d-Limonene Induced Hyaline Droplet Nephropathy in {alpha}2u-Globulin Transgenic Mice

d-Limonene is a hyaline droplet inducing agent and producesnephrotoxicity in male rats when the 1,2-epoxide metabolitebinds to 2u-globulin. Mice, which do not synthesize 2u-globulin,are resistant to hyaline droplet nephropathy. In this study,the ability of d-limonene to cause hyaline droplet nephropathyin a transgenic mouse engineered to express 2u-globulin wasevaluated. The C57BL/6-derived mice excreted 0.4 ± 0.1mg 2u-globulin/day, or approximately 16 mg 2u-globulin/kg bodywt. This represents about 30% of the amount excreted by adultmale rats (11.9 ± 1.1 mg/day or approximately 48 mg/kg).Transgenic mice excreted less mouse urinary protein (9.3 ±1.2 mg/day) than normal mice (15.1 ± 1.6 mg/day). Unlikenormal male rats, untreated transgenic mice did not show significantspontaneous hyaline droplet formation. Liver microsomes fromnaive transgenic mice oxidized d-limonene to the cis- and trans-isomersof the 1,2-epoxide, and following oral treatment with [¹⁴C]d-limonenereversible binding of d-limonene equivalents to renal cytosolicproteins was observed. Furthermore, with d-limonene treatment,hyaline droplets were observed in the transgenic mouse kidneys.These droplets, however, were much smaller in size than thoseseen in d-limonene-treated male rats. The accumulation of 2u-globulinin the kidneys of transgenic mice and normal male rats beforeand after d-limonene treatment was analyzed by Western blotting.These results indicated that 2u-globulin was present in thekidneys of the control transgenic mice, despite the lack ofspontaneous hyaline droplet formation. After d-limonene treatment,approximately a three fold increase in 2u-globulin in the transgenicmouse kidney was observed, a response similar in magnitude tothat seen in d-limonene-treated male rats. These results indicatethat expression of 2u-globulin in a species that does not normallydevelop hyaline droplet nephropathy is necessary and sufficientto render that species sensitive to this renal toxicity.     

Development of a Mechanism-Based Dosimetry Model for 2,4,4-Trimethyl-2-pentanol-lnduced {alpha}2u-Globulin Nephropathy in Male Fischer 344 Rats

A mechanism-based dosimetry model was developed to describe2,4,4-trimethyl-2-pentanol (TMP-2-OH) dosimetry and renal 2u-globulin(2u) nephropathy in the male Fischer 344 rat. Experimental datawere collected to estimate the chemical-specific parameters(metabolic constants, tissue solubility, and oral absorptionrate) necessary to describe TMP-2-OH dosimetry in male rats.The concentrations of 2u and TMP-2-OH were measured in malerats up to 64 hr after a single oral dose of TMP-2-OH (6, 60,or 600 mg/kg). The model predicted the time course behaviorof TMP-2-OH and 2u in the kidney, but overestimated their renalconcentrations by two or threefold. Simulations of renal 2uconcentration were sensitive to changes in TMP-2-OH-2u-bindingaffinity and degradation rate of the TMP-2-OH-protein complex.In contrast, simulation of the concentration of TMP-2-OH inthe kidney was most sensitive to the amount of protein present.Oral absorption of TMP-2-OH was dose dependent. The model predictedthat 2u and TMP-2-OH concentration in the kidney is sensitiveto changes in the rate of TMP-2-OH absorbed after oral administration.This model permitted a more rigorous evaluation than has previouslybeen possible of the combination of protein characteristicsand chemical dosimetry required for the accumulation of 2u inthe kidney of male rats. The behavior of the model is consistentwith the qualitative aspects of the 2u hypothesis. However,further characterization of 2u distribution and renal hydrolysiswill be required in order to fully characterize the hypothesisat the quantitative level.     

