Developmental changes of the proliferative response of mouse epidermal melanocytes to skin wounding

A cut was made on the middorsal skin of mice of various ages of strain C57BL/0J using fine iridectomy scissors. Specimens from the wounded skins were fixed at various days after wounding and were subjected to the dopa reaction and to the combined dopa-premelanin reaction. When the dorsal skins of 1.5-day-old mice were wounded, the melanocyte population positive to the dopa reaction as well as the melanoblast-melanocyte population positive to the combined dopa-premelanin reaction increased dramatically in the epidermis adjacent to a skin wound. Pigment-producing melanocytes in mitosis were frequently found in the vicinity of a wound immediately after wounding. When the dorsal skins of 4.5-day-old mice were wounded, the increase in the melanocyte and melanoblast-melanocyte populations was smaller than that of 1.5-day-old mice. The increase in number of pigment-producing melanocytes in mitosis was reduced and delayed as compared to 1.5-day-old mice. When the dorsal skins of 8.5-, 20.5-, and 60.5-day-old mice were wounded, the increase in the melanocyte and melanoblast-melanocyte populations was much smaller than the newborn mice. Moreover, pigment-producing melanocytes in mitosis were never found. These results indicate that the proliferative response of mouse epidermal melanocytes to skin wounding becomes delayed and diminished with development.     

Relationship between genetic differentiation of the thymus in mice of different strains and malignant growth. IV. Genetic analysis of the thymic index in mice]

Relative thymus weight was estimated in C3H/He, C57BL/6 mice, their F1 and backcross hybrids, as well as in the progeny of complete diallel crosses between the BALB/c, C3H/He, C57BL/6 and AKR/J strains. On the basis of the analysis of these measurements, a conclusion is drawn that this character is inherited with incomplete dominance of smaller relative weight. The genes determining greater thymus weight are concentrated in the genetic pool of AKR/J and C57BL/6 strains. These genes are characterized by some degree of recessivity with respect to the genes determining smaller thymus weight which are concentrated in the genetic pool of C3H/He and BALB/c strains. The highest concentration of the "plus" and "minus" genes is found in the genetic pools of AKR/J and C3H/He strains respectively.     

Sex and strain differences of mouse variant salivary proteins

Proteins of the mouse saliva are resolved into about 20 discrete bands by polyacrylamide gel electrophoresis. Sexual dimorphism and monomorphism were found in a subset (Msp-1) of these salivary proteins from different inbred strains. This sexual dimorphism involves a fast moving band (F-type) and a slow moving one (S-type). Mature males of seven strains (A/J, AKR, CBA/J, C3H/HeN, A/Sn, B10.A, and B10.BR) exhibit the S phenotype while mature females of these strains were typed as F. Sexually immature males and females of these strains were uniformly typed as F, but at puberty (5-6 weeks of age) the phenotype of the males switched to type S, while the phenotype of the females remained the same. This switch to type S at puberty did not take place in males of four strains (BALB/cAnn, B10.D2, C57BL/6, and C57BL/10); therefore, we conclude that these strains were sexually monomorphic with regard to Msp-1. The phenotype of mature males of C3H/HeN reverted to type F following castration, whereas castrated males and mature females switched to type S in response to testosterone administration. The testosterone treatment had no effect on the type S phenotype of males and females of the sexually monomorphic BALB/cAnn strain. The male-specific type S phenotype of Msp-1 was seen only in mice with H-2 haplotype a or k; thus an association with H-2 haplotype was suggested. All F1 males of reciprocal crosses involving the sexually dimorphic and monomorphic strains (e.g., C3H/HeN X BALB/cAnn) demonstrated the type S phenotype at puberty.     

Effects of maternal strain on ethanol responses in reciprocal F1 C57BL/6J and DBA/2J hybrid mice

