Strain Differences In Response Research Articles

Strain differences in response to acute hypoxia: CD-1 versus C57BL/6J mice

Some mammals respond to hypoxia by lowering metabolic demand for oxygen and others by maximizing efficiency of oxygen usage: the former strategy is generally held to be the more effective. We describe within the same species one outbred strain (CD-1) that lowers demand and another inbred strain (C57BL/6J) that maximizes oxygen efficiency to markedly extend hypoxic tolerance. Unanesthetized adult male mice (Mus musculus, CD-1 and C57BL/6J) between 20 and 35 g were used. Sham-conditioned (SC) C57BL/6J mice survived severe hypoxia (4.5% O(2), balance N(2)) roughly twice as long as SC CD-1 mice (median 211 and 93.5 s, respectively; P < 0.0001). Following acute hypoxic conditioning (HC), C57BL/6J mice survived subsequent hypoxia 10 times longer than HC CD-1 mice (median 2,198 and 238 s respectively; P < 0.0001). Therefore, C57BL/6J mice are both naturally more tolerant to hypoxia and show a greater increase in hypoxic tolerance in response to hypoxic conditioning. Indirect calorimetry indicates that CD-1 mice lower mass-specific oxygen consumption (V'o(2) in ml O(2).kg(-1).min(-1)) and carbon dioxide production (V'co(2) in ml CO(2).kg(-1).min(-1)) in response to HC (P = 0.002 and P < 0.0001, respectively), but C57BL/6J mice maintain V'o(2) and V'co(2) after HC. Respiratory exchange ratio and fluorometric assay of plasma ketones suggest that C57BL/6J mice rapidly switch to ketone metabolism, a more efficient substrate, while CD-1 mice reduce overall metabolic activity. We conclude that under severe hypoxia in mice, switching fuel, possibly to ketones, while maintaining V'o(2), may confer a greater survival advantage than simply lowering demand.

Effects of bilateral vibrissotomy on the expression of focused stereotypy (FS) induced by amphetamine in Sprague Dawley (SD) or Fischer 344 (F344) rats

Above doses of about 2.5 mg/kg in SD rats, amphetamine produces FS, a syndrome characterized by a complete lack of locomotion accompanied by rapid, rhythmic head movements. During these movements, the rat’s vibrissae are stimulated by accelerations of the head and by contact with the floor and walls of the cage. Given that previous reports have linked removal of vibrissae with changes in brain dopamine systems and given amphetamine’s dopamine releasing effects in vivo, we hypothesized that bilateral removal of the vibrissae would alter the FS response to amphetamine. Of additional interest was the question of rat strain differences in response to amphetamine. Accordingly, in a between-groups dosing design male SD and male F344 rats were treated with 0, 1.25, 2.5 and 5.0 mg/kg d-amphetamine sulfate every 4th day for a total of 7 injections, and on the 7th day, amphetamine treatment was accompanied by bilateral vibrissotomy. Behavior was recorded continuously in 4-hr sessions with a force-plate actometer, a new type of technology that permits quantitation of FS without human observers. Vibrissotomy did not alter the basic style of FS for either rat strain where style was assessed by the power spectra of the vertical force component of the head movements. Area-under-the-curve analyses of FS scores showed vibrissotomy increased the intensity of the head movements in the F344 rats but not in the SD rats. Indexes of spatial confinement were not significantly affected. These data suggest that the rhythmic, rapid head movements of FS are probably not sustained by, nor appreciably modulated by sensory feedback from the vibrissae. Supported by MH43429 and HD002528.

Radiation-induced strain differences in mouse alveolar inflammatory cell apoptosis

Whole-thorax irradiation results in the development of the diffuse inflammatory response alveolitis in C3H/HeJ (C3H) mice and a milder alveolitis with fibrosis in C57BL/6J (B6) mice. In this study, we investigate if this mouse strain difference in response to radiation is due to differences in lung inflammatory cell apoptosis. Mice of the C3H and B6 strains were given a radiation dose of 18 Gy to the thorax and the animals were sacrificed at 11 or 18 weeks following exposure or when they were moribund. Active caspase-3 staining was used to identify apoptotic cells in the alveolar space of histological lung sections from the mice. The apoptotic index of B6 mice was greater than that of C3H mice at 11 weeks postirradiation (17.8% of airspace cells vs. 7.8%, p = 0.028) and in mice sacrificed because of illness (27.3% vs. 14.4%, p = 0.036). No C3H mice survived to the later time point. The inflammatory cells undergoing apoptosis in the mouse lungs were morphologically consistent with alveolar macrophages. We conclude that a difference in inflammatory cell apoptosis may contribute to the disparate pulmonary radiation response of these mouse strains.

