Effects of the Ay gene on susceptibility to hydrocortisone fetotoxicity and teratogenicity in mice

Effects of the Ay gene, a coat color gene, on susceptibility to hydrocortisone fetotoxicity and teratogenicity were investigated by using the congenic strain of C57BL/6-Ay (Ay/a) which had been maintained by repeated back-crosses of the Ay gene to the C57BL/6 (a/a) background. Matings were conducted as follows (female x male): group I, a/a; group II, a/a x Ay/a; and group III, Ay/a x a/a. Pregnant females were subcutaneously given daily doses of 0, 12.5, 25, or 50 mg/kg of hydrocortisone on days 10-13 of pregnancy. On day 18 of pregnancy, fetuses were sexed, weighed, and examined for external abnormalities. In group I, the mean fetal weight was significantly decreased at a dose of 25 mg/kg or more. The incidences of cleft palate were 3.2 and 22.7% at 25 and 50 mg/kg, respectively. In group II, in which half of the fetuses were expected to carry the Ay gene, the mean fetal weight was decreased significantly at 12.5 mg/kg or more. The incidence of cleft palate in group II at 50 mg/kg was 44.2%, which was significantly higher than that in group I. In group III, in which maternal mice as well as half of their fetuses carried the Ay gene, a decrease in the mean fetal weight was greater than in group II. In addition, the mean percentage of fetal resorptions was significantly increased at 50 mg/kg. The incidence of cleft palate in group III was significantly increased at 25 mg/kg (10.5%) when compared with those in groups I and II. These results indicate that the Ay gene may be associated with susceptibility to hydrocortisone fetotoxicity and teratogenicity in mice.     

Estradiol benzoate for preventing pregnancy in mismated dogs

We investigated the use of a single treatment of estradiol benzoate (E2B) to prevent pregnancy in mismated dogs, including effects of dose, side effects, and mechanism of action. We used 74 female beagles aged 1-10 year. A single treatment of E2B (0.025, 0.05, 0.10, or 0.20 mg/kg; 10 dogs/dose) given 2 days after mating (5 days after ovulation) resulted in pregnancy rates of 70, 50, 10, and 0%, respectively, whereas pregnancy rate was 100% in 5 untreated (control) dogs. There were no side effects in dogs given E2B, regardless of dose. To clarify the mechanism of prevention of pregnancy, we investigated embryonic descent in the uterine tube and embryonic degeneration after treatment with 0.025 or 0.20 mg/kg of E2B; treatment delayed embryonic descent in the uterine tube and increased the incidence of embryonic degeneration. In conclusion, a single treatment of 0.020 mg/kg of E2B given 2 days after mating effectively and safely prevented pregnancy in dogs.     

Recombinants in the H-2S/H-2D interval of mouse chromosome 17 define the map position of a gene for cleft palate susceptibility

The H-2 region of mouse chromosome 17 is known to include one or more genes that affect susceptibility to cortisone-induced cleft palate. We have now studied congenic strains that possess crossovers in the interval between H-2S and H-2D and have observed significant differences in susceptibility among recombinants that had been believed to possess the same H-2 haplotypes. Pregnant mice were injected on days 11 through 14 of gestation with 100 mg of cortisone per kg of body weight. The frequency of cleft palate in B10.A(2R) was significantly greater than in B10.A(1R), despite the fact that both have H-2a/H-2b crossovers in the interval between the S and D loci and have the same alleles at all loci that have been previously characterized. Both B10.BAR5 and B10.BAR12 were significantly more susceptible than B10.A(18R), although these strains also share the same alleles at all loci that have been previously characterized. All three of these strains have H-2b/H-2a recombinant chromosomes, with crossovers in the S/D interval. Genetic linkage between H-2 and the high-susceptibility gene of B10.BAR5 was confirmed by testing H-2 homozygotes derived by intercrossing backcross animals. These data therefore suggest that a gene coding for susceptibility, which we designate Cps-1, maps in the 350-kb interval between H-2S and H-2D, and the congenic strains that we have found to be different have different crossover points within this interval. Alleles at the Cps-1 locus have embryonic effects, but no demonstrable effects on the maternal environment.     