NCI-Black-Reiter (NBR) Male Rats Fail to Develop Renal Disease following Exposure to Agents That Induce {alpha}-2u-Globulin ({alpha}2u) Nephropathy

NCI-Black-Reiler (NBR) Male Rats Fail to Develop Renal Diseasefollowing Exposure to Agents That Induce _2u-Globulin (_2u) Nephropathy.Dietrich, D. R., and Swenberg, J. A. (1991). Fundam. Appl. Toxicol16, 749–762. The NCI-Black-Reiter (NBR) rat is the onlystrain of male rat known not to synthesize the hepatic formof the low molecular weight protein, _2u-globulin. In previousstudies, NBR rats were shown not to develop renal disease whenexposed to decalin, a compound known to induce _2u-globulin nephropathyin other rat strains. The objective of this study was to showthat the presence of _2u-globulin (_2u-) is essential for thedevelopment of this syndrome in rats exposed to 2,2,4-trimethylpentane(TMP), 1,4-dichlorobenzene (DCB), isopho-rone (IP), PS-6 unleadedgasoline (UG), and d-limonene (d-L). The induction of _2u-nephropathyin F344 male rats with lindane was used as a positive controland this response was contrasted to male NBR and female F344rats treated with lindane. Five to seven 11-week-old male NBRrats were exposed to TMP (500 mg/kg/day), DCB (500 mg/kg/day),IP (1000 mg/kg/day), UG (500 mg/kg/day), d-L (1650 mg/kg/day),or lindane (10 mg/kg/day) and five 11-week-old male and femaleF344 rats were exposed to lindane (10 mg/kg/day) by oral gavageon 4 consecutive days. NBR male and F344 male and female ratsgavaged with corn oil were incorporated in the study as vehiclecontrols. The presence of hyaline droplets was assessed in perfusion-fixedkidneys by staining paraffin sections with Mallory-Heidenheinstain and in GMA sections with Lee's methylene basic blue fuchsinstain. Paraffin sections were also analyzed immunohistochemicallyfor the presence of _2u-. Under exposure conditions that clearlyinduce _2u-nephropathy in male F344 rats, no lesions, hyalinedroplets, or _2u- were detectable in treated or control maleNBR and female F344 rats. It is thus concluded that the presenceof _2u is causal to the development of renal disease in ratsexposed to TMP, DCB, IP, UG, d-L, and lindane.     

Metabolism of {alpha}-Olefin Sulfonate (AOS) in Rats

Metabolism of -Olefin Sulfonate (AOS) in Rats. Inoue, S., O'Grodnick,J.S. and Tomizawa, S. (1982). Fundam. Appl. Toxicol. 2:130-138.The metabolic fate of ¹⁴C-AOS (a mixture of ¹⁴C-sodium alkenyl(2)sulfonate and ¹⁴C-sodium 3-hydroxy alkane sulfonate) has beenstudied in rats by a single oral and intravenous injection of100 mg (50 µCi)/kg and 10 mg (5 µCi)/kg, respectively.After oral administration, ¹⁴C-AOS was rapidly absorbed fromthe gastrointestinal tract. The blood level of ¹⁴C-activityreached its peak 3 hr after dosing and then declined. Twenty-fourhr after the dose, about 0.8%/g of the ¹⁴C-AOS given was detectedin cecum content, but in other tissues the figures were under0.02% dose/g. Within 24 hr after the dose, 72% of the dose wasexcreted in the urine and 22% in the feces, while the excretionin the bile was 4.3% within 12 hr. The administered radioactivitywas rapidly eliminated from the whole body within 24 hr. Afterintravenous injection, half of the administered dose of radioactivitywas excreted within 1 hr. In the 0–6 hr interval post-dose,90% of the dose was excreted in the urine. No intact ¹⁴C-AOSwas detected in any of the urine samples after oral and intravenousdoses. The metabolite was apparently more polar than intact¹⁴C-AOS, and results from data of electrophoresis and equilibriumdialysis indicated that intact ¹⁴C-AOS can bind with proteins,while the metabolites cannot. The metabolite was found to containalcoholic, unsaturated and sulfonic acid functionalities. Itis suggested that the metabolite may be a hydroxylated or polyhydroxylatedsulfonic acid of shorter chain length than AOS. These resultssuggest that ¹⁴C-AOS is rapidly absorbed, metabolized and excreted,therefore, no accumulation of ¹⁴C-AOS occurs.     