Variations in maternal behavior, either occurring naturally or in response to experimental manipulations, have been shown to exert long-lasting consequences on offspring behavior and physiology. Despite previous research examining the effects of developmental manipulations on drug-related phenotypes, few studies have specifically investigated the influence of strain-based differences in maternal behavior on drug responses in mice. The current experiments used reciprocal F1 hybrids of two inbred mouse strains (i.e. DBA/2J and C57BL/6J) that differ in both ethanol (EtOH) responses and maternal behavior to assess the effects of maternal environment on EtOH-related phenotypes. Male and female DBA/2J and C57BL/6J mice and their reciprocal F1 hybrids reared by either DBA/2J or C57BL/6J dams were tested in adulthood for EtOH intake (choice, forced), EtOH-induced hypothermia, EtOH-induced activity and EtOH-induced conditioned place preference (CPP). C57BL/6J and DBA/2J mice showed differences on all EtOH responses. Consistent with previous reports that maternal strain can influence EtOH intake, F1 hybrids reared by C57BL/6J dams consumed more EtOH during forced exposure than did F1 hybrids reared by DBA/2J dams. Maternal strain also influenced EtOH-induced hypothermic responses in F1 hybrids, producing differences in hybrid mice that paralleled those of the inbred strains. In contrast, maternal strain did not influence EtOH-induced activity or CPP in hybrid mice. The current findings indicate that maternal environment may contribute to variance in EtOH-induced hypothermia and EtOH intake, although effects on EtOH intake appear to be dependent upon the type of EtOH exposure.     

Establishment of a mouse melanocyte clone which synthesizes both eumelanin and pheomelanin

We isolated cultured melanocyte population from dorsal skin of C57BL/6J (genotype, a/a; C/C) new-born mouse and established several cell lines. One of the melanocyte clones, TM 10, produces both eumelanin and pheomelanin. This cell line seems to be suitable for study of the regulation mechanism of production of these pigments in vitro.     

Association of Lps gene with natural resistance of mouse macrophages against Legionella pneumophila.

Peritoneal macrophages obtained from lipopolysaccharide (LPS)-low responder C3H/HeJ mice (J) permitted the intracellular growth of the bacterium in macrophages of (J x N) F1 progeny was between the parent strains, showing that the traits were co-dominantly expressed. Correlation between intracellular bacterial growth in macrophages and LPS response of spleen cells was examined. Negative correlation was found between the two factors in F2, (J x F1) backcross and (N x F1) backcross progeny. This result implies that Lps gene controls the innate resistance of murine macrophages against the bacteria. Although macrophages of A/J strain also permit intracellular growth of L. pneumophila, gene complementation analysis of A/J and C3H/HeJ mice made clear that the gene control in C3H/HeJ differs from that of A/J strain. Macrophages of C57BL/10ScN, which is LPS-low responder line obtained from C57BL/10, were also defective in controlling the bacterial growth when compared to C57BL/10 mice. We suggest that the Lps gene also controls the natural resistance of murine macrophages against L. pneumophila.     

Genetic and epigenetic factors affecting blastomere fragmentation in two-cell stage mouse embryos

We report here that mouse embryos can exhibit a significant incidence of blastomere fragmentation at the two-cell stage. The incidence of this is influenced by both the maternal and paternal genotype. Embryos from C57BL/6 mothers exhibit a very low incidence of fragmentation at the two-cell stage in crosses involving males of C57BL/6, DBA/2, AKR/J, or SJL strains but exhibit a significantly increased incidence of fragmentation in crosses involving C3H/HeJ males. Increased fragmentation is seen in embryos from C3H/HeJ females crossed with C57BL/6 males but not with C3H/HeJ males. Embryos obtained from reciprocal (C57BL/6 x C3H/HeJ) F1 hybrid females also exhibit an increased incidence of fragmentation at the two-cell stage when the hybrid females are mated to either C57BL/6 or C3H/HeJ males. Interestingly, the results differ significantly between reciprocal F1 hybrid females, indicating a parental origin effect, possibly a result of either genomic imprinting or differences in mitochondrial origin. We conclude that the incidence of blastomere fragmentation at the two-cell stage in the mouse is under the control of more than one genetic locus. We also conclude that blastomere fragmentation is affected by both parental genotypes. These results are relevant to understanding the genetic control blastomere fragmentation, which may contribute to evolutionary processes, affect the success of procedures such as cloning, and affect the outcome of assisted reproduction techniques.     

Strain difference in mouse natural killer activity augmented by mouse interferon and poly I.C

The level of natural killer (NK) activity was found to vary considerably among several mouse strains. In vivo and in vitro, interferon (IFN) and IFN inducers have been shown to augment mouse NK activity. C3H/He mice showed high NK activity, DDD/1 and A/J mice low NK activity, and C57BL/6, BALB/c and DBA/2 mice intermediate NK activity after injection with polyinosinic polycytidylic acid (poly I. C.). The same NK activity correlation was observed in nontreated mice, but the NK activities were lower compared with the poly I. C.-injected mice. Moreover, the DDD/1 and A/J mice showed almost no augmentation of NK activity on injection with poly I.C. In vivo, C3H/He, BALB/c and C57BL/6 mice injected with IFN showed augmented NK activity, but DDD/1 mice showed no such reaction. In vitro, C3H/He, BALB/c and C57BL/6 mouse spleen cells treated with IFN also showed augmented NK activity, but DDD/1 mouse spleen cells showed almost none. F1 hybrids between high (C3H/He) and low (DDD/1) NK-activity strains showed high NK activity. Thus, activity is dominant over low activity. The segregation of (DDD/1 X C3H/He) Fl X DDD/1 back-cross mice suggested that the strain differences in NK activity are under polygenic control.     