Maternal glucocorticoids and prenatal programming of hypertension

Maternal glucocorticoids have been postulated to play an important role in prenatal programming for adult hypertension in the offspring. However, we have shown previously that offspring hypertension caused by maternal dexamethasone subcutaneous administration at 100 microg x kg(-1) x day(-1) can be accounted for by the corresponding reduction in food intake that these mothers experience. The present studies were designed to determine whether there is a lower dose of dexamethasone that does not reduce maternal food intake yet still causes hypertension in the adult offspring. Pregnant rats were treated with subcutaneous dexamethasone at 50 (D50) or 25 (D25) microg x kg(-1) x day(-1) on days 15-20 of pregnancy. An additional group was untreated or received vehicle injections (control). D25 and D50 dams reduced their food intake by 17% during and after treatment and gained 31% less weight than control over the course of gestation. In adulthood ( approximately 21 wk), chronically instrumented male offspring of D50 and D25 had normal blood pressures (D50: 131 +/- 2 mmHg and D25: 127 +/- 3 mmHg vs. 127 +/- 2 mmHg in control). Qualitatively similar results were found in female offspring. Thus neither dexamethasone per se at these doses nor the accompanying modest reductions in maternal food intake and weight gain have blood pressure programming effects. As far as has been tested, there does not appear to be a dose of dexamethasone that, given over this time period in the rat, programs offspring hypertension without reducing maternal food intake and weight gain. These data do not support the hypothesis that maternal glucocorticoids program offspring hypertension directly.     

The Potential of Cr3 [Triaqua‐μ3‐Oxo‐Hexa‐μ‐Propionatotrichromium(III) Chloride] to Reduce Birth Defects in the Offspring of Diabetic CD‐1 Mice

Diabetes mellitus is a growing concern worldwide and leads to multiple complications during pregnancy. Pharmacologic doses of chromium (Cr) have been linked with improving insulin sensitivity and other positive benefits in the treatment of diabetes in animal models. By using streptozotocin induced hyperglycemia in female CD‐1 mice, reproductive outcomes of diabetic and chromium‐dosed diabetic females were examined. After dosing 10 mg/kg Cr in the form of triaqua‐μ₃‐oxo‐hexa‐μ‐propionatotrichromium(III) chloride or Cr3 during gestation days 8–16 (GD8–GD16), all females were sacrificed on gestation day 17 (GD17) and examined for maternal weight gain. The fetuses were examined for gross malformations and for skeletal malformations. The offspring of Cr3‐dosed females tended to have a reduction in the incidence of supernumerary ribs. While hyperglycemia still had negative impacts on the health of dams and their offspring, administration of Cr led to an apparent trend in the reduction in the number of malformations and incidence of supernumerary ribs compared to those of untreated diabetic mothers     

Outcome of challenge with Coxsackievirus B4 in young mice after maternal infection with the same virus during gestation

Enteroviral infections go usually unnoticed, even during pregnancy, yet some case histories and mouse experiments indicate that these viruses may be transmitted vertically. More frequently, however, transmission occurs by (fecal) contamination during and shortly after birth. The aim of this study was to investigate the effect of maternal infection in mice (1) on gravidity outcome and (2) on subsequent challenge of the offspring with the same virus. CD1 outbred female mice were infected by the oral route with coxsackievirus B4 strain E2 or mock-infected at days 4, 10, or 17 of gestation. Weight and signs of sickness were noted daily. Pups were infected at day 25 after birth (4 days postweaning). Organs (brain, pancreas, and heart) were analyzed for viral RNA and histopathology. We observed that maternal infection at day 4 or day 17 of gestation had little effect on pregnancy outcome, whereas infection at day 10 affected dams and/or offspring. Infection of pups resulted in severe inflammation of the pancreas, but only when dams were previously infected, especially at day 17. The blood glucose levels were elevated. Because no trace of infection was found at the time of challenge, a role for immunopathology is suggested.     

Impact of chronic ethanol intake of rat mothers on the seizure susceptibility of their immature male offspring

The aim of present study was to examine the impact of prenatal ethanol exposure on seizure susceptibility of the offspring. Pregnant Wistar rats were compelled to drink either 10% or 20% ethanol solution, as the only drinking fluid since conception up to the weaning of their offspring at the age of 28 days. Pregnant and nursing rats of the control group drank water. Electrophysiological experiments (repeated electrical stimulation and analysis of cortical afterdischarges duration) were than performed on their immature offspring. Rat pups were tested on postnatal day 18, 25, and 35. Shortening of afterdischarges duration was observed in 18-day-old animals (mothers drank 20% ethanol) when compared with age matched controls and failure of post-ictal depression phenomenon was found in 25- and 35-day-old animals. Our findings signalize that ethanol exposure during pregnancy influences seizure susceptibility by acting on excitatory/inhibitory brain systems and this effect is dose- and age-dependent.     

