Dearomatizing Cyclization of 2-Iodoindoles by Oxidative NHC Catalysis to Access Spirocyclic Indolenines and Oxindoles Bearing an All Carbon Quaternary Stereocenter.

An intramolecular dearomatizing spirocyclization of indoles by oxidative N-heterocyclic carbene catalysis is reported. C2-iodinated indoles are used as substrates in combination with aroyl azolium ions as acceptors, which provides C2-iodinated indolenines containing an all carbon quaternary stereocenter. The products are readily further C2-functionalized and give access to valuable oxindoles by simple hydrolysis in very good overall yields and excellent enantioselectivities.

Oxidative N-Heterocyclic Carbene-Catalyzed Intramolecular Friedel-Crafts Alkylation of Indoles for the Synthesis of Spirocyclic Indolenines.

The stereoselective intramolecular dearomatizing spirocyclization of indoles via oxidative N-heterocyclic carbene (NHC) catalysis to afford indolenines bearing an all-carbon quaternary center at the 3-position is reported. The reaction proceeds via the intramolecular nucleophilic addition of the indole to an in situ generated α,ß-unsaturated acyl azolium. The cyclized indolenine bearing an acyl azolium functionality is trapped by a suitable external nucleophile that does not efficiently react with the α,ß-unsaturated acyl azolium via direct acylation.

The company they keep: the influence of peer relationships on adjustment to cystic fibrosis during adolescence.

A grounded theory approach was used to explore the influence of peer relationships on adjustment to cystic fibrosis (CF) in 15 adolescents. Discovering the course was the core category that captured the influence of peers on adjustment to CF. Four subcategories were identified: (1) losing ground, (2) being out of the loop, (3) finding a new company of friends, (4) fighting a never-ending battle. The downward progression of CF and increasing social interactions with peers with CF during hospitalization helped them learn CF was a lifelong disease with relentless demands. Interventions should focus on strategies for promoting peer support, a positive attitude, and hope to create a sense of belonging, social competence, and well-being.

Playing for time: adolescent perspectives of lung transplantation for cystic fibrosis.

A single-case study approach was used to provide an in-depth examination of the special events surrounding the decision of a 21-year-old adolescent to undergo lung transplantation for end-stage cystic fibrosis. The central theme "playing for time" characterized the interplay between the disease progression and adolescent development as illustrated by 3 subthemes: (a) a strange balance; (b) playing chicken; and (c) being listed. The adolescent's developmental needs provided the context for the struggle with the competing demands of physiologic and psychologic readiness for the transplant, quality-of-life issues, and a renewed hope for the future. Developmental needs were more important to the adolescent than the opportunity for increased length of survival provided by lung transplantation. Advanced practice nurses are in an excellent position to provide continuity of care for chronic illness management over time and across settings.

Gaining freedom: self-responsibility in adolescents with diabetes.

This exploratory, qualitative pilot study explored the meaning of the chronic illness experience for adolescents with diabetes in relation to taking on responsibility for their own care. Four adolescents aged 15 to 17 years with insulin-dependent diabetes mellitus participated in indepth interviews. Gaining freedom was the central phenomenon that captured the process of gaining self-responsibility in diabetes management during adolescence. Three themes marked the process: (a) making it fit; (b) being ready and willing; and (c) having a safety net of friends. These adolescents described a gradual transition from dependence to independence in learning to manage their diabetes. These findings should cause advanced practice nurses to re-evaluate their frameworks for adolescents with diabetes and develop a collaborative approach. Intervention strategies must be developed that incorporate adolescent developmental needs, determine readiness and motivation to learn, and provide opportunities to practice independence in self-management.

Pharmacokinetics and pharmacodynamics of sibrafiban (Ro 48-3657), an orally active IIb/IIIa antagonist, administered alone or in combination with heparin, aspirin, and recombinant tissue-type plasminogen activator in beagles.