Divergent effects of leptin in mice susceptible or resistant to obesity.

Consumption of a high-fat diet decreases hypothalamic neuropeptide Y (NPY) and increases proopiomelanocortin (POMC) and brown adipose uncoupling protein (UCP)-1 mRNA in obesity-resistant SWR/J but not obesity-prone C57Bl/6J mice. Although leptin was elevated in both strains in response to a high-fat diet, its role in the development of diet-induced obesity has remained unclear since insulin and other factors that affect similar tissue targets are altered. Thus, we administered recombinant leptin by subcutaneous infusion to chow-fed mice to mimic the changes in plasma leptin across its broad physiologic range. We observed strain differences in responsiveness to reduced and elevated leptin levels. A reduction in leptin during fasting evoked a greater response in C57Bl/6J mice by decreasing energy expenditure and thyroxin, increasing corticosterone and stimulating food intake and weight gain during refeeding. However, C57Bl/6J mice were less responsive to an increase in leptin in the fed state. Conversely, the leptin-mediated response to fasting was blunted in SWR/J mice, whereas an increase in leptin profoundly reduced food intake and body weight in SWR/J mice fed ad libitum. Sensitivity to fasting in C57Bl/6J mice was associated with higher hypothalamic NPY mRNA and reduced POMC and UCP-1 mRNA expression, while the robust response to high leptin levels in SWR/J mice was associated with suppression of NPY mRNA. These results indicate that differences in leptin responsiveness between strains might occur centrally or peripherally, leading to alteration in the patterns of food intake, thermogenesis and energy storage.

Rat sex and strain differences in responses to stress

Sensitivity to stress has been linked to the development of a variety of physical and psychological disorders. Studies to-date have focused on extreme stress phenotypes, have studied mostly male responses, have used limited dependent variables, and have included a limited number of measurement time points. The present experiment was designed to address these limitations. Feeding, body weight, open-field activity, acoustic startle reflex (ASR), and prepulse inhibition (PPI) responses of adult male and female Sprague–Dawley and Long–Evans rats to daily immobilization stress (20 min/day) were evaluated for 3 weeks. Stress significantly decreased feeding and body weight of males but generally not of females. Effects were greatest in Long–Evans males. Stress decreased 15-min activity levels for males on Stress Day 1, but not on other days. Stress did not affect 15-min activity levels of Long–Evans females but decreased 15-min activity levels of Sprague–Dawley females on every measurement day. ASR responses to stress differed based on rat strain; percent PPI responses differed based on rat strain and sex. Stress increased startle responses of Sprague–Dawley males and females but not of Long–Evans males and females. Stress reduced PPI of Long–Evans females on every measurement day but not of other groups. These findings indicate that strain and sex of rat is important to consider in evaluating behavioral and physiological responses to stress.

Rat strain differences in responses of plasma prolactin and PRL mRNA expression after acute amphetamine treatment or restraint stress.

1. The aim of this study was to compare the effects of acute amphetamine (AMPH) treatment and restraint stress on plasma level of prolactin (PRL) and PRL mRNA expression in the adenohypophysis in Sprague-Dawley and Lewis male rats, the latter known to have a deficient hypothalamo-pituitary-adrenal (HPA) axis. 2. Both restraint stress and AMPH treatment (i.p. in a dose of 8 mg/kg of b.w.) were applied 15 or 30 min before termination of the experiment. Plasma PRL and corticosterone (CORT) were determined by radioimmunoassay. PRL mRNA expression was estimated by a dot-blot hybridization. 3. Restraint stress and AMPH treatment induced a significant increase in the CORT plasma level, as an indicator of stress response. Compared to Sprague-Dawley rats, the magnitude of CORT increase after both stimuli was significantly lower in Lewis rats. 4. Although restraint stress significantly increased the PRL plasma levels in both rat strains, AMPH treatment reduced the PRL levels in both rat strains. However, the changes of PRL plasma levels had another pattern in Lewis rats than in Sprague-Dawley rats. Control plasma PRL levels were significantly higher in Lewis rats, and in this rat strain AMPH treatment for 30 min increased the PRL levels as compared to the values obtained after AMPH treatment for 15 min. 5. Expression of PRL mRNA in adenohypophysis by restraint stress and AMPH treatment had a similar pattern. After a 15-min lasting restraint stress, the expression of PRL mRNA was decreased insignificantly in both rat strains. AMPH treatment induced in Sprague-Dawley rats a significant decrease of PRL mRNA after a 15-min interval while after 30 min there was a significant increase. However, in Lewis rats AMPH failed to significantly change PRL mRNA. 6. The results from the present study indicate that the mechanisms mediating the effects of acute restraint stress and acute AMPH treatment differ in PRL response in Sprague-Dawley and Lewis male rat strains. Differences in the observed responses in Lewis rats could be related to the deficient activity of HPA axis in this rat strain.