Application of Molecular Encapsulation for Toxicology Studies: Comparative Toxicity of p-Chloro-{alpha},{alpha},{alpha}-trifluorotoluene in {alpha}-Cyclodextrin Vehicle versus Corn Oil Vehicle in Male and Female Fischer 344 Rats and B6C3F1 Mice

The application of -cyclodextrin (-CD) as an alternative vehiclefor water insoluble and volatile chemicals was investigatedin toxicity studies of p-chloro-,,-trifluorotoluene (CTFT).Groups of F344 rats and B6C3F1 mice of each sex were administeredCTFT (97% pure) by gavage in either corn oil or -CD aqueousformulations daily for 14 consecutive days. The dose levelsused were 10 (mice only), 50, 400, and 1000 mg/kg for corn oilvehicle and 10, 50, and 400 mg/kg (maximum achievable dose atgavage volume of 5 ml/kg) for -CD vehicle. With both vehiclesCTFT and a_2u-globulin were found to accumulate in the male ratkidney after 14 days of exposure and a dose-related toxic nephropathywas observed at dose of 50 mg/kg or higher. The hepatocellularhypertrophy and cytoplasmic vacuolation of the adrenal cortexwhich appeared in dosed male and female rats were also foundto be independent of vehicle. Clinical pathology findings suggesteda mild anemia and cholestasis in rats. With both vehicles notissue bioaccumulation of CTFT was found in male or female mice.Vehicle-independent hepatocellular hypertrophy and cholestasiswere also observed in mice at doses of 400 and 1000 mg/kg. Inconclusion, the -CD vehicle does not affect the toxic responsesof CTFT in both sexes of both species. The results of the studiessuggest that -CD may be an appropriate alternative vehicle fortoxicity studies.     

Lack of Reproductive Toxicity in Adult Male Rats Exposed to Interferon-Alpha

Interferon-alpha (IFN-α), a type I IFN, is a protein with antiviral, antiproliferative, and immunoregulatory activities, widely used in the treatment of several types of cancers as well as hepatitis B and C. Decrease of libido and erectile dysfunction are commonly reported by male patients during treatment of chronic hepatitis C with IFN-α. However, IFN therapy-associated underlying factors attributed to sexual dysfunction are still not well defined. Currently, there are few studies investigating the effects of IFN on male reproductive system functions. Given that, the aim of the present investigation was to examine effects of subchronic exposure to IFN-α (5 × 10⁴ U/kg and 10 × 10⁴ U/kg, 30 d) on serum hormones, sperm parameters, fertility, and testicular and epididymal hystopathology and morphometry in adult male Wistar rats. None of the evaluated parameters was markedly altered by IFN-α. Thus, our results suggest that exposure to IFN-α, in this experimental design, did not adversely affect sperm quality and fertile capacity of male rats.     

Increased Immune and Inflammatory Responses to Dust Mite Antigen in Rats Exposed to 5 ppm NO2

Immune hypersensitivity to house dust mite antigen (HDM) isa frequent cause of respiratory allergy. The objective of thisstudy was to determine whether exposure to NO₂, a common indoorair pollutant, modulates immune responses to HDM and influencesimmune-mediated lung disease. Brown Norway rats were immunizedip with 100 µg semipurified antigen and Bordetella pertussisadjuvant and challenged 2 weeks later with an intratrachealinjection of 50 µg of a crude antigen preparation. Exposureto 5 ppm NO₂ for 3 hr after both immunization and challengeprocedures resulted in significantly higher levels of antigen-specificserum IgE, local IgA, IgG, and IgE antibody than air controls,and increased numbers of inflammatory cells in the lungs. Lymphocyteresponsiveness to antigen in the spleen and MLN was also significantlyhigher in NO₂-exposed animals. These data show that exposureto a common air pollutant can upregulate specific immune responsesand subsequent immune-mediated pulmonary inflammation.     