Frequency of congenital defects and dominant lethals in the offspring of male mice treated with methylnitrosourea

ICR strain male mice injected intraperitoneally with daily doses of MNU (5–25 mg/kg) for 5 days and mated to untreated virgin females of the same strain on days 1–7, 8–14, 15–21 and 64–80 after the last dose. Copulations during these periods involve, respectively, spermatozoa, late spermatids, early spermatids, and spermatogonial stem cells at the time of the last treatment. The uterine contents were examined on day 18 of pregnancy for post-implantation losses (dominant lethality). Fetuses were examined for exteranal and skeletal abnormalities. In contrast to the results reproted for specific-locus mutations, MNU treatment of either postmeiotic cells or spermatogonial stem cells caused dose-dependent significant increases in the incidence of congenital defects and of dominant lethals over the control levels. The relative sensitivity of germ cells sampled on days 1–7, 8–21 and 64–80 to MNU-induced congenital defects was 1:1.6:2. For the induction of dominant lethals, the sensitivity ratio was 1:1.8:0.5. It is proposed that congenital defects in the offspring of mice following paternal treatment with MNU may represent mostly chromasomal rather than genic changes. Cleft palate was the most frequent of the external abnormalities, which were significantly induced in every treatment series; fused ribs were the most frequent of the skeletal abnormalities, which were significatly induced in the treatment series for spermatogonial stem cells.     

Comparative teratogenicity of phenytoin among several inbred strains of mice

Inbred strains of mice differ in their response to the embryopathic effects of phenytoin (PHT). A/J animals, the most susceptible strain, were mated to C57BL/6J mice, the most resistant strain. The susceptibility of the F1 hybrid offspring was determined by the susceptibility of the mother. B6AF1 animals were as resistant as C57BL/6J parental mice, and AB6F1 hybrids were as susceptible as A/J mice. This was especially evident when orofacial anomalies were tallied. (B6A)F2 hybrid offspring were as resistant as their C57BL/6J grandparents.     

Hydrocortisone-induced embryotoxicity and embryonic drug disposition in H-2 congenic mice

Congenic mouse strains C57BL/10Sn (B10) and B10.A/SgSn (B10A), genetically different only in the region of the H-2 complex, were compared for sensitivity to hydrocortisone-induced embryotoxicity and embryonic drug disposition. Pregnant B10A mice dosed intramuscularly with 0, 100, 150, and 200 mg hydrocortisone/kg body weight and B10 mice injected with 0, 200, 400, 600, and 800 mg/kg, both on gestational day (GD) 12, were evaluated on GD 18 for reproductive toxicity. The induction of cleft palate demonstrated a linear dose-response by probit analysis: The ED50s were 143.6 mg/kg and 512.0 mg/kg for B10A and B10 mice, respectively. Comparison of fetal weight revealed statistically significant intrauterine growth retardation at all doses administered to B10 mice. However, growth retardation was shown only in the high-dose group in the B10A strain. Embryonic drug concentrations were evaluated by administration of hydrocortisone to mice of both strains on GD 12, at the ED50 for cleft palate production in the B10A strain, with 3H-hydrocortisone (5 muci/mouse) added as a tracer. Maternal serum and embryos were analyzed for steroid content. Disposition and pharmacokinetics of 3H-hydrocortisone were similar in both strains, with the majority of serum radioactivity recovered as hydrocortisone and the major radioactive peak in embryos comigrating with cortisone. The results indicate that H-2 haplotype does not influence hydrocortisone-induced cleft palate sensitivity through an alteration of embryonic drug exposure.     

