Organ-Specific Hematopoietic Changes Induced by a Recombinant Human Interferon-{alpha} in Mice

Organ-Specific Hematopoietic Changes Induced by a RecombinantHuman Interferon- in Mice. ROSENTHAL, G. J., STRANAHAN, R. P.,ILL, THOMPSON, M., BLAIR, P., GERMOLEC, D. R., COMMENT, C. E.,SCHWAB, K., AND LUSTER, M. I. (1990). Fundam. Appl. Toxicol.14, 666–675. Interferon-a (IFN-) is a naturally occurringcytokine that mediates numerous biological activities and hasdemonstrated therapeutic potential in a variety of malignancies.Encouraging activity against HIV-1 replication has also beenobserved with IFN- in the treatment of AIDS, although hematotoxicityhas been a frequently observed side effect. In addition, invitro studies have suggested that IFN- may function as a down-regulatorof myelopoiesis. A recombinant hybrid of subtypes of human IFN-,rHuIFN-A/D, has antiviral activity in mu-rine cells in vitroand In vivo. This study examines the effect of acute and subchronicexposure to rHuIFN-A/D on hemopoietic and immune parametersin C57B1/6 mice. IFN-a was administered ip at 0, 1000, 10,000,and 100,000 units/day for either 1 or 10 consecutive days. Manyof the known effects of IFN- in humans such as anemia, leukopenia,and thrombocytopenia were observed in mice following subchronicexposure, with the latter two effects also manifested followingacute exposure. Further analysis showed that this leukopeniawas not selective. Both splenic and bone marrow cells were examinedfollowing 10 days of dosing with the high dose of IFN-. Lymphocyteswere reduced in both compartments, while granulocytes were increasedin both compartments. Bone marrow cells programmed to differentiateinto granulocytes (CFU-G) were suppressed, while macrophageprogenitors (CFU-M) were stimulated. Erythroid cells decreasedin the marrow but increased in the spleen, suggesting that themicroenvironmerit may play a significant role in the effectof IFN-. The proliferative capacity of both B and T spleniclymphocytes was significantly suppressed in a dose-related fashionfollowing multiple exposure to IFN-a. Clinically, IFN-a is mostoften given in multiple doses and the present data suggest thatsuch a regimen is toxic to both erythroid and myeloid cells,as well as being immunotoxic to splenic B and T lymphocytes.     

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.     

Inhibition of Human Plasma and Serum Butyrylcholinesterase (EC 3.1.1.8) by {alpha}-Chaconine and {alpha}-Solanine

The purpose of these experiments was to determine the reversibilityof -chaconine and -solanine inhibition of human plasma butyrylcholinesterase(BuChE). For the substrate -naphthylacetate, optimal assay conditionswere 0.50 M sodium phosphate buffer and a substrate concentrationof 3–5 ' 10^–4 M. Dibucaine (1 ' 10^–5 M) indicatedthe usual phenotype for all subjects; -chaconine and -solanineat 2.88 ' 10^–6 M inhibited BuChE about 70 and 50%, respectively.One-and 24-hr incubations at 1 ' 10^–1 M with -chaconine,-solanine, paraoxon, eserine, and ethanol yielded reversibleinhibition with dilution except for paraoxon. Twenty-four-hourdialyses of incubations showed no inhibition except for paraoxon.PAGE enzyme activity gels of 1-and 24-hr incubations also showedno inhibition except for paraoxon. -Chaconine and -solanineare reversible inhibitors of human butyrylcholinesterase. Atestimated tissue levels, -chaconine, -solanine, and solanidineinhibited BuChE 10–86%. In assays which combined -chaconine,-solanine, and solanidine, inhibition of BuChE was less thanadditive. No inhibition of albumin -naphthylacetate esterase(an arylesterase) was noted with any inhibitor. The importanceof these data to adverse toxicological effects of potato alkaloidsis discussed.     

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.     

