Biochemical and Morphologic Responses of Rat Nasal Epithelia to Hyperoxia

Biochemical and Morphologic Responses of Rat Nasal Epitheliato Hyperoxia. NIKULA, K. J., SABOURIN, P. J., FRIETAG, B. C,BIRDWHISTELL, A. J., HOTCHKISS, J. A., AND HARKEMA, J. R. (1991).Fundam. Appl. Toxicol 17, 675–683. While performing itsfunctions in olfaction, modification of inspired air, and protectionof the lower respiratory tract from high concentrations of potentiallyharmful inhalants, the nasal mucosa can be injured by a numberof inhalants. In this study, F344/N male rats were exposed tofiltered air or hyperoxia (85 or 87% oxygen), 24 hr/day, 7 days/week,for 1 (acute exposure) or 11 (chronic exposure) weeks. Therewere distinct differences between the different epithelial regionsexamined in replicative and morphologic responses as well asaltered enzyme activities in response to oxygen exposure. Neitheracute nor chronic hyperoxic exposure caused degenerative, necrotizing,or inflammatory changes in any of the nasal epithelial examined.Hyperoxia-induced hypertrophy, but not hyperplasia, of the non-ciliatedoiboidal (NCC) epithelium occurred after both acute and chronicexposure. Cell replication was increased in portions of theNCC and respiratory epithelia after acute hyperoxia exposure.There were significant increases, compared to controls, in thespecific activity of glucose-6-phosphate dehydrogenase in thenasal turbinates, maxilloturbinates, and lateral wall epithelium(NCC epithelium), the nasal septum (respiratory epithelium),and the ethmoturbinates (olfactory epithelium), and in the specificactivity of glutathione peroxidase in the NCC epithelium andethmoturbinates after acute hyperoxia exposure. The specificactivity of cytochrome P450-dependent monooxy-genase-catalyzedO-deethylation of 3-cyano-7-ethoxycoumarin was significantlydecreased, compared to controls, in the NCC epithelium. Theseresults suggest that hyperoxia exposure induces morphologicand biochemical alterations in nasal epithelia which appearto be protective responses of certain cell types to hyperoxia.     

Effect of Dose on the Disposition of Methoxyethanol, Ethoxyethanol, and Butoxyethanol Administered Dermally to Male F344/N Rats

The glycol ethers methoxyethanol (ME), ethoxyethanol (EE), andbutoxyethanol (BE) are widely used in industrial and householdproducts. Rodent studies indicate the ME and EE are potentiallytoxic compounds causing teratogenic, fetotoxic, hematotoxic,and testicular effects. Exposure of rodents to high concentrationsof BE resulted in anemia due to hemolysis of blood cells, leukopenia,hemoglobinuria, and liver and kidney damage. The purpose ofthis study was to determine the uptake, metabolism, and excretionof dermally administered glycol ethers as a function of theexternally applied dose. Three different amounts of the ¹⁴C-labeledglycol ethers (450-4000 µmole/kg) were applied to same-sizedareas on the clipped backs of F344/ N rats, and nonoccludedpercutaneous absorption was measured. The rates of excretionof the ^l4C-labeled parent compound and metabolites by differentroutes were measured, as well as the amount of ¹⁴C remainingin the carcass. Within the dose range studied, the absorptionand metabolism of these three glycol ethers by F344/N rats waslinearly related to the dermally applied dose. The absorptionof all three glycol ethers was approximately 20–25%, regardlessof the chain length of the alkyl group or the dose administered.The majority of the absorbed dose was excreted in the urine.Feces and exhaled CO₂ represented minor routes of excretion.The alkoxyacetic acid was a major metabolite for all three glycolethers. The formation of small amounts of ethylene glycol indicatedcleavage of the ether bond. Dermally administered glycol etherswere metabolized differently than glycol ethers administeredin drinking water (M. A. Medinsky, G. Singh, W. E. Bechtold,J. A. Bond, P. J. Sabourin, L. S. Birnbaum, and R. F. Henderson,1990, Toxicol. Appl. Pharmacol. 102, 443-455). In general, administrationin drinking water enhanced the production of ethylene glycoland glycol ether-derived CO₂.     

