of PBR in cell growth/tumor formation in nonsteroidogenic tissues. However, PPs did not inhibit testosterone production and testis PBR expression in PPARalpha-null mice. These results suggest that the antiandrogenic effect of PPs is mediated by a PPARalpha-dependent inhibition of Leydig cell PBR gene expression.

Abstract  Di(2-ethylhexyl) phthalate (DEHP) is a well-known testicular toxicant inducing adverse effects in androgen responsive tissues. Therefore, di(2-ethylhexyl) adipate (DEHA) is currently being evaluated as a potential substitute for DEHP. Similarities in structure and metabolism of DEHP and DEHA have led to the hypothesis that DEHA can modulate the effects of DEHP. Wistar rats were gavaged with either vehicle, DEHP (300 or 750mg/kg bw/day) or DEHP (750mg/kg bw/day) in combination with DEHA (400mg/kg bw/day) from gestation day (GD) 7 to postnatal day (PND) 17. Decreased anogenital distance (AGD) and retention of nipples in male offspring were found in all three exposed groups. Dosed males exhibited decreased weights of ventral prostate and m. levator ani/bulbocavernosus. Histopathological investigations revealed alterations in testis morphology in both juvenile and adult animals. The litter size was decreased and postnatal mortality was increased in the combination group only, which is likely a combined effect of DEHP and DEHA. However, no combination effect was seen with respect to antiandrogenic effects, as males receiving DEHP in combination with DEHA did not exhibit more pronounced effects in the reproductive system than males receiving DEHP alone.

Abstract  Recent studies have revealed that the pituitary adenylate cyclase-activating polypeptide (PACAP) might act as a psychostimulant. Here we investigated the mechanisms underlying motor hyperactivity in patients with pervasive developmental disorders, such as autism, and attention-deficit hyperactivity disorder (ADHD). We studied the effects of intracisternal administration of 6-hydroxydopamine (6-OHDA) or endocrine disruptors (EDs) on spontaneous motor activity (SMA) and multiple gene expression in neonatal rats. Treatment with 6-OHDA caused significant hyperactivity during the dark phase in rats aged 4-5 weeks. Motor hyperactivities also were observed after treatment with endocrine disruptors, such as bisphenol A, nonylphenol, diethylhexyl phthalate and dibutyl phthalate, during both dark and light phases. Gene-expression profiles produced using cDNA macroarrays of 8-week-old rats with 6-OHDA lesions revealed the altered expression of several classes of gene, including the N-methyl-D-aspartate (NMDA) receptor 1, glutamate/aspartate transporter, gamma-aminobutyric-acid transporter, dopamine transporter 1, D4 receptor, and peptidergic elements such as the galanin receptor, arginine vasopressin receptor, neuropeptide Y and tachykinin 2. The changes in gene expression caused by treatment with endocrine disruptors differed from those induced by 6-OHDA. These results suggest that the mechanisms underlying the induction of motor hyperactivity and/or compensatory changes in young adult rats might differ between 6-OHDA and endocrine disruptors.

Abstract  It is hypothesized that the teratogen di(2-ethylhexyl) phthalate (DEHP) acts by in vivo hydrolysis to 2-ethylhexanol (2-EHXO), which in turn is metabolized to 2-ethylhexanoic acid (2-EHXA), the proximate teratogen. Teratological studies were conducted with Wistar rats, with administration of these agents on day 12 of gestation. On an equimolar basis DEHP was least potent, 2-EHXO was intermediate, and 2-EXHA was the most potent of the three agents, which is consistent with the hypothesis. Similarity in the types of defects found with these agents also suggests a common mechanism, with 2-EHXA as the proximate teratogen. All three agents were potentiated by caffeine. Valproic acid, which is an isomer of 2-EXHA, also produced similar defects, and was approximately twice as potent as 2-EHXA.