Evaluation of the Primary Humoral Immune Response Following Exposure of Male Rats to 17 {beta}-Estradiol or Flutamide for 15 Days

There is a concern that certain industrial chemicals found inthe environment may mimic or antagonize endogenous hormonesand adversely affect the endocrine as well as the immune system.The objective of this study was to determine if exposure ofCrl:CD (SD)BR male rats to 17ß-estradiol (17ß-E2),an estrogen receptor agonist, or flutamide (FLUT), an androgenreceptor antagonist, would significantly alter the primary IgMhumoral immune response to sheep red blood cells (SRBC). Thisstudy was conducted in the context of a male in vivo Tier Ibattery designed to identify endocrine-active compounds (EACs).The Tier I male battery consists of organ weights coupled witha comprehensive hormonal assessment Rats were dosed by the intraperitonealroute for 15 days with vehicle or 0.001, 0.0025, 0.0075, or0.050 mg/kg/day 17ß-E2 or 0.25, 1, 5, or 20 mg/kg/dayFLUT. Six days prior to termination, selected rats were injectedintravenously with SRBC for assessment of humoral immune function.Spleen cell number and spleen and thymus weights were obtained.Serum was analyzed for anti-SRBC IgM antibody by using an enzyme-linkedimmunosorbent assay. At 0.050 mg/kg/day 17ß-E2, meanfinal body and absolute thymus weights were significantly decreasedto 84 and 65% of control, respectively. 17ß-E2 didnot significantly alter spleen weight, spleen cell number, orthe primary IgM humoral immune response to SRBC. The no-observed-adverse-effectlevel (NOAEL) for immune system alteration was 0.050 mg/kg/day17B-E2 since the decrease in absolute thymus weight was judgedto be secondary to the decrements in body weight. In the TierI male battery, responses to 17ß-E2 included decreasedabsolute testis and epididymis weights, decreased relative accessorysex gland unit weights, hormonal alterations (decreased serumtestosterone (T), dihydrotestosterone (DHT), and luteinizinghormone (LH), and increased serum prolactin and E2 levels).The lowest-observed-adverse-effect level (LOAEL) for the reproductiveindices was 0.001 mg/kg/day 17ß-E2 based on the hormonalalterations seen at this level; no NOAEL was established. Exposureto FLUT did not significantly alter mean final body, spleen,or absolute thymus weights, spleen cell number, or the primaryIgM humoral immune response to SRBC. A significant increase(118% of control) in relative thymus weight was observed at20 mg/kg/ day FLUT. The NOAEL for immune system alteration was5 mg/kg/day FLUT based on the increased relative thymus weightsthat were judged to be compound-related. In the Tier I malebattery, responses to FLUT included decreased absolute epididymisand relative accessory sex gland unit weights and hormonal alterations(increased serum T, DHT, E2, and LH, and decreased folliclestimulating hormone levels). The LOAEL for the reproductiveindices was 0.25 mg/kg/day FLUT based on the hormonal alterationsseen at this level; no NOAEL was established. Based on thesedata, the reproductive and not the immune system appears tobe the primary target organ of toxicity in young adult malerats treated with either 17ß-2 or FLUT.     

Influence of ALDH2 Polymorphism on Ethanol Kinetics and Pulmonary Effects in Male and Female Rats Exposed to Ethanol Vapors