Major strain differences in response to chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid in rats: implications for neuroprotection studies

Chronic systemic treatment with 3-nitropropionic acid in rats produces persistent dystonia and bradykinesia, and striatal lesions reminiscent of Huntington's disease. However, the interpretation of results obtained with this model are complicated by a heterogeneous distribution of the response to a given toxic dose of 3-nitropropionic acid: approximately half of the animals develop selective striatal lesions, which in certain cases are associated with extrastriatal lesions, and the other half are apparently spared. Thus, the chronic 3-nitropropionic acid lesion model can be difficult for neuroprotection studies in which a consistent response to neurotoxic treatment is prerequisite. We hypothesized that some of the variability in the model was related to the use of Sprague–Dawley rats, since inter-individual variability in response to various stressful conditions has been described previously in this rat strain. We therefore compared 3-nitropropionic acid toxicity in rat strains known to be highly (Fisher 344) or poorly (Lewis) responsive to stress and compared the distribution of responses to that of Sprague–Dawley rats. In a protocol of intraperitoneal injection, toxicity of 3-nitropropionic acid was highest in Fisher rats, intermediate in Sprague–Dawley rats and lowest in Lewis rats. In addition, survival curves showed a more heterogeneous response to 3-nitropropionic acid toxicity in Sprague–Dawley rats than that observed in Lewis and Fisher rats. These differences between Sprague–Dawley and Lewis rats were confirmed in a protocol of subcutaneous 3-nitropropionic acid intoxication using osmotic minipumps, where doses up to 36–45 mg/kg per day for five days were necessary to induce striatal lesions in Lewis rats as compared to 12–14 mg/kg per day for five days in Sprague–Dawley rats. The selectivity of the striatum to lesions, and homogeneous progression of symptoms and neurodegeneration, were more consistently observed in Lewis as compared to Sprague–Dawley rats. These results suggest that vulnerability to 3-nitropropionic acid may depend on genetic factors, which could also influence the physiological response to stress. The present findings also establish an improved model of progressive striatal degeneration in the rat adapted for the testing of new neuroprotective strategies.

Rat strain differences in response to galanin on the Morris water task

Galanin acts as an inhibitory modulator of cholinergic transmission in the septohippocampal pathway of the rat. Centrally administered galanin induces performance deficits on rodent learning and memory tasks, including delayed non-matching to position, T-maze delayed alternation, passive avoidance, starbust radial maze acquisition, and the Morris water task. The present study investigates differences in responsiveness to intraventricularly administered galanin across three strains of laboratory rat on acquisition of spatial learning in the Morris water task. Sprague–Dawley rats showed normal performance during training, but lack of selective quadrant search on the probe trial in response to galanin treatment. Long–Evans rats showed no effects of galanin on performance during training or probe trial. Wistar rats showed longer latencies to reach the hidden platform during training, and lack of selective quadrant search on the probe trial in response to galanin. Performance on the visible platform task and on locomotor activity in the open field was normal in rats treated with galanin. These results are consistent with an interpretation of strain differences in sensitivity to the inhibitory actions of galanin on learning and memory.