Abstract  The developmental toxicity and placental transfer of di-n-butyl phthalate (DBP) were evaluated in Sprague-Dawley rats given a single oral dose of DBP on Gestational Day 14. In the developmental toxicity study, dams were dosed with 0, 0.5, 1, 1.5, or 2 g DBP/kg and were necropsied on GD21. Increased incidence of resorptions and reduced fetal body weight were observed at 1.5 and 2 g/kg. Higher incidences of skeletal variations were found at doses > or = at 1 g/kg. No embryotoxic or teratogenic effects were observed at a dose of 0.5 g/kg. In the placental transfer study, dams were dosed with 0.5 or 1.5 g [14C]DBP/kg. Maternal and embryonic tissues were collected at intervals from 0.5 to 48 h. Embryonic tissues accounted for less than 0.12-0.15% of the administered dose. Levels of radiocarbon in placenta and embryo were one-third or less of those in maternal plasma. No accumulation of radioactivity was observed in the maternal or embryonic tissues. From HPLC analyses, it was shown that unchanged DBP and its metabolites mono-n-butyl phthalate (MBP) and MBP glucuronide were rapidly transferred to the embryonic tissues, where their levels were constantly lower than those in maternal plasma. MBP accounted for most of the radioactivity recovered in maternal plasma, placenta, and embryo. Unchanged DBP was found only in small amounts. These findings support the hypothesis that MBP, a potent teratogen, largely contributes to the embryotoxic effects of DBP.

Abstract  The absorption of undiluted phthalate diesters [dimethyl phthalate (DMP), diethylphthalate (DEP), dibutyl phthalate (DBP) and di-(2-ethylhexyl)phthalate (DEHP)] has been measured in vitro through human and rat epidermal membranes. Epidermal membranes were set up in glass diffusion cells and their permeability to tritiated water measured to establish the integrity of the skin before the phthalate esters were applied to the epidermal surface. Absorption rates for each phthalate ester were determined and a second tritiated water permeability assessment made to quantify any irreversible alterations in barrier function due to contact with the esters. Rat skin was consistently more permeable to phthalate esters than the human skin. As the esters became more lipophilic and less hydrophilic, the rate of absorption was reduced. Contact with the esters caused little change in the barrier properties of human skin, but caused marked increases in the permeability to water of rat skin. Although differences were noted between species, the absolute rates of absorption measured indicate that the phthalate esters are slowly absorbed through both human and rat skin.

Abstract  People are exposed to a variety of chemicals throughout their daily lives. To protect public health, regulators use risk assessments to examine the effects of chemical exposures. This book provides guidance for assessing the risk of phthalates, chemicals found in many consumer products that have been shown to affect the development of the male reproductive system of laboratory animals. Because people are exposed to multiple phthalates and other chemicals that affect male reproductive development, a cumulative risk assessment should be conducted that evaluates the combined effects of exposure to all these chemicals. The book suggests an approach for cumulative risk assessment that can serve as a model for evaluating the health risks of other types of chemicals.

Abstract  BIOSIS COPYRIGHT: BIOL ABS. RRM REVIEW NEUROTOXICITY CARCINOGENESIS TERATOGENESIS MUTAGENESIS

Abstract  Oiled impaction substrates have been used to prevent particle bounce during the collection of size-segregated aerosol samples, which have been analyzed for trace-level airborne organic compounds, including polycyclic aromatic hydrocarbons (PAHs). The use of the oiled impaction substrates, however, may introduce another sampling artifact-the absorption of semivolatile species from the gas phase which could artificially increase the amount of PAHs attributed to the aerosol. In this article, laboratory measurements of the absorption of a particular PAH, pyrene, from the gas phase to impaction substrates of polytetrafluoroethylene membranes impregnated with dibutyl phthalate are reported. Overall mass transfer coefficients are determined from the data. These results are used to calculate the absorption of gas phase PAHs during sampling of size-segregated atmospheric particles. Criteria are developed to determine if the absorption artifact is negligible. The first criterion requires that the analyte be negligibly soluble in the oil; this criterion is met by none of the impaction oils reported in the literature. The second criterion is that species do not have time to reach an equilibrium distribution between the gas phase and impaction oil; this criterion is met for nonvolatile species, those with vapor pressures equal to or less than that of benzo[a]pyrene (3.5 x 106 Pa). We recommend that oiled impaction substrates be used only if the absorption artifact is expected to be negligible on the basis of these criteria.