Ethanol is being added in various proportions to fuel in order to reduce greenhouse gas emissions. This is likely to result in involuntary exposure to ethanol vapors. Whether or not such exposure might cause health effects is still unknown. Acetaldehyde, an important metabolite of ethanol detoxified by aldehyde dehydrogenase (ALDH2) is more toxic that ethanol. This study assessed the impact of genetic ALDH2 polymorphism in male and female Sprague-Dawley rats on ethanol kinetics and pulmonary effects following sub-chronic exposure to ethanol vapors. Homozygote rats ALDH2^Q/2^Q (fast ALDH2 activity) and ALDH2^R/2^R (ALDH2 deficiency) were exposed to 1000 or 3000 ppm, 6 h/day, 5 days/week for 13 weeks. Blood ethanol concentrations (BEC) were measured at various post-exposure times. Cellularity in bronchoalveolar lavages (BAL) and lung histological evaluation were performed at week 13. Results showed that BEC in males were systematically lower than in females, e.g. BEC in ALDH2^Q/2^Q males (2 min, 1,000 ppm, day 1) was significantly (p < 0.05) lower (66.8 ± 10.7 μ M) compared to females (87.6 ± 15.3 μ M). BEC for ALDH2^Q/2^Q rats were different from ALDH2^R/2^R only for males exposed for more than 64 days. Repeated exposures resulted in a significant decrease of BEC, e.g. for ALDH2^Q/2^Q males (3,000 ppm) BEC on day 1 and day 85 were 324.6 ± 102.6 μ M and 187.5 ± 32.1 μ M, respectively. BAL and histological evaluation revealed no pulmonary toxicity for all groups. Overall, results showed that 3,000 ppm of ethanol vapors represents no observed adverse effect level (NOAEL) for pulmonary toxicity in the rat.     

The Use of in vitro Fertilization to Detect Reductions in the Fertility of Male Rats Exposed to 1,3-Dinitrobenzene

The Use of in vitro Fertilization to Detect Reductions in theFertility of Male Rats Exposed to 1,3-Dinitrobenzene. HOLLOWAY,A. J., MOORE, H. D. M., AND FOSTER, P. M. D. (1990). Fundam.Appl. Toxicol. 14, 113–122. 1,3-Dinitrobenzene (DNB) isan intermediate chemical in the manufacture of dyes and explosivesand its toxic effects include specific damage to the Sertolicells of the testis. This investigation determined the effecta toxic insult to Sertoli cells had on the functional capacityof developing germ cells as assessed by in vitro fertilization.Male rats were given a single, oral dose of 5, 15, or 25 mgDNB/kg. At selected times after treatment, spermatozoa recoveredfrom the cauda epididymidis were tested for fertilizing capacityusing in vitro fertilization techniques and the testicular responseto DNB was determined by histologica] examination. Treatmentwith 15 and 25 mg DNB/kg resulted in substantial exfoliationof germ cells between 0.5 and 3.5 weeks after exposure and againafter 4.5 weeks; seminiferous tubules which were not depletedshowed signs of disrupted spermatogenesis. Reduced sperm fertilizingcapacity in vitro was observed from 1.5 to 5 weeks and between7.5 and 8.5 weeks after treatment with 15 and 25 mg DNB/kg.There were slight, but significant, reductions in fertilityat 3, 5.5, 7.5, and 8.5 weeks after dosing with 5 mg DNB/kg.These data suggested that DNB did not affect all Sertoli cellsequally, but acted in a stage-specific manner. Stages III, IV,XII, and XIV were most vulnerable to the toxicant Germ cellsassociated with an affected Sertoli cell were usually sloughedoff, resulting in lowered fertility at the time when these cellsshould have reached maturity in the epididymis. The extent ofthe testicular lesions and the loss of fertility were dose dependent.This investigation confirmed the use of in vitro fertilizationto detect the effects of testicular toxicants.     

Effects of Dietary 17{beta}-Estradiol Exposure on Serum Hormone Concentrations and Testicular Parameters in Male Crl:CD BR Rats

A 90-day/one-generation reproduction study was conducted inmale and female Crl:CD BR rats using dietary levels of 0, 0.05,2.5, 10, and 50 ppm 17ß-estradiol. The goals of thisstudy were to set dose levels and evaluate several mechanisticend- points for inclusion in multigeneration reproduction andcom- bined chronic toxicity/oncogenicity studies with 17ß-estradiol.In this report we discuss the effects of dietary 17ß-estradiolexposure on serum hormonal levels and sperm parameters fromP₁ and F₁ male rats. Sperm parameters were also evaluated inrecovery P₁ and F₁ male rats that were fed control diets for105 and 103 days, respectively, following 97 and 86–94days of estradiol exposure, respectively. Measurement of Sertolicell number from F₁ male rats was performed to test the hypothesisthat in utero exposure to estrogens will decrease Sertoli cellnumber and sperm production. Other findings from this 90-day/one-generation reproduction study are summarized elsewhere.17ß-Estradiol produced a dose-dependent decrease inbody weight in P₁ male rats at     