Sex and strain differences of mouse variant salivary proteins

Abstract. Proteins of the mouse saliva are resolved into about 20 discrete bands by polyacrylamide gel electrophoresis. Sexual dimorphism and monomorphism were found in a subset (Msp-1) of these salivary proteins from different inbred strains. This sexual dimorphism involves a fast moving band (F-type) and a slow moving one (S-type). Mature males of seven strains (A/J, AKR, CBA/J, C3H/HeN, A/Sn, B10.A, and B10.BR) exhibit the S phenotype while mature females of these strains were typed as F. Sexually immature males and females of these strains were uniformly typed as F, but at puberty (5–6 weeks of age) the phenotype of the males switched to types, while the phenotype of the females remained the same. This switch to type S at puberty did not take place in males of four strains (BALB/cAnn, B10.D2, C57BL/6, and C57BL/10); therefore, we conclude that these strains were sexually monomorphic with regard to Msp-1. The phenotype of mature males of C3H/HeN reverted to type F following castration, whereas castrated males and mature females switched to type S in response to testosterone administration. The testosterone treatment had no effect on the type S phenotype of males and females of the sexually monomorphic BALB/cAnn strain. The male-specific type S phenotype of Msp-1 was seen only in mice with H-2 haplotype a or k; thus an association with H-2 haplotype was suggested. All F₁ males of reciprocal crosses involving the sexually dimorphic and monomorphic strains (e.g., C3H/HeN × BALB/cAnn) demonstrated the type S phenotype at puberty.     

Factors affecting the glycosphingolipid composition of murine tissues

The effects of genetic strain, sex, age, and pathological state on the distribution and concentration of glycosphingolipids in mouse kidneys and livers were studied. The concentrations of glycosphingolipids and phospholipids in the kidneys and livers of different strains were compared. The major glycosphingolipid in the kidneys of male and female BALB/c, C3H/He, C57/BL, A, and C57xA (F(1) hybrid) mice was a sulfatide, monoglycosyl-(3-sulfate) ceramide; monoglycosyl ceramide was the major component in livers. The kidneys of males of all strains contained significant amounts of diglycosyl ceramide, but those of females contained, at most, only traces. Glycosphingolipid concentration in the male kidneys of C57/BL and C57xA (F(1) hybrid) was much higher than in the female and was also much higher than in the male kidneys of C3H/He, BALB/c, and A strains. The kidneys of "old" (36 wk) male and female C3H/He mice contained much higher proportions of monoglycosyl ceramide than 10-12-wk-old adults. The distributions of glycosphingolipids in kidneys of female C3H/He mice with BP8 ascites tumors and male C57xA (F(1) hybrid) mice with EL4 ascites tumors differed from those in the normal mice. An unknown lipid, present in all glycosphingolipid extracts from kidney and liver, was tentatively identified as cholesterol sulfate.     

The effects of single gene substitution on the mammalian melanocyte system—a qualitative and quantitative histological study in the C57BL and DBL mice

About 160 skin samples from the tail, sole, palm, ear and scrotum of DBL and C57BL/St mice were “split” with NaBr and treated with DOPA. A quantitative and qualitative microscopic analysis showed that: (a) the two strains did not differ consistently in the frequency of epidermal or dermal melanocytes; nor did the sexes differ from each other in this respect; (b) the melanocytes of the two strains differed morphologically. The DBL melanocytes were generally larger, with melanin-congested perikarya. They had fewer dendrites than the C57BL melanocytes and their dendrites were shorter; and (c) the melanocytes of the DBL and C57BL strains differed in activity, the DBL melanocytes donating less melanin to Malpighian cells than did the C57BL melanocytes. It was concluded that the morphology of DBL and C57BL melanocytes is largely autonomously determined, although regional differences in melanocyte morphology suggest that the cellular environment also plays some part in influencing melanoblast differentiation.     