This study characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of sibrafiban (Ro 48-3657) in the presence of aspirin, heparin, and recombinant tissue-type plasminogen activator (rt-PA) in beagles. Sibrafiban is a double prodrug that undergoes bioconversion to the inactive prodrug Ro 48-3656 and to the active IIb/IIIa antagonist, Ro 44-3888, after oral administration. After oral sibrafiban, peak Ro 48-3656 plasma concentrations were observed earlier than Ro 44-3888 and were five- to sixfold higher than Ro 44-3888 peak concentrations. Administration of sibrafiban with heparin and aspirin or heparin and rt-PA did not alter sibrafiban PK. Ro 48-3656 and Ro 44-3888 PK and inhibition of platelet-aggregation profiles in groups treated with sibrafiban and heparin/aspirin or sibrafiban and heparin/rt-PA were similar to those of the group receiving sibrafiban alone. Sibrafiban resulted in >80% inhibition of adenosine diphosphate (ADP)-mediated platelet aggregation and an approximate sixfold increase in bleeding time (BT) compared with baseline measurements. The BT increase was greater in the sibrafiban, heparin, and rt-PA-treated group, during rt-PA administration, compared with the group treated with sibrafiban alone. The recovery of platelet aggregation may be slower after administration of sibrafiban with heparin and rt-PA. Sibrafiban had no effect on rt-PA PK or heparin PD.

The child's eye: memories of growing up with cystic fibrosis.

This qualitative study used a grounded theory approach to explore adolescent conceptualizations of their chronic illness experience and related life events. A purposive sample of 20 adolescents (12-18 years of age) with cystic fibrosis were interviewed. Adolescents used three protective strategies for reducing a sense of difference from peers: (1) keeping secrets, (2) hiding visible differences, and (3) discovering a new baseline. "Good friends" were a critical source of support and decreased the importance of differences in their social world. Interventions should focus on strategies for dealing with difficult peer situations and the negative reactions of others.

Through the looking glass: children's perceptions of growing up with cystic fibrosis.

This qualitative study used a grounded theory approach to explore the unfolding of the chronic illness experience for children during middle childhood. A purposive sample of 20 children (6-12 years) with cystic fibrosis (CF) were interviewed. Discovering a sense of difference was found to be the central phenomenon that described the experience of having CF during the middle childhood years. Four central themes emerged in the stories of these children: (a) puzzling out the diagnosis, (b) being teased and picked on, (c) telling others, and (d) keeping up. The study concluded that interventions must focus on the psychosocial demands made on children with CF along their course of development. By designing interventions around meaningful outcomes in their daily lives, we will help children with CF find ways to feel normal while adhering to treatment regimens, thereby helping to improve the quality of their lives.

Responses to chronic illness: analysis of psychological and physiological adaptation.

The Adaptation Nursing Model provided the theoretical framework for the comparative analysis of psychological and physiologic adaptation of 211 adults representing three diagnostic groups (rheumatoid arthritis, hypertension, and multiple sclerosis). Data were collected through interviews and completion of the Mental Health Index, Health-Related Hardiness Scale, and Margin in Life. Psychological adaptation was found to be independent of diagnosis. Four predictor variables (health promotion activities, psychological distress, physiologic adaptation, and dependence on medications) significantly discriminated among the three groups and correctly classified 73.08% of the total sample. Presence of the hardiness characteristic was significantly related to psychological and physiologic adaptation, involvement in health promotion activities, and participation in patient education programs. It can be concluded that a diagnosis-specific view of psychological status is not tenable or clinically meaningful.

EJ/ras neoplastic transformation of simian virus 40-immortalized human uroepithelial cells: a rare event.

To determine if expression of mutant p21 ras could convert Simian Virus 40-immortalized human uroepithelial cell line (SV-HUC) to tumorigenicity, SV-HUC cells were transfected with pSV2-neo (a neomycin-resistant gene) or PREJ/ras (c-HA-ras-1 with the 12th codon mutation and neo). Seven independent G418-resistant clones (A----G) were isolated from each group (SV-HUC/ras and SV-HUC/neo). SV-HUC/ras clones were morphologically altered, while SV-HUC/neo clones retained a typical SV-HUC epithelial morphology. Electrophoretic analysis of immunoprecipitated ras proteins detected altered p21 ras protein in four of seven SV-HUC/ras clones at passage (P)2 and in five of seven clones at P12 posttransfection. The relative levels of ras p21 differed among the clones and appeared to increase with passage in culture. RNA and DNA dot blot analyses showed that clones with more abundant mutant p21 also had higher ras RNA levels and, in one case, increased ras gene copy number. No altered ras protein was detected in any SV-HUC/neo clones. ras- and neo-transfected clones were tested for tumorigenicity at P2 posttransfection and again at P12 by four s.c. inoculations each into athymic nude mice. None of 56 inoculations of SV-HUC/neo clones was tumorigenic. None of the SV-HUC/ras clones at P2 gave rise to tumors at all four injection sites. However, two ras-transfected clones, SV-HUC/ras-B and SV-HUC/ras-F, produced one tumor each. One clone, SV-HUC/ras-D which produced abundant mutant p21, was negative when inoculated at P2, but produced tumors in four of four sites when reinoculated after ten passages in vitro. All tumorigenic clones had detectable levels of mutant ras p21. However, the relative levels of altered p21 ras protein among the SV-HUC/ras clones did not directly predict their tumorigenic potential, as several nontumorigenic SV-HUC/ras clones had protein levels equal to or higher than the most tumorigenic clone (SV-HUC/ras-D at P12). Cell lines established from the tumor explants exhibited higher ras gene copy numbers, higher RNA levels, and more abundant p21 than was seen in the clones at the time of inoculation. Therefore, increases in ras protein abundance occurred during tumor formation in vivo, as well as during passage of cells in culture, and such cells apparently had a selective growth advantage. However, expression of abundant mutant ras protein was not in itself sufficient for neoplastic transformation of SV-HUC.(ABSTRACT TRUNCATED AT 400 WORDS)