The Behavior of Spontaneously Hypertensive and Wistar Kyoto Rats Under a Paced Fixed Consecutive Number Schedule of Reinforcement

Spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY) were trained under paced FCN schedules of reinforcement to complete a minimum number of consecutive responses on one lever, before responding on a second. The levers were retracted from the test chamber for a short period after each response to control the speed at which the rats could complete the sequence (paced FCN). Changes in the average chain length may reflect the influence of impulsivity on the execution of behavioral patterns. Although they quickly learned to press the levers, SHR rats performed poorly compared to the WKY rats when the chain length requirement was increased to FCN 6 and FCN 8. Eventually stable performance was obtained under paced FCN 6, although the SHR rats continued to have a consistently lower average chain length. Both strains of rats were treated with imipramine (10 mg/kg), chlordiazepoxide (3 and 10 mg/kg), d-amphetamine (0.4 and 0.8 mg/kg), haloperidol (0.05 and 0.1 mg/kg), 8-OH-DPAT (0.1 mg/kg), WAY-100635 (0.1 mg/kg), and DOI (0.3 and 1.0 mg/kg). The SHR rats were less sensitive to the effects of d-amphetamine, chlordiazepoxide, and DOI and slightly more sensitive to the effects of haloperidol. All of these drugs reduced the average chain length. There was no difference in the response of the two strains to imipramine and 8-OH-DPAT, both of which increased the average chain length. These results support the suggestion that SHR rats may more impulsive than WKY rats. The data with d-amphetamine and haloperidol support biochemical findings that these rats have a deficit in dopaminergic function, and the strain differences in response to chlordiazepoxide and DOI suggest that that there may be differences in GABAergic and 5-HT 2-mediated neurotransmission relevant to regulating impulse control in the rat.

Strain differences in corticosteroid receptor efficiencies and regulation in Brown Norway and Fischer 344 rats.

During the dark phase of the diurnal cycle, and during recovery from restraint stress, Brown Norway (BN) rats secrete less corticosterone than Fischer 344 (F344) rats. These strains also display different levels of corticosteroid receptors in the hippocampus, and of plasma transcortin. Because corticosteroid receptors, plasma transcortin and corticosterone secretion are mutually regulated, we examined brain and pituitary mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) expression and some of the parameters modulated by these receptors (i.e. body and thymus weight, fluid intake, plasma transcortin) in BN and F344 rat strains, by comparing the effects of either hormone deprivation by long-term (21 days) adrenalectomy (ADX), or chronic elevation of corticosterone given in drinking fluid to ADX rats. In BN rats, body weight gain and fluid intake were insensitive to corticosterone deprivation, suggesting that MR-related mechanisms are constitutively active in this strain. Body weight (b.w.) gain, plasma transcortin and thymus weight were reduced to a greater extent by chronic corticosterone in BN rats than in F344 rats, possibly as a consequence of higher free, active fraction of plasma corticosterone due to lower plasma transcortin concentrations and/or a greater efficiency of GR-related mechanisms in BN rats. F344 rats displayed twofold higher brain and pituitary MR levels than BN rats, whereas tissue-and strain-specific regulations were observed for GR levels. The differences in MR levels observed between BN and F344 strains cannot completely explain the differences in corticosterone actions, suggesting that strain differences in response to ADX or corticosterone treatment result from variable receptor efficiencies.

Selection of phenytoin responders and nonresponders in male and female amygdala-kindled Sprague-Dawley rats.

We recently described that, by repeated testing of the anticonvulsant phenytoin (PHT), it is possible to select responders and nonresponders from large populations of amygdala-kindled Wistar rats. Whereas responders show marked and reproducible increases of focal seizure threshold (afterdischarge threshold: ADT) on repeated testing of PHT, 75 mg/kg i.p., nonresponders do not show any significant ADT increase after this dose, thus allowing use of these subgroups in the search for mechanisms of pharmacoresistance in temporal lobe epilepsy. In this study, we examined whether PHT responders and nonresponders can also be selected from large groups of kindled rats of the Sprague-Dawley strain. Male and female Sprague-Dawley rats were amygdala kindled, followed by once weekly i.p. testing of PHT. In contrast to recent experiments in Wistar rats, 75 mg/kg PHT did not induce significant ADT increases in Sprague-Dawley rats, indicating strain differences in response to this drug after kindling. When the dose was lowered to 50 or 25 mg/kg, significant and reproducible ADT increases were obtained in Sprague-Dawley rats of both genders. Therefore these doses were used for selection of responders and nonresponders in a total of 42 rats. Almost 50% of the rats were PHT responders, whereas no rat was a nonresponder when tested in up to six subsequent drug trials. Many rats were variable responders (i.e., showed ADT increases in some but not all trials), which was not due to low or variable drug absorption after i.p. injection. The data indicate that, in contrast to Wistar rats, Sprague-Dawley rats are not suited for selection of PHT nonresponders, but rather are quite responsive to this drug. A further difference to the Wistar strain is the truncated dose-response with loss of anticonvulsant efficacy at 75 mg/kg in kindled Sprague-Dawley rats, which may, at least in part, explain the inconsistent results reported on the anticonvulsant efficacy of PHT in this strain in the literature. The lack of anticonvulsant activity after administration of 75 mg/kg may be a result of kindling, because administration of this dose before kindling causes a significant ADT increase in this strain. This kindling-induced alteration of the anticonvulsant activity of PHT is a phenomenon that contrasts Sprague-Dawley with Wistar rats and deserves further investigation.