The Subchronic Oral Toxicity of the {beta}-Isomer of Hexachiorocyclohexane in Rats

The Subchronic Oral Toxicity of the ß-Isomer of Hexachlorocyclohexanein Rats VAN VELSEN, F. L., DANSE, L. H. J. C., VAN LEEUWEN,F. X. R., DORMANS, J. A. M. A., AND VAN LOGTEN, M. J. (1986).Fundam. Appl. Toxicol. 6, 697–712. The 13-week oral toxicityof ß-HCH, a non pesticidal isomer of hexachlorocyclohexane,was investigated in rats with doses of 0,2, 10, 50, or 250 mg/kgfeed. Parameters studied comprised clinical signs, growth andfood intake, biochemistry, hematology, organ weights, and histopathology.In all dose groups liver effects comprising increase of organweight, centrilobular hepatocytic hypertrophy, and proliferationof smooth endoplasmic reticulum or increased activity of microsomalenzymes, were observed. In the 50 mg/kg group the weights ofthymus and testes were affected. In the highest dose group,progressive clinical signs leading to the unscheduled sacrificeof approximately 50% of the rats were observed. Moreover, inthe males of this group atrophy of the testes, characterizedby a reduced size of the seminiferous tubules and a decreasednumber of interstitial cells was observed in association withspermatogrnic arrest. The females in this group showed atrophyof the ovaries with impaired oogenesis and focal hyperplasiaand metaplastic changes of the endometrial epithelium. Theseeffects are discussed with respect to a possible estrogenicaction of ß-HCH.     

Identification of Genes Controlled by the Pregnane X Receptor by Microarray Analysis of mRNAs from Pregnenolone 16{alpha}-Carbonitrile-Treated Rats

Mammalian liver contains a pregnane X receptor (PXR, NR1I2),which binds drugs and other xenobiotics, and stimulates (orsuppresses) expression of numerous genes involved in the metabolicelimination of foreign compounds and some toxic endogenous substances.In the present study, we used microarray analysis to identifygenes whose expression in rat liver was significantly alteredby pregnenolone 16-carbonitrile (PCN) treatment. PCN is a syntheticsteroid that induces cytochrome P4503A expression and is hepatoprotectiveby increasing resistance to subsequent stressful insults. Significantinduction was seen for 138 genes while expression of 82 geneswas significantly repressed. We found induction of genes knownto be induced by PCN, such as enzymes involved in drug metabolismand transport. In addition, many genes were differentially expressedwhose functions concerned intracellular metabolism, transportof essential small molecules, cell cycle, and redox balance.Our results support the idea that the domain of PXR-controlledgene networks may be even more extensive than currently thoughtand may extend to functions apart from xenobiotic metabolism.     

Investigations of the Potential for Five {beta}-Lactam Antibiotics to Elicit Type II Hypersensitivity Reactions in Rats and Monkeys