Basis for the differential modulation of the uptake of 5-iododeoxyuridine by 5'-aminothymidine among various cell types.

We have previously reported that 5'-aminothymidine (5'-AdThd), an antagonist of the feedback inhibition exerted by dTTP that regulates thymidine kinase, enhances the uptake and cytotoxicity of 5-iododeoxyuridine in various human bladder cancer cell lines but not in normal human urothelial cells (HU) propagated in vitro. In this work we have analyzed the factors that could potentially account for the differential effect of 5'-AdThd among various cell types: 647V (a human bladder cancer cell line); HU; SV-HU (a SV40-transformed human urothelial cell line), and C3H/10T1/2 mouse embryo fibroblasts (10T1/2) cells. 5'-AdThd enhanced the uptake of IdUrd in SV-HU cells (greater than 400%), similar to what we have observed before for 647V cells. However, in 10T1/2 and HU cells, 5'-AdThd only minimally increased the uptake of 5-iododeoxyuridine (about 160%). Thymidine kinases purified from the different sources were similarly sensitive to inhibition by dTTP or 5'-AdThd and to deinhibition of the dTTP-induced regulation of enzyme activity by 5'-AdThd. Furthermore, [3H]-5'-AdThd permeated and accumulated intracellularly in all cell types. In none of these cultures was nucleoside phosphorylase activity detected, as indicated by the inability of the cells to produce thymine or iodouracil after exposure to the appropriate nucleosides. Also, 5'-AdThd did not affect the breakdown of dTMP by crude preparations of cytosolic 5'-nucleotidase from the different cells. We found that intracellular dTTP pools in the various cell types were substantially high (15-26 microM) compared to the sensitivity of thymidine kinase to inhibition by dTTP (IC50 2-4 microM). This suggests that thymidine kinase is in a strongly inhibited state in situ. To test the sensitivity of thymidine kinase (in situ) to regulation by dTTP we investigated: (a) the effect of depleting intracellular dTTP pools with methotrexate on the uptake of thymidine (dThd); and (b) the effect of pH on the uptake of dThd and its perturbation by 5'-AdThd, since the inhibition of thymidine kinase activity by dTTP is known to be pH dependent. We found that a 47% reduction of dTTP pools by methotrexate in 10T1/2 and HU cells did not result in an increase in thymidine kinase activity, as indicated by the lack of an effect on the uptake of dThd. However, we have previously shown that, under similar conditions, 647V cells show a substantial increase in dThd uptake.(ABSTRACT TRUNCATED AT 400 WORDS)

Marker chromosome stability associated with neoplastic transformation of human uroepithelial cells.

Chromosome studies were performed on three independently derived tumor cell lines established from carcinomas induced in nude mice after innoculation of SV40 immortalized human uroepithelial cells that had been treated with methylcholanthrene. Tumor 1 was an undifferentiated carcinoma, while tumors 7 and 9 were both squamous carcinomas. After six to eight passages in vitro the tumor cells were each reinoculated into other nude mice to yield secondary tumors (1.1 and 7.1). Chromosome studies on both primary and secondary tumors demonstrated the same distinctive chromosome markers. Tumors 1 and 1.1 shared the same histopathology in addition to the same modal chromosome number and identical chromosomal duplications and deficiencies; the same was true of tumors 7 and 7.1. Tumor 9, which did not yield a secondary tumor, nevertheless showed the same chromosome pattern in different passages. The stability of the characteristic marker chromosomes in the three tumor cell lines distinguishes these malignant lines from the nonmalignant SV40 transformed parent line from which the three tumors derived because the parent line was characterized by extreme marker instability. This suggests that the stable marker chromosomes that characterize the tumor cell lines may be critical for their tumorigenicity, and that evolution of an adaptive neoplastic genome may select for cytogenetic stability as long as there are no new selective pressures.