Murine strain differences in airway inflammation caused by diesel exhaust particles.

To elucidate whether immunoglobulin (Ig) E or IgG are involved in the murine asthma model, we compared the pathogenic features of mice that were high IgG responders (C3H/He) with mice that were high IgE responders (BALB/c) after intratracheal instillation of diesel exhaust particles (DEP) and ovalbumin sensitization. Both mouse strains received DEP intratracheally once a week for 5 weeks. After the second injection of DEP, ovalbumin and aluminium hydroxide were injected intraperitoneally. After the last DEP administration, the mice were challenged by exposure to an aerosol of ovalbumin. DEP caused increased IgG1 production and airway hyperresponsiveness after ovalbumin sensitization in C3H/He mice, although IgE production did not change in either strain. Furthermore, in C3H/He mice, the number of eosinophils and goblet cells in the bronchial epithelium, and the expression of interleukin-5 and interleukin-2 were increased by DEP and ovalbumin treatments. In contrast, the pathogenic changes in BALB/c mice were weak, even though the same protocol was used. In conclusion, murine strain differences in response to air pollutants and allergens seem to be related to antigen-specific immunoglobulin G1 production and cytokine expression in the lungs.

Murine Strain Differences in Response to Mercuric Chloride: Antinucleolar Antibodies Production Does Not Correlate with Renal Immune Complex Deposition

Mercuric chloride (HgCl2) induces the production of antinucleolar antibodies (ANucA) in susceptible strains of mice. Responder strains bearing the H-2shaplotype as well as several ANucA resistant strains have been shown to develop renal immune complex deposits after HgCl2treatment. Sera obtained throughout 12 to 16 weeks of HgCl2treatment from mice of four ANucA responder strains (A.SW/SnJ, A.CA/SnJ, DBA/1J, and P/J) and one ANucA-resistant strain (C57BL/10SnJ) were examined for ANucA production. Terminal sera were also tested for the presence of anti-glomerular basement membrane antibodies, and the kidneys were examined for the deposition of IgG and C3. Only one strain, A.SW, developed significant deposits of IgG in the renal glomeruli, although all four responder strains exhibited similar ANucA induction/production profiles. The differences seen by direct immunofluorescence assay (IFA) in renal immune complex deposition between the A.SW and histocompatibility congenic A.CA mice were corroborated by individually eluting and then quantitating the deposited IgG from renal tissues of Hg-treated A.SW and A.CA mice as well as control A.SW mice. The average amount of IgG eluted from A.SW renal tissue was significantly greater than that eluted from either A.CA or control A.SW renal tissues. All eluates from Hg-treated animals gave only a nucleolar fluorescence pattern when assayed by indirect IFA against a panel of rat organ tissues. In summary, no correlation was found between ANucA production and renal IgG deposition in response to treatment with HgCl2.

In vitro fertilization in mice: Strain differences in response to superovulation protocols and effect of cumulus cell removal