The Effects of 10 Triterpenoid Compounds on Experimental Liver Injury in Mice

The purpose of this study was to compare the hepatoprotec tiveeffects of 10 oleanane-type triterpenoid compounds on threeknown hepatotoxicants in mice. These compounds in clude oleanolicacid, ursolic acid, uvaol, -hederin (-H), heder agenin, glycyrrhizin,18-glycyrrhetinic acid (-GA), 18ß-glycyrrhetinic acid(ß-GA), 19-hydroxyl asiatic acid 28-O-ß-D-glucoside (HAG), and 19-hydroxyl asiatic acid (HA). They wereadministrated sc for 3 days at 200 µmol/kg, except for-H, which was given at 100 , imol/kg for 2 days. Acute liverinjury was produced in male CF-1 mice by CCI (15 µl/kg,ip), acetaminophen (500 mg/kg, ip), and cadmium chloride (3.7mg/kg, iv). Liver damage was assessed by serum activities ofalanine aminotransferase and sorbitol dehydrogenase, as wellas by his topathological examination. -Hedenn, ursolic acid,and olean olic acid markedly decreased the toxicity producedby all three hepatotoxicants. Uvaol significantly decreasedCd and Cd- induced hepatotoxicity, but had no effect on acetaminophentox icity. Glycyrrhizin, -GA, and ß-GA decreased acetaminopheninduced liver injury, whereas hederagenin, HAG, and HA did notprotect against any of the hepatotoxicants. In addition, -hederin,ursolic acid, oleanolic acid, and uvaol increased hepatic metallothioneinlevels by 87-, 48-, 28-, and 1 0-fold, respectively, as determinedby the Cd/hemoglobin assay. In conclusion, among the 10 triterpenoidcompounds examined, -hederin, ur solic acid, and oleanolic acidappear to be the most effective in protecting against CCl_4-acetaminophen-, and Cd-induced liver injury.     

Possible Involvement of Prostaglandins in Increases in Rat Plasma Adrenocorticotropic Hormone and Corticosterone Levels Induced by Radiation and Interleukin-1{alpha} Alone or Combined

Exposing rats to 1–10 Gy of ionizing radiation increasedplasma adrenocorticotropic hormone (ACTH) and corticoste-rone(CORT) levels. In both irradiated and nonirradiated rats, recombinanthuman interleukin-1 (rhIL-1 1 hr before radiation/sham exposure)enhanced plasma ACTH and CORT levels. Indomethacin, a cyclooxygenaseinhibitor, attenuated plasma ACTH and CORT levels induced byradiation. Indomethacin also attenuated ACTH and CORT levelsinduced by radiation and interleukin-1 alone or combined. Theseresults suggest that prostaglandins are involved in the increasein plasma ACTH and CORT levels induced by radiation and rhIL-1alone or combined.     

Increased Hyaline Droplet Formation in Male Rats Exposed to Decalin Is Dependent on the Presence of {alpha}2u-Globulin

Increased Hyaline Droplet Formation in Male Rats Exposed toDecalin Is Dependent on the Presence of _2u-Globulin. RIDDER,G. M., VON BARGEN, E. C., ALDEN, C. L., AND PARKER, R. D. (1990).Fundam. Appl. Toxicol. 15, 732–743. A peculiar decalin-inducedmale rat nephropathy associated with the altered renal handlingof filtered protein appears limited to the accumulation of theprotein, _2u-globulin. Several strains of male rats that produce_2u-globulin (Fischer-344, Sprague-Dawley, Buffalo, and NorwayBrown) demonstrate spontaneous renal cortical hyaline dropletswhich are exacerbated after exposure to decalin. In all cases,a close correlation exists between hyaline droplet formationobserved histologically and _2u-globulin accumulation measuredbiochemically. In stark contrast, the NCI-Black-Reiter strain,which does not produce measurable quantities of _2u-globulin,neither forms hyaline droplets nor accumulates any filteredprotein in its kidney cortex either spontaneously or after exposureto decalin. Also, female rats injected ip with male rat _2u-globulinexhibit increased hyaline droplet formation and _2u-globulinaccumulation when treated with decalin. These data provide evidencethat the presence of _2u-globulin is key in understanding whythis nephropathy appears unique to the male rat.     

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.     