Genetic control of sex-chromosomal univalency in the spermatocytes of C57BL/6J and DBA/2J mice

The genetic control of sex-chromosomal univalency was examined in the primary spermatocytes of the mouse. The C57BL/6J strain expresses 3% X-Y univalency and DBA/2J expresses 37% univalency. The reciprocal F1 and the eight types of reciprocal backcross males were examined. In the C57BL/6J--DBA/2J strain pair, X--Y univalency is controlled by three genetic systems. Autosomal factors of unknown number that are dominant in DBA/2J increase the probability of univalency from 3% in C57BL/6J to 12%. The DBA/2J-Y chromosome, in place of the C57BL/6J-Y chromosome, has an additive effect to increase the probability of univalency from 12 to 37% in the DBA/2J strain. Two X-chromosome factors that differ between C57BL/6J and DBA/2J regulate the probability of univalency. The X-chromosome factors appear to be separated by sufficient distance so that, with the DBA/2J-Y chromosome and dominant DBA/2J autosomal factors, there are two recombinant classes of X--Y univalency at 20 and 60%. The genetic factors in the univalency trait may be involved in the regulation or structure of the terminal attachment sites between the X and Y chromosomes.     

Genetic control of serum neutralizing-antibody response to rabies vaccination and survival after a rabies challenge infection in mice.

Quantitative differences in serum neutralizing-antibody (SNAb) responses to rabies vaccination and survival after a rabies challenge infection between two inbred mice strains, C3H/J and C57BL/6J, were shown to be under genetic control. A 99% confidence limit calculated from the SNAb response titers of 14 C57BL/6J mice resulted in an upper limit for the SNAb response titer of C57BL/6J mice at 50.63. A SNAb titer less than or equal to 50.63 in response to rabies vaccination was assigned the phenotype of hyporesponder, and a SNAb titer greater than 50.63 in response to rabies vaccination was assigned the phenotype of hyperresponder in this study. The hyper-SNAb response to rabies vaccination and the higher frequency of survival after rabies challenge infection behave as Mendelian dominant alleles in F1 hybrids (C3H/J X C57BL/6J) and backcross (BC) (F1 [C3H/J X C57BL/6J] X C57BL/6J) progeny. Both a relatively hyper-SNAb response and a higher frequency of vaccine-inducible survival phenotypes occur in C3H/J mice. On the other hand, both the relatively hypo-SNAb response and a lower frequency of vaccine-inducible survival phenotypes behave as Mendelian recessive alleles and occur in C57BL/6J mice. C3H/J mice are H-2 Kk, and C57BL/6J mice are H-2 Kb. All three phenotypic traits (H-2 type, SNAb response, and survival after rabies challenge infection) segregate as independent (unlinked) monogenic traits in BC progeny (F1 [C3H/J X C57BL/6J] X C57BL/6J). The genetically controlled survival trait is inducible by rabies vaccination, but SNAb response is not a parameter that measures successful vaccine induction of preexposure protection from a rabies challenge infection in the BC progeny. The essential role of vaccination in developing preexposure protection in genetically responsive mice is confirmed, but indicates that in vitro measurements other than SNAb titers need to be developed to identify mice that have failed to achieve preexposure protection by rabies vaccination. This study confirms Lodmell's findings (D. L. Lodmell and B. Chesebro, J. Virol. 50:359-362, 1984; D. L. Lodmell, J. Exp. Med. 157:451-460, 1983) that susceptibility to rabies infection is genetically controlled in some mice strains. Additionally, this study indicates that conventional rabies vaccination even with more potent vaccines may not induce protection from infection in some genetically susceptible individuals.     

Radiation induction of mutations affecting sperm morphology in mice

To investigate the basis of the sperm abnormality assay, studies have been made of the frequency of sperm abnormalities in the genital tracts of the progeny of irradiated males. Male C57BL/6 mice were irradiated (75-600 rad X-rays to the testes) and were then bred in the pre-sterile period to untreated C57BL/6 females. The sperm of their male progeny were examined for the frequency of sperm abnormalities. Variant males with clearly elevated levels of sperm abnormalities were more frequently seen amongst the progeny of irradiated fathers than with the progeny of sham-irradiated controls (10 in 170 compared with 2 in 188; P less than 0.02). Although no clear dose-response relation could be discerned with the number of animals studied, similar differences were observed with irradiated male SWR, C3H/He in inbred crosses and with C57BL/6 in hybrid crosses with C3H/He females. In contrast, matings of males made at longer times following irradiation did not lead to a significant increase in the number of affected progeny for the number tested. Breeding experiments with the affected F1 males showed that the sperm morphology defect could be transmitted in 7 of 19 cases. Parallel cytogenetic studies showed that 3 of the initial affected progeny had detectable reciprocal translocations and that in 2 of these cases the translocation was transmitted with the sperm defect. The studies thus showed that radiation can induce mutations that affect the levels of sperm abnormalities and that these mutations can be associated with reciprocal translocations.     