Strain differences have proven to be crucial components in mouse in vitro fertilization (IVF) and superovulatory protocols. To maximize the yield of IVF-derived mouse eggs, a series of experiments was conducted using different injection timing intervals for administration of pregnant mare serum gonadotropin (PMSG) and hCG to induce follicular development and ovulation. Strains were chosen that were representative of those commonly used in genetic engineering experimentation. These strains included ICR outbred, C57BL/6 inbred, and B6SJLF1 hybrid (C57BL/6J × SJL/J F1) mice. Females were superovulated using 4 PMSG/hCG/IVF timing regimens (group), with sperm obtained from males of the same strain. Group designations were based on the following PMSG/hCG and hCG/oocyte collection intervals, respectively: Group 1, 55 and 21.5 h; Group 2, 60 and 14.5 h; Group 3, 55 and 14.5 h; Group 4, 48 and 14.5 h. After overnight culture of ova, fertilization rates (development to the 2-cell stage) were assessed. A logistic regression was performed using indicator variables for both strain and group. There was a significant strain influence on ova fertilization rate, based on the coefficients of mouse strain (ICR, β = −1.1067, P = 8E-17 and C57BL/6, β = −0.5172, P = 8E-06). Additionally, group affected the proportion of fertilized ova obtained (coefficient of Group 1, β = −1.3152, P = 0.00 and Group 3, β = 0.9531, P = 3E-12). From the coefficients for the interaction terms, the effect of groups varies across mouse strain. Therefore, the treatment that produces the highest fertilization rate is related to and contingent upon the strain of mouse. In the second study, the Group 3 protocol was used to evaluate fertilization differences between cumulus-intact and cumulus-free oocytes. Again, there was a significant strain influence on ova fertilization rate based on the coefficients of mouse strain (ICR, β = −2.6639, P = 0.00; C57BL/6, β = −2.5114, P = 0.00). However, there was no difference between Cumulus and No Cumulus groups (cumulus coefficient, β = 0.1640, P = 0.59872), indicating that there was no affect of cumulus presence on fertilization rate. In summary, responses to standardized mouse IVF protocols vary significantly. The efficiency of IVF procedures can be optimized between and within specific mouse strains by the timing of superovulatory regimens. However, absence of cumulus cells during the IVF procedure does not adversely affect fertilization rate.

Strain-dependent variability in nitrous oxide withdrawal seizure frequency

Exposure to nitrous oxide produces handling induced convulsions following withdrawal in mice. Since strain differences in responsiveness to the antinociceptive potency of N 2O have been found, we examined whether there were differences in susceptibility to N 2O withdrawal seizures. Significant differences were found between mouse strains, varying between 100% and 0% of mice exhibiting withdrawal seizures. There was a lack of correlation between the sensitivity of the mouse strains to N 2O-induced analgesia and N 2O withdrawal seizures, suggesting different mechanisms of action.

Enhancement of murine gustatory neural responses to d-amino acids by saccharin

Taste enhancing effects of sodium saccharin (Sac) on responses to particular sweet-tasting d-amino acids were found during the recording of mouse chorda tympani nerve responses to various taste stimuli in C57BL and BALB strains. In both strains, responses to d-tryptophan and d-histidine significantly increased (167.7–216.7% of control) after the stimulation with Sac as compared with those applied before Sac. In C57BL mice, the enhancement by Sac was also observed in response to d-phenylalanine (262.5% of control), but this was not the case for BALB mice, suggesting a prominent strain difference in response to d-phenylalanine, as shown previously. Responses to other sweet-tasting d and dl-amino acids and sugars were not enhanced by Sac. Enhancement of responses to these d-amino acids by Sac was also evident when responses to a mixture of d-amino acids and Sac were compared with the sum of responses to each component, although in this response analysis, the calculated magnitude of enhancement generally become smaller (135.7–180.5% of the sum) and enhancement of d-histidine responses disappeared. Except for Sac, various sweet-tasting amino acids and sugars and NaCl also tested showed no enhancing effect on d-phenylalanine responses in C57BL mice. Sac and d-amino acids, to which responses were enhance by Sac, possess some common molecular features, namely ring structures. This structural similarity probably relates to the occurrence of the enhancement at the receptor sites.

Genetic influences on tissue deposition of aluminum in mice.

Aluminum is a known neurotoxin and has been suggested to play a role in the development of Senile Dementia of the Alzheimer's Type. The relationship between aluminum exposure and senile dementia cannot be a simple one, however, as not all exposure results in neurotoxic manifestations. To determine if there are genetic differences in susceptibility to moderate aluminum exposure, 16 mice of five inbred strains were divided into two groups. The control group was fed a purified diet containing all known requirements for mice; the experimental group was fed the same diet supplemented with 260 mg Al/kg diet for 28 d. Analysis of brains, livers, and tibias for aluminum concentrations revealed strain differences in response to dietary treatment. The most notable results occurred in the DBA/2 and C3H/2 strains, with brain aluminum levels higher in the experimental groups. In contrast, A/J, BALB/c, and C57BL/6 strains showed no differences in brain aluminum in response to dietary treatment. These findings suggest that there are genetic differences in the permeability of the blood brain barrier and lend support to the hypothesis that variability in aluminum toxicity may be, in part, genetically determined.