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 Fish Peritoneal Macrophages as a Model for Higher Vertebrates in Immunotoxicological Studies: I. Characterization of Trout Macrophage Morphological, Functional, and Biochemical Properties

Development of Fish Peritoneal Macrophages as a Model for HigherVertebrates in Immunotoxicological Studies. I. Characterizationof Trout Macrophage Morphological, Functional, and BiochemicalProperties. ZELIKOFF, J. T., ENANE, N. A., BOWSER, D., SQUIBB,K. S., AND FRENKEL, K. (1991). Fundam. Appl. Toxicol. 16, 576–589.The immune defense mechanisms of fish are not as well characterizedas those of mammals but seem to be related and similarly competent.Because of this, there is an increased interest in the immuneresponses of fish as models for higher vertebrates in immunotoxicologicalstudies. Prior to such studies, baseline criteria for specificcomponents of the immune response needed to be established.For this study, we have examined trout macrophage morphologyusing light and scanning electron microscopy, phagocytic activity,random and stimulus-directed migration, and superoxide anionradical (^{dot}) production for resident and lipopolysacharide (LPS) or Aeromonas salmonicidae-elicited rainbowtrout (Oncorhynchus mykiss) peritoneal macrophages (M). Followingperitoneal lavage, >89% of the cells were M as determinedby differential counts and nonspecific esterase staining. Immunizationwith LPS and A. salmonicidae increased M number {small tilde}5and 13-fold, respectively, and overall size. Trout M were phagocyticallyactive engulfing serum opsonized latex particles and were mobile,migrating both randomly and in a directed fashion towards formyl-methionine-L-leucine-L-phenylalanine(FMLP) and trout serum-derived complement fragment C5a. Concentrationsof FMLP (100 nM) and C5a (0.01–1%) effective for attractingtrout M are the same as those used to attract rabbit M. Residenttrout M produced negligable quantities of-(^{dot}) following stimulation with 1 µg/ml phorbol myristate acetate;Aeromonas-elicited M produced (^{dot}) in a time-dependen manner which peaked after 60 min at 2.9 nmolper 2 ? 10₅ cells and then declined. The results of this studyprovide a data base for future toxicological studies with troutperitoneal M and indicate the usefulness of this system forimmunotoxicological studies.     

Nickel and the Microbial Toxin, MALP-2, Stimulate Proangiogenic Mediators from Human Lung Fibroblasts via a HIF-1{alpha} and COX-2-Mediated Pathway

Hypoxia-inducible factor (HIF-1) and cyclooxygenase-2 (COX-2)have been implicated in the regulation of inflammatory-likeprocesses that lead to angiogenesis and fibrotic disorders.Here we demonstrate that in human lung fibroblasts (HLFs) treatedwith mixed exposures to chemical and microbial stimuli, HIF-1stabilization plays a pivotal role in the induction of COX-2mRNA and protein, driving the release of vascular endothelialgrowth factor (VEGF) and proangiogenic and profibrotic chemokines.Upon costimulation with Ni and the mycoplasma-derived lipopeptidemacrophage-activating lipopeptide-2 (MALP-2), there was a synergisticinduction of CXCL1 and CXCL5 mRNA and protein release from HLF,as well as an enhanced response in VEGF compared to either stimulusalone. Consistent with our previous findings that Ni and MALP-2stimulates the induction of CXCL8 via a COX-2-mediated pathway,CXCL1, CXCL5, and VEGF release were also regulated by COX-2.Ni induced the stabilization of HIF-1 protein in HLF, whichwas further enhanced in the presence of MALP-2. Depletion ofHIF-1 using siRNA blocked COX-2 induction by Ni and MALP-2 alongwith the release of VEGF, CXCL1, CXCL5, and CXCL8. Our resultsindicate that Ni and MALP-2 interact to promote an angiogenicprofibrotic phenotype in HLF. Moreover, these findings reveala potential role for HIF-1 in mediating chemical-induced alterationsin cellular response to microbial stimuli, modulating pulmonaryinflammation and its consequences such as fibrosis and angiogenesis.     