Abstract  Three kinds of particulate matter were collected: diesel and gasoline exhaust particles emitted directly from exhaust nozzle, and suspended particulate matter (SPM) near the traffic route. Soxhlet extraction was performed on each sample. By gas-chromatograph–mass spectrometer (GC–MS) analysis of these extracts, di-ethyl phthalate and di-n-butyl phthalate were detected from the extract of SPM and diesel exhaust particles (DEPs). Because these phthalates were sometimes suspected as contamination, time-of-flight secondary ion mass spectrometry (TOF-SIMS) measurements were also performed on the samples collected at the same environment. By comparing obtained spectra, it is clear that these environmental endocrine disrupters (EEDs) were adsorbed on DEP surface. Thus, we concluded that the combination of conventional method and TOF-SIMS measurement is one of the most powerful techniques for analyzing the toxic air pollutants adsorbed on SPM surface.

Abstract  A number of factors have contributed to increased awareness of the potential hazards to the unborn of various physical, biological, and chemical agents encountered occupationally in the workplace and the laboratory. The number of women of childbearing age in the work force has increased dramatically and precedents establishing legal rights of the unborn have been set. Equal rights to work have put women, and thus possibly the unborn, in contact with agents and stresses previously not commonly experienced. Most important, experimental and epidemiological data have identified, generally in a semiquantitative manner, that high levels of exposure to certain chemicals may represent potential risks to the unborn.

Abstract  BACKGROUND: Exposure to endocrine disruptors (EDs), including some phthalates, phytoestrogens and phenols can be quantified using biomarkers of exposure. However, reliability in the use of these biomarkers requires an understanding of the timeframe of exposure represented by one measurement. Data on the temporal variability of ED biomarkers are sparse, especially among children. OBJECTIVE: To evaluate intraindividual temporal variability in 19 individual urinary biomarkers (eight phthalate metabolites from six phthalate diesters, six phytoestrogens (two lignans and four isoflavones) and five phenols) among New York City children. METHODS: Healthy Hispanic and Black children (N=35; 6-10 years old) donated several urine samples over 6 months. To assess temporal variability we used three statistical methods: intraclass correlation coefficient (ICC), Spearman correlation coefficients (SCC) between concentrations measured at different timepoints, and surrogate category analysis to determine how well the tertile categories based on a single measurement represented a 6-month average concentration. RESULTS: Surrogate category analysis indicated that a single sample provides reliable ranking for all analytes; at least three of four surrogate samples predicted the 6-month mean concentration. Of the 19 analytes, the ICC was >0.2 for 18 analytes and >0.3 for 10 analytes. Correlations among sample concentrations throughout the 6-month period were observed for all analytes; 14 analyte concentrations were correlated at 16 weeks. CONCLUSIONS: The reasonable degree of temporal reliability and the wide range of concentrations of phthalate metabolites, phytoestrogens and phenols suggest that these biomarkers are appropriate for use in epidemiologic studies of environmental exposures in relation to health outcomes in children.

Abstract  Developmental neurotoxicity of low-dose di-n-butyl phthalate (DBP) to rats was studied. Pregnant rats were orally given DBP at doses less than 1.0 mg/kg/day during gestation period. The body weight of all dams and their offspring as well as the offspring's motor function showed no significant adverse effect. At 21 weeks, behaviors of male rats were examined by placing into a test cage. The rats born from dams exposed to 10 microg DBP/kg/day exhibited a significant decrease of grooming. This indicates low-dose DBP adversely affects emotional stability in a novel environment.

Abstract  Undescended testis is a common finding in boys, and the majority of cases have no discernible aetiology. There are unexplained geographical differences and temporal trends in its prevalence. Cryptorchidism, especially bilateral, is associated with impaired spermatogenesis and endocrine function and increases the risk of testicular cancer. There is an urgent need to identify factors that adversely affect testicular development and optimize treatment. Conclusion: Cryptorchidism may reflect a primary testicular maldevelopment with long-term consequences.