THINNING `DELICIOUS' APPLE: TRIALS AND TRIBULATIONS

Response of `Delicious' apple to chemical thinning is often erratic. Experiments were conducted to test the effects of crop density, thinning and strain on yield and fruit size. The relationship between crop density and fruit size was determined in 3 orchards over 2 years. In one orchard the relationship was consistent in both years, but in the other two, it varied widely. Naphthaleneacetic acid (NAA) was applied to 10-year-old trees at one location in 2 successive years (1989-90). NAA treatments were compared with early hand thinning (15 days post bloom) in 1989 and with NAA plus carbarl (Sevin) in 1990. In 1989 both NAA and hand thinning reduced crop density and yield, but only hand thinning increased fruit size. No treatments applied in 1990 reduced crop density, and effects upon size and economic return were minimal. Strain differences in response to NAA and its amide (NAAm) were evaluated in 1989 and 1990. NAA (13 and 20 ppm) failed to reduce crop density in 1989, but fruit size was reduced. NAAm at 50 ppm overthinned both years, but was effective at 25 ppm in 1990. Fruit set was generally lower in non-spur than in spur strains.

Strain differences in the response of Fischer 344 and Sprague-Dawley rats to monocrotaline induced pulmonary vascular disease

The pyrrolizidine alkaloid (PA) monocrotaline (MCT) is thought to be activated in the liver to monocrotaline pyrrole (MCTP) which is then transported to the lungs where it causes a pulmonary vascular syndrome characterized by elevated pulmonary artery pressure and right ventricular hypertrophy. We have found that, as opposed to Sprague-Dawley (SD) rats, Fischer 344 (F344) strain rats are resistant to the ventricular hypertrophy and pressure changes induced by MCT. To determine whether this strain difference might be related to differences in hepatic activation of MCT to MCTP, we compared the response of SD and F344 rats to treatment with MCT or MCTP. We determined right ventricular pressure and ventricular weight ratios with each treatment for each strain. We also compared subjective lesion scores of histopathologic changes characteristic of MCT pneumotoxicity. Sprague-Dawley rats treated with either MCT or MCTP had elevated right ventricular pressures Control 13 ± 1 mmH 2O, MCTP 29 ± 3 mmH 2O, MCT 24 ± 2 mmH 2O) and increased right ventricular weight ratio (RV/LV + S) of 0.30 ± 0.01 (Control), 0.44 ± 0.05 (MCTP), 0.44 ± 0.02 (MCT). Histopathologic evaluation demonstrated that significant alveolar septal fibrosis, edema and type II cell hypertrophy was induced by both PAs in both rat strains but that F344 rats had significantly less vascular medial hypertrophy and adventitial inflammation than SD rats. MCTP treated SD rats had similar vascular and parenchymal alterations as those treated with MCT but with a lessor inflammatory component. We conclude that the strain differences in cardiac and pulmonary vascular responses to MCT also occur with MCTP treatment. This, combined with the similarity in alveolar parenchymal response to both PAs in both strains, suggests that these differences are related to the pulmonary vascular response rather than differences in hepatic metabolism.

Proliferative Responses of Peripheral Blood Lymphocytes of Mice and Humans Stimulated with Recombinant Interleukin 2

In vitro proliferative responses of human and murine peripheral blood lymphocytes (PBL) were studied. The cells were stimulated with recombinant interleukin 2 (IL-2) or with a mixture of phorbol-13-myristate-12-acetate with either IL-2 or calcium ionophores. Proliferation of human PBL could be induced by doses of human IL-2 or phorbol that were much lower than those required to produce responses of murine cells. However, the magnitude of the responses of human PBL was definitely lower than that of the responses of murine PBL. Murine IL-2 did not induce proliferation of human PBL, but it synergized with phorbol. The responses of murine PBL reflected the previously described strain differences in responses of spleen cells that were shown to be under complex polygenic control. The proliferation of murine spleen cells could be induced with human, as well as murine IL-2, and both species of IL-2 synergized with phorbol. While no clear-cut low and high responders could be identified among normal healthy human subjects, 2 individuals produced consistently low responses to IL-2 and 1 individual displayed low responses to phorbol and calcium ionophore A23187. Available data suggest, but do not allow a firm conclusion, that proliferative responses of human PBL are under genetic control, perhaps as complex as that reported for mice.