Pulmonary and Pleural Responses in Fischer 344 Rats Following Short-Term Inhalation of a Synthetic Vitreous Fiber: I. Quantitation of Lung and Pleural Fiber Burdens

The pleura is an important target tissue of fiber-induced disease,although it is not known whether fibers must be in direct contactwith pleural cells to exert pathologic effects. In the presentstudy, we determined the kinetics of fiber movement into pleuraltissues of rats following inhalation of RCF-1, a ceramic fiberpreviously shown to induce neoplasms in the lung and pleuraof rats. Male Fischer 344 rats were exposed by nose-only inhalationto RCF-1 at 89 mg/m³ (2645 WHO fibers/cc), 6 hr/day for 5 consecutivedays. On Days 5 and 32, thoracic tissues were analyzed to determinepulmonary and pleural fiber burdens. Mean fiber counts were22x10⁶/lung (25x10³/pleura) at Day 5 and 18x10⁶ (16x10/pleura)at Day 32. Similar geometric mean lengths (GML) and diameters(GMD) of pulmonary fiber burdens were observed at both timepoints. Values were 5 µm for GML (geometric standard deviationGSD 2.3) and 0.3 µm for GMD (GSD 1.9), with correlationsbetween length and diameter () of 0.2–0.3. Size distributionsof pleural fiber burdens at both time points were approximately1.5 µm GML. (GSD 2.0) and 0.09 µm GMD (GSD 1.5; 0.2–0.5). Few fibers longer than 5 µm were observedat either time point. These findings demonstrate that fiberscan rapidly translocate to pleural tissues. However, only short,thin (<5 µm in length) fibers could be detected overthe 32-day time course of the experiment.     

The Perturbation of Hepatic Glutathione by {alpha}2-Adrenergic Agonists

The Perturbation of Hepatic Glutathione by ₂ -Adrenergic Agonists.James, Robert C, Roberts, Stephen M. and Harbison, Raymond D.(1983). Fundam. Appl. Toxicol.. 3: 303–308. Single injectionsof epinephrine significantly lowered the hepatocellular levelsof reduced glutathione (GSH) while producing small but significantelevations in serum glutamic-pyruvic transaminase (SGPT) activity.Hormones, i.e. glucagon and the corticosteroids, were also foundto depress significantly hepatic glutathione. Based upon theagonist-antagonist studies performed, the hepatic GSH loweringeffects of epinephrine appear to be mediated solely by ₂ receptors.Adrenergic antagonists with ₂ receptor blocking properties,phenotolamine and yohimbine, prevented the epinephrine-inducedlowering of GSH while agonists with ₂ activity, clonidine andguanabenz, mimicked epinephrine's response. Antagonists witheither ₁or ß activity, i.e. prazosin, phenoxybenzamineand propranolol, did not prevent the epinephrine-induced loweringof hepatic GSH. Contrary to these findings antagonists witheither or P receptor blocking activity significantly reducedthe epinephrine-induced elevations in SGPT activity. Thus, therewas no apparent relationship between the elevation of SGPT activityand the reduction in hepatic glutathione levels. It is concludedthat the therapeutic administration of these compounds, or physiologicresponses to stress or pain, may exacerbate the hepatotoxicityof compounds detoxified by GSH or alter important glutathione-mediatedhepatocellular processes.     

Vaiproic Acid Teratogenicity in Mice after Various Administration and Phenobarbital-Pretreatment Regimens: The Parent Drug and Not One of the Metabolites Assayed Is Implicated as Teratogen

Vaiproic Acid Teratogenicity in Mice after Various Administrationand Phenobarbital-Pretreatment Regimens: The Parent Drug andNot One of the Metabolites Assayed Is Implicated as Teratogen.NAU, H. (1986). Fundam. Appl. Toxicol. 6,662–668. Theantiepileptic drug vaiproic acid (VPA) was administered viafour different routes in the mouse during gestational stagessensitive for interference with neural tube defect formation:a single oral intubation or injection, sc or ip, on Day 8, orinfusion via subcutaneously implanted osmotic minipumps fromDay 7 to 8 of gestation. Embryotoxicity was evaluated on Day18 (incidence of exencephaly, embryolethality and fetal weightretardation). Oral intubation of VPA resulted in significantlylower peak concentrations of VPA as well as lower embryotoxicityas compared to sc and ip administration. The metabolites ofthe ß-, - and -1 oxidation pathways were present inboth maternal serum and gestational tissues in very low concentrations(usually less than 2% of corresponding VPA levels). Infusionof VPA via osmotic minipumps (lower steady-state VPA levelsas compared to peak levels following injection of VPA) resultedin embryolethality and fetal weight retardation, but littleexencephaly. The metabolic pattern was similar in all four administrationexperiments. Phenobarbital pretreatment of the dams (previouslyshown to reduce VPA serum concentrations and induce the and-1 oxidation pathways) reduced the embryotoxicity of VPA. Theseresults suggest that VPA embryotoxicity is mediated by the parentdrug, and not one of the metabolites considered in this study.     