Investigations of the Potential for Five ß-LactamAntibiotics to Elicit Type II Hypersensitivity Reactions inRats and Monkeys. KORNBRUST, D., EYDELLOTH, R., AND GARRATTY,G.(1989). Fundam. Appl Toxicol. 12, 558–566. Immunologicreactions are occasionally elicited in patients by various ß-lactamantibiotics (e.g., pencillins and cephalosporins). A relativelyrare reaction (type II hypersensitivity) may involve antibody-mediateddestruction of erythrocytes, leukocytes, and/or platelets. Duringthe safety evaluation of several modified ß-lactamcompounds (carbapenems), hemolytic anemia and/or neutropeniawere observed in rhesus monkeys, and anemia, neutropenia, andthrombocytopenia in rats, after approximately 2 weeks of intravenousadministration. Antiglobulin tests and other clinicopathologicfindin indicated an immune basis for the cytopenias. A reviewof summaries of the predinical data for numerous marketed ß-lactamantibiotics revealed that various cytopenias of unknown etiologywere commonly seen in animals given high doses of these compounds.To determine whether these hematologic abnormalities were relatedto those produced by the above carbapenems, we investigatedthe potential of five widely used ß-lactam antibiotics(penicillin G, cephalothin, cefazolin, cefoperazone, and cefamandole)to elicit immune-mediated cytopenias in rhesus monkeys and Sprague-Dawleyrats when given intravenously. After approximately 1 month ofadministration of these compounds at a dose level of 500 mg/kg/day,slight anemia occurred in several drug-treated monkeys; however,direct and indirect antiglobulin tests were negative for allanimals, indicating that the anemias were not immune-mediated.In rats, no drug-induced hematologic changes were observed after1 month of intravenous administration of 500 and 1000 mg/kg/dayof each of the ß-lactams. In addition, direct antiglobulintests were negative in rats. Therefore, it appears that theability of certain carbapenem antibiotics to produce a highincidence of type II hypersensitivity reactions in animals isnot typical of ß-lactam compounds in general.     

The Relative Bioavailability and Metabolism of Bisphenol A in Rats Is Dependent upon the Route of Administration

Bisphenol A (BPA) is used to produce polymers for food contactapplications, thus there is potential for oral exposure of humansto trace amounts via the diet. BPA was weakly estrogenic inscreening assays measuring uterine weight/response, althoughmuch higher oral doses of BPA were required to elicit a uterotropicresponse as compared to other routes of administration. Theobjective of this study was to determine if a route dependencyexists in the pharmacokinetics and metabolism of ¹⁴C-labeledBPA following single oral (po), intraperitoneal (ip), or subcutaneous(sc) doses of either 10 or 100 mg/kg to Fischer 344 rats. Resultsindicated a marked route dependency in the pharmacokineticsof BPA. The relative bioavailability of BPA and plasma radioactivitywas markedly lower following oral administration as comparedto sc or ip administration. The major fraction of plasma radioactivityfollowing oral dosing was the monoglucuronide conjugate of BPA(68–100% of plasma radioactivity). BPA was the major componentin plasma at Cmax following sc or ip administration exceededonly by BPA-monoglucuronide in females dosed ip. Up to fouradditional unidentified metabolites were present only in theplasma of animals dosed ip or sc. One of these, found only followingip administration, was tentatively identified as the monosulfateconjugate of BPA. The monoglucuronide conjugate was the majorurinary metabolite; unchanged BPA was the principal componentexcreted in feces. These results demonstrated a route dependencyof BPA bioavailability in rats, with oral administration resultingin the lowest bioavailability, and offer an explanation forthe apparent route differences in estrogenic potency observedfor BPA.     

茶多酚对染铅大鼠肝脏的保护作用

目的 探讨茶多酚对染铅大鼠肝脏的保护作用. 方法 SD大鼠40只,随机分成正常对照组,模型组,茶多酚高、中、低剂量组,每组8只. 正常对照组给予去离子水1.0 mL腹腔注射,其余4组腹腔注射醋酸铅15 mg.kg-1,每日1次,连续10 d;给予腹腔注射醋酸铅当天,空白对照组及模型组灌胃0.9%氯化钠溶液,茶多酚组高、中、低剂量组分别灌胃给予茶多酚2.0,1.0,0.5 g.kg^-1,连续30 d. 测定血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)及肝匀浆超氧化物歧化酶(SOD)、丙二醛(MDA)评价茶多酚对染铅大鼠肝脏的保护作用. 结果正常对照组,模型组,茶多酚高、中、低剂量组ALT 分别为(52±7),(245±32),(139±47),(158±67),(240±28) U.L^-1;AST分别为(45±8),(256±35),(147±53),(174±23),(236±32) U.L^-1;SOD分别为(120±13),(33±9),(89±28),(79±24),(67±15) U.mg^-1,MDA分别为(2.6±0.7),(10.5±1.6),(3.6±1.2),(5.3±1.5),(9.5±1.2) nmol.mg^-1. 与正常对照组比较,模型组ALT、AST显著升高(P<0.01);与模型组比较,茶多酚高、中剂量组ALT、AST显著降低(P<0.01),低剂量组无明显降低作用. 与空白对照组比较,模型组肝匀浆SOD显著降低、MDA显著升高(P<0.01);与模型组比较,茶多酚高、中剂量组肝匀浆SOD显著升高,MDA显著降低(P<0.01),低剂量组SOD活性显著升高(P<0.01),但MDA清除不明显. 结论 茶多酚具有一定的肝脏保护作用,其作用机制可能与提高过氧化物酶活性、清除过氧化产物从而保护细胞膜有关.     