Neoplastic transformation of SV40-immortalized human urinary tract epithelial cells by in vitro exposure to 3-methylcholanthrene.

Normal human urinary tract epithelial cells (HUC) were neoplastically transformed in vitro using a step-wise strategy. First, a partially transformed non-virus-producing cell line was obtained after infection of HUC with simian virus 40 (SV40). This cell line (SV-HUC-1) was demonstrated to be clonal in origin, as 100% of cells contained at least five of seven marker chromosomes. Marker chromosomes were formed by balanced translocations resulting in a 'pseudodiploid' cell line. SV-HUC-1 showed altered growth properties in vitro (e.g. anchorage independent growth) but failed to form tumors in athymic nude mice, even after 3 years in culture (80 passages). In the studies reported here, SV-HUC-1 at early passages (P15-P19) were exposed to 3-methylcholanthrene (MCA) in three separate experiments. After a six-week post-treatment period of cell culture, cells were inoculated s.c. into athymic nude mice. In all experiments, MCA-treated SV-HUC-1 formed carcinomas in mice usually with a latent period of 5-8 weeks. These carcinomas showed heterogeneity with respect to histopathologies and growth properties in the mice and karyotypes. All the tumors retained SV-HUC-1 chromosome markers, but each independent transformant was aneuploid and contained unique new marker chromosomes. Chromosomes usually altered in tumor cells included numbers 3, 5, 6, 9, 11 and 13. Mutations in the ras family of cellular proto-oncogenes resulting in altered mobility of the p21 protein product were not detected in six cell lines established from independently derived tumors. It is not yet known whether other cellular proto-oncogenes are activated in these tumorigenic transformants. Neither control SV-HUC-1 (which were not exposed to MCA), nor early passage HUC exposed to MCA formed tumors when inoculated into mice. Thus, the tumorigenic transformation of HUC resulted from the combined actions of SV40 and MCA.

Cytogenetic instability with balanced chromosome changes in an SV40 transformed human uroepithelial cell line.

Cytogenetic analysis at the 15th, 34th, 50th, and 56th passages of an SV40 immortalized human uroepithelial cell line (SV-HUC-1) showed continuous chromosome change and marker formation. Throughout these passages the transformed cells maintained their epithelial morphology, were SV40 T antigen positive, did not shed infectious SV40 virus, and were repeatedly found to be nontumorigenic when innoculated into athymic nude mice. Each of the passages studied was characterized by extensive karyotypic changes due to formation, rearrangement, and disappearance of different markers. A marker involving chromosome 1 was stable at three of the passages studied, whereas markers involving the X chromosome changed at each passage studied. Because of the incorporation of several chromosomes or chromosome arms into markers, the karyotype was genetically balanced in the first passage studied, with no net loss or gain of chromosomal material despite a modal number of 44. In subsequent passages, despite continued instability and generation of new markers, there was a slight but additive loss of genomic balance which increased with time in culture. Since continued karyotypic rearrangements did not lead to tumorigenic conversion, it is probable that genetic instability coupled with selection for the most balanced genome may be important for the immortalization of this cell line.

Characterization of human uroepithelial cells immortalized in vitro by simian virus 40.

Normal human uroepithelial cells (HUC) were transformed with simian virus 40 (SV40) in vitro. SV40-transformed HUC (SV-HUC) were selected by their ability to survive senescence which normally occurs in HUC between passages 4 and 6. At passage 6, 100% of SV-HUC stained positive for SV40 T-antigen. The epithelial nature of SV-HUC was confirmed by positive staining for human cytoplasmic keratins in all cells. SV-HUC have altered growth characteristics compared to HUC including the capacity to grow on plastic, independent of a collagen-gel substrate; loss of the dependence on medium supplements for optimal growth, loss of the dependence on feeder cells for growth at clonal density, and an apparently unlimited lifespan in culture (greater than 2 years). Although SV-HUC have an increased percentage of viable cells and increased saturation density compared to HUC, the generation time of SV-HUC during log phase is similar to that of HUC. Cultures of SV-HUC are epithelial in appearance and show some morphological heterogeneity in cell size and shape. At the ultrastructural level, SV-HUC have numerous alterations such as, irregularly shaped nuclei and nucleoli, pleomorphic microvilli, and the lack of a glycocalyx on the cell surface. In addition, SV-HUC does not stratify in culture, suggesting an inability to differentiate. Unlike HUC, SV-HUC are capable of growth in soft agarose, a property which increased with serial passage. Yet, through at least P50, SV-HUC remained nontumorigenic as determined by the inability to form tumors in athymic nude mice. This cell line of human epithelial origin may be suitable for studying the conversion of cells to tumorigenicity by subsequent treatment with another oncogenic agent.