Evaluation of the Immunotoxicity of {eta}-Hexachlorocyclohexane ({eta}-HCH)

Evaluation of the Immunotoxicity of-Hexachlorocyclohexane -HCH).CORNACOFF, J. B., LAUER, L. D., HOUSE, R. V., TUCKER, A. N.,THURMOND, L. M., VOS, J. G., WORKING, P. K., AND DEAN, J. H.Fundam Appl. Toxicol. 11,293–299.0-HCH, an isomeric contaminantformed during the manufacture of the insecticide lindane, isa persistent environmental and food chain pollutant which hasbeen reported to exhibit estrogenic activity in rodents andin fish. To investigate potential toxic effects on the reproductiveand immune systems, -HCH was fed to female B6C3F1 mice for 30days. Mice exposed to 0, 100, or 300 mgo-HCH/kgofdiet were evaluatedfor changes in ovarian and uterine histology, body weight, lymphoidorgan weight and histology, splenic cellularity, antigen-specificIgM and IgG plaque-forming cells (PFQ, proliferative responsesto mitogens, natural killer (NK) cell activity, and inductionof cytolytic T lymphocytes. The ovaries and endometrial epitheliumexhibited normal architecture. No alterations were observedin body weight, lymphoid organ weight and histology, or spleniccellularity whereas significant changes were found in severalimmune functions at the 300 mg/kg dose. Proliferation of splenocytesto the mitogens LPS, PHA, and Con A was decreased by 39,43,and 57%, respectively. T-lymphocyte-mediated cytolysis of tumortargets was decreased by 25% with a concurrent reduction of45% in NK activity. There was no significant reduction in thenumber of IgM or IgG PFC in exposed animals. These data indicatethat -HCH causes nonestrogenic immune function changes in theadult mouse without gross changes in lymphoid organ weight,histology, or cellularity.     

Renal Glutathione and Mercury Uptake by Kidney

Renal Glutathione and Mercury Uptake by Kidney. BERNDT, W. O.,BAGGETT, J. MCC., BLACKER, A., AND HOUSER, M. (1985). Fundam.Appl. Toxicol.. 5,832-839. The kidney is well documented asthe target organ for mercuric ion. Mechanisms by which thision accumulates in renal tissue, however, are less well understood.Sulfhydryl groups in renal tissue might well bind this metaland serve as a sink for its accumulation. Various studies haveindicated that both methyl mercury as well as mercuric ion areaccumulated less by renal tissue after depletion of nonproteinsulfhydryl groups. A similar reduction in hepatic accumulationof mercuric ion or methyl mercury does not occur after nonproteinsulfhydryl depletion. This observation may relate to the highertissue content of nonprotein sulfhydryls in liver than kidneyor to a fundamentally different mechanism of metal uptake. Mercuricion accumulation by renal tissue also can be reduced by ureteralocclusion, a reduction that is less than that for inulin incomparable experiments. These data are complex and do not clearlyestablish a role for filtration in the delivery of mercury tothe kidney. Inhibition of the renal enzyme glutamyl transpeptidase(-GT) results in a marked increase in the excretion of bothglutathione and mercury in the urine. Although there is a tendencyfor kidneys of the GT-inhibited animals to contain less mercurythan controls, the change in renal content was not significant.These observations suggest that -GT may have a role in the reabsorptionof mercury from the tubular lumen. Interestingly, both mercuricchloride-induced mortality and effects on renal slice accumulationof organic ions were enhanced in the presence of nonproteinsulfhydryl depletion caused both by immediate depletion of theglutathione pool and by inhibition of its synthesis.