Antigenic Analysis of Human Trophoblast Membrane: Detection of a Lymphocyte Cross-Reactive Antigen

ABSTRACT: The antigenicity of human syncytiotrophoblast membrane (TM) was analyzed using rabbit antiserum raised against TM. From immunoblot analysis, about ten protein bands in TM were recognized by the anti-TM. These included placental alkaline phosphatase and TM-bound albumin. From limited antigenic specificity studies, these antigens, with the exception of albumin, were not detectable in membranes of liver, kidney, heart, and erythrocyte, or in human normal serum. Therefore, these antigens appear to be placental membrane specific. Analysis of lymphocyte membrane by Immunoelectrophoresis, crossed Immunoelectrophoresis, and immunoblot techniques revealed that a single protein band, designated “40 kDa,” was cross-reactive with the anti-TM antiserum, indicating that this antigen is shared commonly between placenta and lymphocyte membranes. Experimental evidence suggesting that the 40-kDa membrane antigen is probably a unique trophoblast-Iymphocyte cross-reactive antigen is based on the following observations: 1) the 40-kDa antigen was not detectable in liver, heart, and kidney membrane; 2) γ₂-microglobulin (12,000 daltons) was not detectable in our TM preparation; and 3) the lymphocyte membrane showed only a single protein band at 40,000 daltons, not at 12,000 for γ-microglobulin.     

Interspecies Comparisons of A/D Ratios: A/D Ratios Are Not Constant across Species

Interspecies Comparisons of A/D Ratios: A/D Ratios Are Not Constantacross Species. DASTON, G. P., ROGERS, J. M., VERSTEEG, D. J.,SABOURIN, T. D., BAINES, D., AND MARSH, S. S. (1991). Fundam.Appl. Toxicol. 17, 696–722. The hypothesis that the ratioof the adult (A) and developmental (D) toxicity of a chemicalis constant across animal species has been proposed as the basisfor identifying developmental hazards, both from traditionaldevelopmental toxicity screens using laboratory mammals andfrom alternative systems such as the coelenterate Hydra attenuata.The purpose of this study was to determine whether A/D ratiosare constant across species. The developmental and adult toxicityof 14 chemicals was assessed in four phylogenetically differentspecies. The chemicals tested were aminopterin, bromodeoxyuridine,cadmium chloride, caffeine, congo red, dinocap, dinoseb, diphenylhydantoin,epinephrine, ethylenethiourea, 2-methoxyethanol, mirex, all-trans-rtinoicacid, and trypan blue. These chemicals are representative ofa variety of toxic mechanisms and a range of potencies. Speciesused were the CD-1 mouse (Mus musculus), South African clawedfrog (Xenopus laevis), fathead minnow (Pimephales promelas),and fruit fly (Drosophila melanogaster). The mouse is a commonlyused model for developmental toxicity. The other species areknown to be sensitive to mammalian toxicants and have well-studiedembryologies. Mice were exposed to chemicals either po or bysc injection using a standard Segment II protocol in which pregnantmice are administered the test agent on a daily basis from GestationDays 6 to 15, adult toxicity is evaluated during and after treatment,and developmental toxicity is evaluated in fetuses at term.The exposzure duration spans the period of organ formation inthe embryo. The other species were exposed to test agents fora developmentally comparable period. This was from blastulation(shortly after fertilization) to the free-swimming tadpole stagein Xenopus (4 days); from blastulation to the free-swimmingfry stage in Pimephales (7 days); and for the entire larvalperiod, the period of development of the imaginal discs, inDrosophila (6 days). Adults of each species were exposed totest agents for 4, 7, and 6 days, respectively. The route ofexposure was via the water column in the two aquatic speciesand via the diet in Drosophila. Statistical lowest observedeffect level (LOEL) and no observed effect level (NOEL) valueswere generated for adult and developmental toxicity in eachspecies. A/D ratios were calculated using both LOEL and NOELvalues. The results indicate little concordance of A/D amongspecies: (1) A/D ratios calculated from LOEL data are withinthe same order of magnitude for all four species for only fourchemicals: dinocap, diphenylhydantoin, epinephrine, and mirex;(2) based on NOEL data, again only four have A/D ratios forall species in the same order of magnitude: dinocap, diphenylhydantion,epinephrine, and ethylenethiourea. It has been suggested thatan A/D ratio of 3 or greater is indicative of a developmentalhazard. Using this criterion, there was consistent agreementamong species only for dinocap (NOEL only), diphenylhydantoin,and all-trans -retinoic acid. Several statistical analyses forconcordance were applied to the data. In no case was A/D foundto correlate between species. These data indicate that A/D ratiosare not constant across these representative species, and thereis no basis for using A/D for hazard assessment.