Effect of different sampling designs on outcome of endocrine disruptor studies.

In this article, we demonstrate how sampling strategy can influence the outcome of endocrine disruptor studies. In a study of the weak xenoestrogen bisphenol A (BPA), possible treatment-related effects on ventral prostate (VP) fresh weight were found in rat offspring at 6 months of age when only one or two male pups were randomly selected from each litter. In subsequent BPA and di-n-butyl phthalate studies, large intralitter variability of this specific end point was apparent when the VP weights from entire litter complements were examined.

Rudimentary hemidesmosome formation in congenital generalized junctional epidermolysis bullosa in the Sprague-Dawley rat.

Seven of 14 newborn pups in a litter of Sprague-Dawley rats were found to have generalized detachment of the epidermis, which was thin, wrinkled, and hung in loose folds over distal extremities. Histologic and ultrastructural examination of the skin showed noninflammatory separation of the epidermis from the dermis at the lamina lucida of the basement membrane zone. Ultrastructurally, hemidesmosomes were small and had a rudimentary appearance; keratin tonofilaments in basal keratinocytes were detached from the hemidesmosomes.

Loss of p53 in benzene-induced thymic lymphomas in p53+/- mice: evidence of chromosomal recombination.

The purpose of this study was to examine the role of chromosomal recombination in mediating p53 loss in benzene-induced thymic lymphomas in C57BL/6-Trp53 haploinsufficient (N5) mice (p53+/- mice). We characterized loss of heterozygosity (LOH) on chromosome 11 using seven microsatellite markers in 27 benzene-induced and 6 spontaneous thymic lymphomas. Eleven patterns of LOH were found between the induced and spontaneous tumors, with only one pattern being in common between the tumor groups.

Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators.

Peroxisome proliferators (PPs) are a large class of structurally dissimilar chemicals that have diverse effects in rodents and humans. Most, if not all, of the diverse effects of PPs are mediated by three members of the nuclear receptor superfamily called peroxisome proliferator-activated receptors (PPARs). In this review, we define the molecular mechanisms of PPs, including PPAR binding specificity, alteration of gene expression through binding to DNA response elements, and cross talk with other signaling pathways.

Pubertal development and reproductive functions of Crl:CD BR Sprague-Dawley rats exposed to bisphenol A during prenatal and postnatal development.

Bisphenol A (BPA) is used on a large scale in the manufacture of polycarbonate plastics. BPA has been shown to bind weakly to both estrogen receptor (ER)alpha and ERbeta, and to transactivate reporter genes in vitro. The purpose of the present study was to determine whether exposure of rats to BPA during pre- and postnatal development affects estrogen-mediated end points related to pubertal development and reproductive functions.

Inhibition of cytochrome P450 2E1 decreases, but does not eliminate, genotoxicity mediated by 1,3-butadiene.

1,3-Butadiene (BD), a rodent carcinogen, is metabolized to mutagenic and DNA-reactive epoxides. In vitro data suggest that this oxidation is mediated by cytochrome P450 2E1 (CYP2E1). In this study, we tested the hypothesis that oxidation of BD by CYP2E1 is required for genotoxicity to occur.

Olfactory neuron loss in adult male CD rats following subchronic inhalation exposure to hydrogen sulfide.

Dysosmia and anosmia are reported to occur following human exposure to hydrogen sulfide (H2S) gas. The clinical association between H2S exposure and olfactory dysfunction in humans necessitates evaluation of the nasal cavity and olfactory system in experimental animals used to study H2S toxicity. The purpose of this study was to subchronically expose 10-week-old male CD rats to relatively low concentrations of H2S and to histologically evaluate the nasal cavity for exposure-related lesions.

Neurotoxicity of manganese chloride in neonatal and adult CD rats following subchronic (21-day) high-dose oral exposure.

The purpose of this study was to evaluate the relative sensitivity of neonatal and adult CD rats to manganese-induced neurotoxicity. Identical oral manganese chloride (MnCl(2)) doses (0, 25, or 50 mg kg(-1) body wt. day(-1)) were given to neonatal rats throughout lactation (i.