Altered regulation of adrenal steroidogenesis in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats.

A single treatment of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (50 micrograms/kg) produced two distinct effects on adrenal steroidogenesis in rats 13 days post-treatment. In unstressed rats, the very low corticosterone levels early in the light phase (AM) increased 4-fold relative to ad libitum-fed control (ALC) rats, but the peak level of corticosterone that is seen late in the light phase (PM) decreased up to 40% relative to ALC rats. The AM stimulation was also observed in rats pair-fed to compensate for the diminished feed intake of TCDD-treated animals, indicating that the change results from nutritional deprivation. The PM suppression, however, was not observed in pair-fed rats. In rats given a lower dose of TCDD (15 micrograms/kg), there was no AM stimulation, whereas the suppression of the PM diurnal peak of corticosterone was retained. Plasma adrenocorticotropin (ACTH) levels and adrenal size were not changed by these treatments, indicating that TCDD affects adrenal responsiveness. TCDD did not, however, have a significant effect on corticosterone secretion in rats receiving high doses of ACTH. In control animals, the availability of cholesterol to cytochrome P-450scc limits the rate of steroidogenesis. While the specific content of the cytochrome was unaffected by TCDD, cholesterol turnover by this enzyme appeared to be affected following TCDD treatment, as evidenced by small increases in the mitochondrial levels of free cholesterol, reactive cholesterol, and in the proportion of P-450scc complexed with cholesterol relative to both ad libitum- and pair-fed controls. This accumulation of mitochondrial cholesterol following TCDD treatment is consistent with an inhibition of cholesterol metabolism at cytochrome P-450scc in vivo that is removed upon isolation of the mitochondria. These TCDD-induced increases were enhanced substantially in ACTH-stimulated rats, probably because ACTH enhances cholesterol influx into the mitochondria. Normally, substrate availability is rate limiting in cholesterol side-chain cleavage, and the AM stimulation of steroidogenesis by TCDD may result from such increased cholesterol transfer. The inhibition of cholesterol side-chain cleavage resulting from TCDD treatment may, however, only become rate limiting for corticosterone synthesis when cholesterol transfer is more substantially activated, as for peak PM secretion.

Intermediary metabolism of the mature rat following 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment.

Changes in body weight, feed intake, hepatic cellularity, and intermediary metabolism were assessed in the mature male (450 g) rat following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) administration. All animals were schedule-fed (8-hr feeding period/24 hr) and treated with a single oral dose of either TCDD (75 micrograms/kg) or vehicle. Blood and tissues were sampled 16 to 18 hr following the end of the feeding period on 2, 4, 6, and 8 days post-treatment. Mature rats treated with TCDD exhibited a slight but progressive reduction in both body weight and feed intake throughout the 8-day experimental period. An increase in liver mass that was apparent at 2 days and plateaued by 4 days after TCDD treatment was associated with a decrease in the concentration of DNA per gram of wet liver. However, the total liver content of DNA in TCDD-treated rats remained similar to pair-fed animals. Thus, TCDD treatment produced liver enlargement in the mature rat that was the result of hepatocellular hypertrophy and not an increase in cell number. Hepatic glycogen content in TCDD-treated rats was threefold higher than their pair-fed counterparts at 2 to 6 days post-treatment, and this augmentation would account, in part, for the hypertrophy of the liver cell found after administration of TCDD. Plasma glucose and lactate concentrations were similar in TCDD-treated and pair-fed rats, suggesting that the Cori cycle remained unaltered following TCDD administration. Likewise, heart and gastrocnemius glycogen concentrations were similar in all experimental groups. Urinary excretion of urea, ammonia, and creatinine was comparable in TCDD-treated rats and their pair-fed counterparts, indicative of a nitrogen balance that was not disturbed by TCDD. Plasma glutamine concentrations in TCDD-treated rats tended to be reduced and were significantly lower at Day 6 post-treatment when compared to those of pair-fed counterparts, suggestive that amino acid release from muscle was not enhanced in TCDD-treated rats. Likewise, plasma concentrations of branched-chain amino acids, which are metabolized to a large extent in muscle, tended to be lower on Day 6 following TCDD treatment. Yet at Day 6 post-treatment, the circulating concentrations of amino acids that are metabolized by the liver were elevated in TCDD-treated animals. TCDD administration also resulted in an increase in total hepatic protein concentration which was evident at 4 days and increased progressively at 6 and 8 days post-treatment. Liver content of phospholipids also increased gradually following administration of TCDD.(ABSTRACT TRUNCATED AT 400 WORDS)