Abstract  It has been speculated that maternal phthalate exposure may affect reproductive development in human newborns. However, the mechanism awaits further investigation. The aim is to evaluate the association between maternal phthalate exposure and cord sex steroid hormones in pregnant women and their newborns from the general population. A total of 155 maternal and infant pair were recruited and analyzed. Levels of urinary phthalate metabolites and sex steroid hormones were determined using liquid chromatography/electrospray tandem mass spectrometry (LC-ESI-MS/MS) and radioimmunoassay (RIA), respectively. No significant correlation was found between each steroid hormones and phthalate metabolites for male newborns, except MMP was marginally significantly correlated with E(2). After adjusting for maternal age, estradiol (E(2)) levels in cord serum from male newborns were not correlated with maternal urinary phthalate metabolites. In female newborns, the maternal urinary levels of mono-(2-ethylhexyl) phthalate (MEHP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP) were negatively correlated with the free testosterone (fT) and fT/E(2) levels in cord serum with Pearson correlation coefficients ranging between -0.24 and -0.29 (p<0.05). Additionally, after gestational age was adjusted, the maternal urinary level of DEHP was negatively correlated with the free testosterone (fT) and fT/E(2) levels in cord serum. We suggest that maternal exposure to phthalates may affect sex steroid hormones status in fetal and newborn stage.

Abstract  Some phthalates are developmental and reproductive toxicants in animals. Exposure to phthalates is considered to be potentially harmful to human health as well. Based on a comprehensive literature research, we present an overview of the sources of human phthalate exposure and results of exposure assessments with special focus on human biomonitoring data. Among the general population, there is widespread exposure to a number of phthalates. Foodstuff is the major source of phthalate exposure, particularly for the long-chain phthalates such as di(2-ethylhexyl) phthalate. For short-chain phthalates such as di-n-butyl-phthalate, additional pathways are of relevance. In general, children are exposed to higher phthalate doses than adults. Especially, high exposures can occur through some medications or medical devices. By comparing exposure data with existing limit values, one can also assess the risks associated with exposure to phthalates. Within the general population, some individuals exceed tolerable daily intake values for one or more phthalates. In high exposure groups, (intensive medical care, medications) tolerable daily intake transgressions can be substantial. Recent findings from animal studies suggest that a cumulative risk assessment for phthalates is warranted, and a cumulative exposure assessment to phthalates via human biomonitoring is a major step into this direction.

Abstract  The testicular dysgenesis syndrome (TDS) hypothesis proposes that a proportion of the male reproductive disorders-cryptorchidism, hypospadias, infertility and testicular cancer-may be symptoms of one underlying developmental disease, TDS, which is most likely a result of disturbed gonadal development in the embryo. TDS may be caused by genetic factors, environmental/life-style factors, or a combination of both. Some rare disorders of sex development of genetic origin are among the best-known examples of severe TDS. Among the environmental and life-style factors that are suspected to influence the hormonal milieu of the developing gonad are the endocrine disrupters. A prenatal exposure to commonly used chemicals, e.g. phthalates, may result in a TDS-like phenotype in rats. Currently, this animal model is the best model for TDS. In humans the situation is much more complex, and TDS exists in a wide range of phenotypes: from the mildest and most common form, in which impaired spermatogenesis is the only symptom, to the most severe cases, in which the patient may develop testicular cancer. It is of great importance that clinicians in different specialties treating patients with TDS are aware of the association between the different symptoms.

Abstract  Phthalate esters with short alkyl chains, such as di-ethyl (DEP), di-n-propyl (DPP), and di-butyl phthalate (DBP), have adjuvant effects on an FITC-induced contact hypersensitivity mouse model. The adjuvant effects of DPP and DBP are associated with enhanced trafficking of FITC-presenting CD11b(+) dendritic cells (DC). DEP has relatively weak activity as to FITC-positive cell migration. Here we demonstrated that DBP and DPP also increased the number of FITC-positive CD8alpha(+) DC in draining lymph nodes. We also found enhanced production of interleukin-4 in draining lymph nodes after FITC sensitization with DEP, DPP, or DBP, suggesting an additional adjuvant mechanism of phthalate esters.