Dose-dependent alterations in androgen-regulated male reproductive development in rats exposed to Di(n-butyl) phthalate during late gestation.

Di(n-butyl) phthalate (DBP) is a commercially important plasticizer and ubiquitous environmental contaminant. Since previous, limited dose-response studies with DBP that reported alterations in male reproductive development and function failed to establish a NOAEL (no-observed-adverse-effect level), an extensive dose-response study was conducted. Pregnant CD rats were given DBP by gavage at 0, 0.

Alterations in endocrine responses in male Sprague-Dawley rats following oral administration of methyl tert-butyl ether.

Methyl tert-butyl ether (MTBE) is an oxygenated fuel additive used to decrease carbon monoxide emissions during combustion. MTBE is a nongenotoxic chemical that induces Leydig cell tumors (LCT) in male rats. The mechanism of MTBE-induced LCT is not known; however, LCT induced by other nongenotoxic chemicals have been associated with the disruption of the hypothalamus-pituitary-testicular (HPT) axis.

Central role of PPARalpha in the mechanism of action of hepatocarcinogenic peroxisome proliferators.

Peroxisome proliferators (PP) are a large class of structurally dissimilar chemicals. These chemicals have diverse effects in rodents and humans, including regulation of lipid metabolism, growth promotion, and induction of hepatocarcinogenesis. Most, if not all, effects of PP are mediated by three members of the nuclear receptor superfamily called PP-activated receptors (PPAR).

Effects of di-n-butyl phthalate (DBP) on male reproductive development in the rat: implications for human risk assessment.

The National Toxicology Program (NTP) conducted a continuous breeding study in SD rats with di-n-butyl phthalate (DBP) given via the diet at dose levels of up to 650 mg/kg/day. In the parental generation effects on reproduction were modest (small decreases in litter size and pup weight following treatment). However, the F(1) male offspring had marked decreases in fertility (at 650 mg/kg/day), with reduced sperm counts and reproductive tract malformations on reaching adulthood.

Pharmacokinetics of inhaled manganese phosphate in male Sprague-Dawley rats following subacute (14-day) exposure.

Methylcyclopentadienyl manganese tricarbonyl (MMT) is used as a gasoline octane enhancer. Manganese phosphate is the primary respirable (PM(2.5)) MMT-combustion product emitted from the automobile tailpipe.

Analysis of respiratory exchange of methanol in the lung of the monkey using a physiological model.

A physiologically based pharmacokinetic (PBPK) model was developed for the monkey, to account for fractional systemic uptake of inhaled methanol vapors in the lung. Fractional uptake of inhaled [14C]-methanol was estimated using unreported exhaled breath time course measurements of [14C]-methanol from the D.C.

An integrative approach to neurotoxicology.

Exposure of human populations to a wide variety of chemicals has generated concern about the potential neurotoxicity of new and existing chemicals. Experimental studies conducted in laboratory animals remain critical to the study of neurotoxicity. An integrative approach using pharmacokinetic, neuropathological, neurochemical, electrophysiological, and behavioral methods is needed to determine whether a chemical is neurotoxic.

Mesotheliomas induced in rats by the fibrous mineral erionite are independent from p53 alterations.

The development of human malignant mesothelioma (MM) is strongly associated with occupational or environmental exposure to certain natural mineral fibers, although the genetic mechanisms underlying this malignancy remain unclear. Although the p53 gene is frequently mutated in various tumors, human asbestos-associated MMs appear to develop independently from p53 alterations. The high mesotheliomagenic potency of natural fibrous mineral erionite is well established in humans and rodents, but no data regarding genetic alterations in erionite-associated tumors are currently available.

Fertility and developmental neurotoxicity effects of inhaled hydrogen sulfide in Sprague-Dawley rats.