Heritable translocations induced by dermal exposure of male mice to acrylamide

Acrylamide (AA) is an important industrial chemical used mainly in the production of polymers. It can be absorbed through the skin. AA was shown to be a germ cell clastogen that entails a genetic risk for exposed workers. The genetic risk calculation was based on mouse heritable translocation test data obtained after acute intraperitoneal (ip) exposure (Adler et al., 1994). To obtain a correction factor between ip and dermal exposure, dominant lethal and heritable translocation tests were carried out with dermal exposure of male mice to AA. In the dominant lethal test, male (102/El x C3H/El)F1 mice were exposed by dermal application to the shaved backs of 50 mg/kg AA per day on five consecutive days or to five daily ip injections of 50 mg/kg AA. One day after the end of exposure, the males were mated to untreated females of the same hybrid stock for four days and females were changed every four days for a total of five matings. Dominant lethal effects were found during matings 1-3. For ip exposure, these values were 81.7, 85.7 and 45.4%, respectively; for dermal exposure the corresponding values were 22.1, 30.6 and 16.5%, respectively. In the heritable translocation assay, male C3H/El mice were treated with five dermal exposures of 50 mg/kg AA and mated 1.5-8.5 days after the end of exposure to untreated female 102/El mice. Pregnant females were allowed to come to term and all offspring were raised to maturity. Translocation carriers among the F1 progeny were selected by a sequential fertility testing and cytogenetic analysis including G-band karyotyping and M-FISH. A total of 475 offspring were screened and 41 translocation carriers were identified. The observed translocation frequency after dermal exposure was 8.6% as compared to 21.9% after similar ip exposure (Adler, 1990). The calculated ratio of ip vs. dermal exposure of 0.39 can be applied to obtain a more realistic calculation of genetic risk for dermally exposed workers.     

Genetic mapping of a Ptch1-associated rhabdomyosarcoma susceptibility locus on mouse chromosome 2

Mutations in the Patched (Ptch1) gene are responsible for various familial and sporadic cancers. Ptch1(neo67/+) mice, in which exons 6 and 7 are deleted, show genetic background-dependent susceptibility to the development of muscle tumors resembling human rhabdomyosarcoma (RMS); BALB/c (BALB) is a susceptible strain whereas C57BL/6 (B6) shows resistance. A genome-wide linkage analysis was carried out using Ptch1(neo67/+)mice produced from B6 x (BALB x B6) backcrosses to identify loci involved in the control of RMS susceptibility. Quantitative trait locus mapping with the censored tumor latency time as the quantitative parameter was used to detect a significant RMS susceptibility modifier locus, Parms1 (Patched-Associated RMS 1), on chromosome 2 between D2Mit37 and D2Mit102 (LRS = 10). A Kaplan-Meier survival curve revealed that mice with the B6/BALB genotype develop tumors more frequently and much faster as compared to mice homozygous for the B6 allele (P = 0.02). Additional loci not reaching linkage significance were also detected for medulloblastoma resistance.     

妊娠期给予可卡因对母体和胎儿的影响: 小鼠动物模型

探讨妊娠期给予可卡因对母体和胎儿的影响。妊娠小鼠分为3组：可卡因注射组（每日两次注射盐酸可卡因10mg/kg,COC);盐水对照组（每日两次注射生理盐水10ml/kg,SAL);饮食对照组（每日两次注射生理盐水10ml/kg,饮食参考可卡因给药组,SPF）。用高压液相色谱分析法检测胎鼠血中可卡因浓度及纹状体中神经递质多巴胺和5－羟色胺的含量,并结合HE染色观察胎鼠肝脏和胎盘的形态学改变。尽管COC和SPF组母鼠摄食量和体重增长量均降低,但是仅仅COC组胎鼠的体重和脑重减少。高压液相色谱分析结果显示,在COC组胎鼠血浆中可检测出可卡因,并伴有纹状体神经递质含量的异常增高。同时,也观察到了COC组胎盘和肝脏的形态学变化。本研究表明,妊娠期给予可卡因能引起妊娠母体营养不良,子代脑、肝脏和胎盘发育异常;可卡因引起的胎儿发育异常是由可卡因的毒性作用而不是母体营养不良产生的。     

Congenital defects in the offspring of male mice treated with ethylnitrosourea

Daily doses of ENU (25-100 mg/kg) were injected intraperitoneally into ICR strain male mice for 5 days. The males were mated to untreated virgin females of the same strain on days 1-16 and 64-80 after the last dose. Copulations during these periods involve, respectively, treated postmeiotic cells and spermatogonial stem cells. The uterine contents were examined on day 18 of pregnancy for evidence of dominant lethal effects. The fetuses were examined for external and skeletal abnormalities. ENU treatment of either postmeiotic cells or spermatogonial stem cells caused dose-dependent significant increases in the incidence of abnormal fetuses over the control level. The induction rate per live fetus per unit dose in mg/kg by treating spermatogonial stem cells was estimated to be 1.0 X 10(-4), which is 3-fold lower than the rate previously estimated for the same endpoint at the same germ cell stage with MNU. Cleft palate was the most frequent external abnormality in the ENU-treated and the control series. Malformed vertebrae was the most frequent skeletal abnormality in the treated series. Rib fusion was the only skeletal malformation seen in the control series. Dominant lethals were clearly induced when germ cells were treated as postmeiotic cells.     