Abstract  A routine method which is simple, quick and precise has been set up and validated for phthalate analysis in environmental samples (tomato plants and sewage sludges). Six phthalates have been studied simultaneously: dimethylphthalate, diethylphthalate, di-n-butylphthalate, n-butylbenzylphthalate, di-2-ethyl-hexyl phthalate (DEHP) and di-n-octylphthalate. Optimization of sample, solvent extraction uses a Soxtec apparatus and extract purification with an a solid-phase extraction cartridge allows between 90 and 110% recovery of phthalates. Precise, sensitive and selective identification and quantifying of analytes is by GC-MS in the single ion monitoring mode. This protocol allows analytes with concentrations as low as 10 microg/kg dry matter (DM) to be determined from small (1-2 g DM) samples. This analytical method has been applied to the phthalate transfer study for agricultural recycling of sludges, where phthalate bioavailability has been studied in aquiculture using two types of experiments. Tomatoes have been grown in containers where the trace organics have been directly introduced as pure substances, and in a second experiment under the same growth conditions, sewage sludge has replaced the pure substances. Transfer of these trace organics has been followed into the various parts of the tomato plant and in general only the DEHP is worthy of note although its percentage transfer remains very low even in an experiment designed to maximize this.

Abstract  Potential toxicological interactions of 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and/or dibuthyl phthalate (DBP) on ozone were investigated after 32- and 52-wk exposures using hprt mutation assay. Male and female B6C3F1 mice exposed to ozone (0.5 ppm), NNK (1.0 mg/kg), DBP (5,000 ppm), and two or three combinations of these toxicants 6 h per day for 32- and 52-wk showed increases in the frequencies of TG rlymphocytes compared to the control groups. Additive interactions were noted from two combination groups compared to the ozone alone in both sexes of 32- and 52-wk studies. The most common specific mutation type in the hprt genes of test materials-treated male and female mice was transversion with very few transition. The results indicate that such dominant transversion may be responsible for toxicity and combined exposure to ozone, NNK, and DBP induces additive genotoxicities compared to ozone alone.

Abstract  A gas chromatographic method for the identification and quantification of n-octyl esters (from n-octyl tetradecanoate to n-octyl hexa-cosanoate including dioctyl hexanedioate) and phthalates [dibutyl phthalate, benzyl butyl phthalate and di(2-ethylhexyl) phthalate] in sediments and biota from estuarine environments is described. Standards used for identification and quantification of some n-octyl esters were synthesized. The method has allowed the analysis of these compounds in polychaeta (Nereis diversicolor), oysters (Crassostea angulata), crabs (Carcinus maenas) and fish (Chelon labrosus, Platichtys flesus and Chondostroma polylepis) that were collected at different locations of the Urdaibai estuary (Bizkaia, Basque Country, Spain). Total phthalates and n-octyl esters ranged between 0.01 and 12 microg g(-1) and 0.05 and 9.4 microg g(-1), respectively, and were predominantly found in polychaeta and fish. Sediments did not contain these compounds in significant amount, only benzyl butyl phthalate, dioctyl hexanedioate and di(2-ethylhexyl) phthalate were found above limit of detection (0.01-0.05 microg g(-1)).

Abstract  The loss of the plasticizers dibutylphthalate, butylphthalylbutyl glycolate, benzylbenzoate, methylsalicylate, and benzylsalicylate from four soft lining materials was measured. A 0.1% aqueous solution of triton X-100, reduced was used as immersion medium, since the solubility of plasticizer in this medium was close to that of saliva. The loss of plasticizer was monitored up to 30 d after mixing. For two of the materials, the average amount of leached dibutylphthalate within the first day exceeded the proposed tolerable daily intake (TDI) by about 11 and 32 times, respectively, for an average adult person. Similarly, for these two materials, the average daily amount within the first 30 d of leached dibutylphthalate was 2.2 and 6.6 times larger, respectively, than the TDI limit. The cumulative amount leached over 30 d for each of the four materials was 128-253 mg plasticizer g(-1). The results indicate the need for further biological evaluations of these products.