In this study, we examined whether perinatal exposure by inhalation to hydrogen sulfide (H2S) had an adverse impact on pregnancy outcomes, offspring prenatal and postnatal development, or offspring behavior. Virgin male and female Sprague-Dawley rats (12 rats/sex/concentration) were exposed (0, 10, 30, or 80 ppm H2S; 6 h/day, 7 days/week) for 2 weeks prior to breeding. Exposures continued during a 2-week mating period (evidence of copulation = gestation day 0 = GD 0) and then from GD 0 through GD 19.

In utero exposure to antiandrogens alters the responsiveness of the prostate to p,p'-DDE in adult rats and may induce prostatic inflammation.

DDE is an environmental pollutant with antiandrogenic properties. Following administration to pregnant rats, DDE was shown to cause feminization in the male offspring at the neonatal stages but did not affect the pubertal growth of accessory sex organs. In this study, we examined the potential of in utero exposure to antiandrogens to alter the responsiveness of the male rats to subsequent DDE challenge.

Dosimetry of Particles: Critical Factors Having Risk Assessment Implications.

Species differences in the handling of particles are topics of interest for setting ambient particulate matter standards as well as for studies involving the phenomenon of lung overload and the implications, if any, of such studies for workplace dust exposure standards. The dosimetry of inhaled particles differs among the three major regions of the respiratory tract (extrathoracic, tracheobronchial, and pulmonary). Particulate dosimetry includes both deposition, which is the process of removing particles from inhaled air to various locations in the respiratory tract during breathing, and clearance, which refers to the rates and routes by which deposited particles are removed from the respiratory tract.

Protein Carbonyls in Bronchoalveolar Lavage Fluid in Mice, Rats and Hamsters Following Inhalation of Pigmentary Titanium Dioxide Particles.

Elevation of protein carbonyls has been implicated in the clinical setting as a result of oxidant damage associated with a number of disease states in both humans and laboratory animals. Protein carbonyls, the product of oxidative modification of amino acid residues, may result from macrophage and neutrophil inflammatory responses to inhaled particles. We hypothesized that increased levels of protein carbonyl groups in the bronchoalveolar lavage fluid (BALF) may serve as a biomarker of oxidative stress in rodents exposed to extremely high airborne concentrations of poorly soluble particles (PSP) of low toxicity.

Comparison of Selected Pulmonary Responses of Rats, Mice, and Syrian Golden Hamsters to Inhaled Pigmentary Titanium Dioxide.

We present a preliminary report of a bioassay designed to compare and contrast selected pulmonary responses of female B6C3F1 mice, Fischer 344 rats, and Syrian golden hamsters to inhaled pigmentary titanium dioxide (TiO2). Animals were administered 10, 50, or 250 mg/m(3) TiO2 for 6 h/day and 5 days/wk, for 13 wk. Recovery groups were held for an additional 4-, 13-, or 26-wk period.

Differential interaction of the methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane with estrogen receptors alpha and beta.

Concern that some chemicals in our environment may affect human health by disrupting normal endocrine function has prompted research on interactions of environmental contaminants with steroid hormone receptors. We compared the activity of 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), an estrogenic metabolite of the organochlorine pesticide methoxychlor, at estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). Human hepatoma cells (HepG2) were transiently transfected with either human or rat ERalpha or ERbeta plus an estrogen-responsive, complement 3-luciferase construct containing a complement 3 gene promoter sequence linked to a luciferase reporter gene.

Hepatic expression of acute-phase protein genes during carcinogenesis induced by peroxisome proliferators.

Concern exists regarding peroxisome proliferator (PP) xenobiotic exposure because many PPs are potent hepatocarcinogens in rodents. The mechanism of carcinogenicity induced by PPs is atypical compared with those of other hepatocarcinogens in that the former appears to involve alterations in expression of PP-activated receptor (PPAR) target genes rather than direct mutagenicity. To begin to identify some of these genes, we used differential display to compare mRNA expression between hepatic adenomas and adjacent non-tumor liver from rats fed the potent PP Wy-14643 (WY) for 78 wk.