Effects of Maternal LPS Exposure during Pregnancy on Metabolic Phenotypes in Female Offspring

It is increasingly recognized that intra-uterine growth restriction (IUGR) is associated with an increased risk of metabolic disorders in late life. Previous studies showed that mice exposed to LPS in late gestation induced fetal IUGR. The present study investigated the effects of maternal LPS exposure during pregnancy on metabolic phenotypes in female adult offspring. Pregnant mice were intraperitoneally injected with LPS (50 µg/kg) daily from gestational day (GD)15 to GD17. After lactation, female pups were fed with standard-chow diets (SD) or high-fat diets (HFD). Glucose tolerance test (GTT) and insulin tolerance test (ITT) were assessed 8 and 12 weeks after diet intervention. Hepatic triglyceride content was examined 12 weeks after diet intervention. As expected, maternal LPS exposure during pregnancy resulted in fetal IUGR. Although there was an increasing trend on fat mass in female offspring whose dams were exposed to LPS during pregnancy, maternal LPS exposure during pregnancy did not elevate the levels of fasting blood glucose and serum insulin and hepatic triglyceride content in female adult offspring. Moreover, maternal LPS exposure during pregnancy did not alter insulin sensitivity in adipose tissue and liver in female adult offspring. Further analysis showed that maternal LPS exposure during pregnancy did not exacerbate HFD-induced glucose tolerance and insulin resistance in female adult offspring. In addition, maternal LPS exposure during pregnancy did not aggravate HFD-induced elevation of hepatic triglyceride content in female adult offspring. In conclusion, LPS-induced IUGR does not alter metabolic phenotypes in adulthood.     

Early-in-life dietary zinc deficiency and supplementation and mammary tumor development in adulthood female rats

Zinc deficiency during pregnancy and postnatal life can adversely increase risk of developing human diseases at adulthood. The present study was designed to evaluate whether dietary zinc deficiency or supplementation during the pregnancy, lactation and juvenile stages interferes in the development of mammary tumors induced by 7,12-dimethylbenzanthracene (DMBA) in female Sprague–Dawley (SD) rats. Pregnant female SD rats were allocated into three groups: zinc-adequate diet (ZnA - 35-mg/kg chow), zinc-deficient diet (ZnD - 3-mg/kg chow) or zinc-supplemented diet (ZnS - 180-mg/kg chow) during gestational day 10 (GD 10) until the litters' weaning. Female offspring received the same diets as their dams until postnatal day (PND) 51. At PND 51, the animals received a single dose of DMBA (50 mg/kg, ig) and zinc-adequate diets. At PND 180, female were euthanized, and tumor samples were processed for histological evaluation and gene expression microarray analysis. The ZnD induced a significant reduction in female offspring body weight evolution and in mammary gland development. At late in life, the ZnD or ZnS did not alter the latency, incidence, multiplicity, volume or histological types of mammary tumors in relation to the ZnA group. However, the total tumor number in ZnS group was higher than in ZnA group, accompanied by distinct expression of 4 genes up- and 15 genes down-regulated. The present findings indicate that early-in-life dietary zinc supplementation, differently to zinc deficiency, has a potential to modify the susceptibility to the development of mammary tumors induced by DMBA.     

A potent modifier of liver cancer risk on distal mouse chromosome 1: linkage analysis and characterization of congenic lines

The C3H/HeJ (C3H) and CBA/J (CBA) mouse strains are classical mouse models of cancer susceptibility, exhibiting high risks for both spontaneous and chemically induced liver cancer. By analysis of backcrosses and intercrosses between C3H or CBA and resistant B6 mice, we have mapped a potent modifier of hepatocellular carcinoma development to distal chromosome 1, linked to the marker D1Mit33 with combined LOD(W) scores of approximately 5.9 (C3H) and 6.5 (CBA). We previously identified this region as one of two that modify susceptibility in the more distantly related C57BR/cdJ (BR) strain. Congenic B6.C3H(D1Mit5-D1Mit17) and B6.BR(D1Mit5-D1Mit17) mice developed significantly more liver tumors than B6 mice did (6- to 13-fold, P < 10(-11), in males; 3- to 4-fold, P < 10(-3), in females). Thus, distal chromosome 1 carries one or more genes that are sufficient to confer susceptibility to liver cancer.     