Relationship of the wasting syndrome to lethality in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Young adult male Sprague-Dawley rats treated with a LD95 dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exhibited a progressive reduction in feed intake and body weight until death occurred 15 to 32 days post-treatment. The time course and magnitude of weight loss and lethality of pair-fed control rats were essentially identical to that of TCDD-treated rats with each pair-fed control animal dying within 3 days of its TCDD-treated partner. Body composition analysis of the dead animals revealed that the total amounts of protein, fat, water, and ash in the carcasses of TCDD-treated and pair-fed control rats were each reduced to a similar extent. The temporal pattern of daily feed intake in TCDD-treated and pair-fed control rats (3 meals/day) or (1 meal/day) did not influence the results. Studies conducted at LD25-62 doses of TCDD in male Sprague-Dawley rats of different ages--weanling (90 g), young adult (275 g), and mature (450 g)--showed that the severity of the wasting syndrome in all age groups was greatest for animals that died. Also, young adult rats treated with a LD25 dose of TCDD that died displayed the same degree of hypophagia and weight loss prior to death as rats administered a LD95 dose. Histopathology of the liver and gastrointestinal tract was compared in TCDD-treated (LD95 dose) and pair-fed control rats killed 1 day before they otherwise would have died. Hepatocytes of TCDD-treated rats were enlarged relative to those of pair-fed control rats and contained nuclei that varied in size and number. Pair-fed control rats exhibited atrophy of the liver cords due to a decrease in the cytoplasmic volume of their hepatocytes. The stomach and small intestine of TCDD-treated rats were histologically similar to those of ad libitum-fed controls. In contrast, the glandular mucosa of the stomach of pair-fed control rats was ulcerated and the intestinal mucosa was atrophied. Stomach ulcers were the source of clotted blood found throughout the gastrointestinal tract of pair-fed control rats but not that of TCDD-treated animals. These findings demonstrate that hypophagia-induced weight loss is one of perhaps several responses that contribute to the death of TCDD-treated rats. That other responses are also involved is suggested by differences between pair-fed control and TCDD-treated rats in the weight and histopathology of certain organs. In addition, gastrointestinal blood loss contributes to the death of pair-fed control rats but not TCDD-treated animals.

Hypophagia-induced weight loss in mice, rats, and guinea pigs treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin.

C57BL/6 mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 360 micrograms/kg) displayed a significant reduction in feed intake and body weight until just before death, when they developed ascites and subcutaneous edema. This caused body weight of the mice that died to suddenly increase during the terminal stage of toxicity. TCDD-treated mice that survived did not develop ascites or edema, and maintained a body weight that was slightly less than that of pair-fed mice. Cumulative lethality in TCDD-treated mice (69%) was greater than that of pair-fed controls (14%). In guinea pigs treated with TCDD (2 micrograms/kg) both the time course and magnitude of hypophagia were closely associated with weight loss. Pair-fed guinea pigs did not lose quite as much weight as TCDD-treated animals because their total body water content was higher. Water intake in pair-fed guinea pigs was greater than that of TCDD-treated animals. The time course and magnitude of lethality tended to be similar in TCDD-treated guinea pigs (81%) and pair-fed controls (64%). In Fischer F-344 rats treated with TCDD (100 micrograms/kg) body weight loss was associated with a reduction in both feed and water intake. The time course and magnitude of weight loss in TCDD-treated and pair-fed rats was essentially identical. Lethality was higher in TCDD-treated rats (95%) than pair-fed control animals (48%). Taken together, these findings suggest that hypophagia is responsible for the loss of adipose and lean tissue in mice, guinea pigs, and rats treated with a LD70-95 dose of TCDD. Under these dosage conditions, weight loss contributes more to the lethality of guinea pigs than to that of Fischer F-344 rats or C57BL/6 mice.