Beneficial Effects of Tinospora cordifolia on Blood Profiles in Male Mice Exposed to Lead

This study was carried out to evaluate in vivo protective role of aqueous extract of stem and leaves of Tinospora cordifolia (TC) on the toxic effects of lead on the hematological values. The lead-treated (5 mg/kg body weight, intraperitonially, once daily) male albino mice concurrently received either T. cordifolia stem or leaves extracts (400 mg/kg body weight, orally, once daily) for the duration of 30 days. The animals exposed to lead showed significant decrease in RBC and Hb level. Significant decline in WBC, DLC, and PCV was also noticed. Increase in MCV values displaying reciprocal relationship with RBC, PCV, and Hb values in lead-treated mice were also recorded. These influences of lead were prevented by concurrent daily administration of T. cordifolia stem and leaves extract. These results suggested that simultaneous supplementation of T. cordifolia protects against lead intoxication.     

Mucous Cell Metaplasia in the Airways of Rats Exposed to Machining Fluids

Occupational exposure to microbial-contaminated machining fluidsis associated with a variety of adverse pulmonary effects includingchronic bronchitis and increased sputum production. We havepreviously demonstrated in F344 rats that inhaled endotoxincan increase the amount of stored intraepithelial mucosubstances(Vs) in the respiratory tract. The purpose of the present studywas to examine the effect of endotoxin-contaminated machiningfluid aerosols on mucous production. Rats were exposed to aerosolsof pyrogen-free water, 1 or 10 mg/m³ used machining fluid, or10 mg/m³ unused machining fluid for 3 hr/day for 3 days. Twenty-fourhours after the final exposure, right lung lobes were lavagedand the nasal cavity and left lung were fixed in formalin. Theamount of Alcian blue/periodic acid-Schiff-stained mucosubstanceswas determined by morphometry. Exposure to 10 mg/m³ used machiningfluid (equivalent to 0.8 µg/m³ endotoxin) produced a significantincrease in Vs in the epithelial lining of both the nasal septumand intrapulmonary airways. These changes in Vs were accompaniedby a significant increase in total cells and neutrophils inthe lavage fluid. No changes in stored mucosubstances or lavageparameters were found in animals exposed to 1 mg/m³ used machiningfluid aerosols. A significant increase in Vs was observed inthe nasal septum but not in the intrapulmonary airways of animalsexposed to 10 mg/m³ unused machining fluids (no measurable endotoxin).These results suggest that in addition to endotoxin, nonendotoxincomponents of machining fluids may contribute to the increasein sputum and chronic bronchitis reported for workers exposedto machining fluid aerosols.     

吸烟对男性铅作业者体内血铅、锌卟啉的影响

目的了解吸烟对男性铅作业者体内血铅、锌卟啉的影响。方法采用职业流行病学方法进行研究。结 果吸烟对男性铅作业者体内的血铅、锌卟啉水平没有影响;对经常吸烟者进一步研究,在作业场所吸烟与在作业场 所不吸烟者体内血铅水平比较有显著差异(P<0.05)。结论 在作业场所吸烟对男性铅作业者体内的血铅水平有影响。