Effects of Pulsed Microwave Radiation Pre -and Post-Natally on the Developing Brain in Mice

Pregnant mice were irradiated for 5 hours daily throughout the pregnancy with pulsed microwaves at an incident average power density of 8 mW/cm², or were sham irradiated. After birth, from day 3 to day 20, half the offspring delivered by irradiated mice were irradiated (RR group) and half were sham-irradiated (RC group). The same procedure was used for offspring delivered by sham-irradiated mice (CR and CC). All offspring were sacrificed at 22 days of age. Histochemical analyses of the hypothalamus and liver were performed with a microspectrophotometer. The data suggested that succinate dehydrogenase in the hypothalamus was reduced by either pre-or post-natal microwave exposure. Similar changes occurred in the liver. The same pattern appeared with hypothalamic catechol-amine and monoamine oxidase. The data indicate that low-intensity microwave exposure can induce subtle alterations in offspring not detected with previously used techniques.     

Gastroschisis is caused by the combination of carbon monoxide and protein-zinc deficiencies in mice

BACKGROUND: Gastroschisis is a rare congenital defect of the abdominal wall. Its occurrence is noted primarily in the offspring of young mothers who often smoke during pregnancy. The incidence of gastroschisis has been increasing in many countries in recent years. The etiology of gastroschisis is not known. METHODS: Pregnant mice of CD‐1 strain were maintained on 17 and 9% protein diets mixed with deficient, normal, or supplemental zinc levels throughout gestation. The dams in each protein‐zinc diet group were randomly divided in two groups. One group was exposed to air (control) and the other to 500 ppm carbon monoxide (CO) in air, in environmental chambers, from gestation days (GD) 8–18. The dams were sacrificed by carbon dioxide asphyxiation on GD 18, and data on malformations was collected. RESULTS: The rates of fetal mortality and malformations were increased by protein and zinc deficiencies. Carbon monoxide exposure also increased fetal mortality. In the low protein group, the rate of fetal mortality was inversely related to the dietary zinc level, and the rate of fetal malformations was highest in the zinc deficient group. The incidence of gastroschisis in the low protein/zinc deficient/CO exposed group was 47%, and 60% of the litters were affected. The incidence of gastroschisis in the rest of the low protein/zinc diets/air or CO groups was 0. CONCLUSION: The data indicates that gastroschisis is caused by the combination of protein‐zinc deficiencies and carbon monoxide exposure during gestation. The finding may be relevant to human populations that experience protein and zinc deficiencies during gestation, and are exposed to CO pollution, or cigarette, or marijuana smoke during pregnancy. Birth Defects Res B 68:355–362, 2003. © 2003 Wiley‐Liss, Inc.     

Genetic control of the natural killer cell activity in SJL and other strains of mice

Murine natural killer (NK) cell activity against lymphoma targets can be classified into three major functional phenotypes, i.e., low, inducible, and high, according to the levels of endogeneous activity and the extent of augmentation by interferon (IFN) or IFN inducers, as previously described. The prototype strains identifying these three phenotypes are SJL, A.SW, and B10.S, respectively, all bearing the H-2s haplotype. In the present study, the genetic basis of the low phenotype of SJL mice was examined further. F1 hybrid offspring of crosses between SJL and a strain with the high NK phenotype (B10.S, B10.D2, B10, C3H/HeN, or D1.LP) invariably expressed the high NK phenotype, indicating recessiveness of the low phenotype. Crosses between SJL and another low NK strain, such as A/J, A/HeN, or I/St, resulted in offspring of either the inducible or the high NK phenotype. Such genetic complementation between the low NK pairs indicates that the low phenotype of SJL and that of the other strains have different genetic bases. F1 hybrid mice between SJL and an inducible strain, A/WySn, were inducible, but those between SJL and the second inducible strain, A.SW, had the high NK phenotype. Thus, the congenic A/WySn and A.SW have distinct genotypes resulting in the same inducible phenotype. According to analyses of the segregating offspring from backcrosses of (SJL X B10.S)F1 mice to SJL, a single gene difference is responsible for the low endogenous level of NK activity in SJL as opposed to the high endogenous level in B10.S, and that the difference in three genes accounts for the poor responsiveness of NK cells to IFN in SJL mice. Studies of the two congenic lines of SJL, i.e., SJL-Igha and SJL-nu, indicated that the Igh locus is irrelevant for the low NK phenotype of SJL, but the nu locus clearly is relevant; SJL mice homozygous for the nu allele were phenotypically inducible in contrast to the nu/+ or +/+ mice which are low. The nu gene homozygosity rendered SJL mice responsive to IFN, not only in NK activity against lymphomas but also in ADCC activity against antibody-coated lymphoma cells.