Role of interferon in the pathogenesis of viral diseases of mice as demonstrated by the use of anti-interferon serum. V. Protective role in mouse hepatitis virus type 3 infection of susceptible and resistant strains of mice

Potent sheep anti-mouse interferon globulin has been used to determine the role of virus-induced interferon in mouse hepatitis virus type 3-infected susceptible (C57BL/6), semiresistant (C3H/He), and resistant (A/J) strains of mice. Injection of anti-interferon globulin accelerated the onset of death in C57BL/6 mice, induced almost 100% mortality in C3H/He mice that usually do not die of acute disease, and caused death in 4- and 6-week-old A/J mice, but not in older mice. We conclude that interferon is an important host defense factor in the initial response of different strains of mice to MHV-3 infection. Other factors, however, such as the capacity of macrophages to restrict viral multiplication probably underlie the genetically determined susceptibility or resistance of mice to MHV-3 infection.     

Streptobacillus moniliformis epizootic in barrier-maintained C57BL/6J mice and susceptibility to infection of different strains of mice

We report a Streptobacillus moniliformis epizootic in barrier-maintained SPF mice. Although various inbred and F1 hybrid strains of mice have been kept in this animal facility, only C57BL/6J Han [corrected] mice showed clinical signs of disease. During the course of the epizootic, 825 breeding animals (approximately 36% of the breeders) died or had to be killed because of severe clinical signs. Although sequential treatment with ampicillin and chlortetracycline gave good therapeutic results, the animal facility was vacated in order to exclude any risk of cross-contamination of the other rodent colonies in our institute. The source and route of transmission of S. moniliformis could not be elucidated. To investigate strain dependent differences experimental infection of different strains of mice with our S. moniliformis isolate was performed. After oral infection only C57BL/6J showed the typical signs of a cervical lymphadenitis and gave an immunological response. BALB/cJ, C3H/He, DBA/2J, CB6F1 and B6D2F1 mice were not affected except in two cases of DBA/2J and B6D2F1 mice where seroconversion was observed. After intravenous infection of C57BL/6J, DBA/2J [corrected] and BALB/cJ all animals showed positive titers in the indirect immunofluorescence test (IIF). One hundred percent of the C57BL/6J, forty percent of the DBA/2J, and none of the BALB/cJ mice developed severe symptoms. The results demonstrate that the susceptibility to streptobacillosis is predominantly influenced by genetic factors.     

Effects of genic substitution at the pink-eyed dilution locus on the proliferation and differentiation of mouse epidermal melanocytes in vivo and in vitro

Cells positive to the dopa reaction (melanocytes) as well as to the combined dopa-premelanin reaction (melanoblasts and melanocytes) in the epidermis of C57BL/10JHir-p/p (pink-eyed dilution) mice were fewer and less reactive than in C57BL/10JHir (black, P/P) mice, suggesting that the proliferation and differentiation of p/p melanocytes are inhibited. To confirm the inhibitory effects of p gene on the proliferation and differentiation of epidermal melanocytes, we cultured epidermal cell suspensions of neonatal skins from P/P and p/p in a serum-free medium. The proliferation and differentiation of p/p melanoblasts/melanocytes in primary culture were greatly inhibited as compared to P/P melanoblasts/melanocytes. The morphology of p/p melanoblasts/melanocytes cultured in melanocyte growth medium, though non-pigmented, was similar to P/P melanocytes; namely, dendritic, polygonal, or epithelioid. About 8% of p/p cells cultured in melanocyte growth medium were positive to the dopa reaction, and about 25% were reactive to the combined dopa-premelanin reaction. Eumelanin content in p/p was extremely reduced compared to P/P. The immunocytochemical staining of p/p melanoblasts/melanocytes revealed that they are negative to tyrosinase, but reactive to tyrosinase-related protein (TRP)-1, TRP-2, and c-kit. However, the reactivities in p/p were lower than in P/P. Although the differentiation of p/p melanoblasts was not induced by endothelin (ET)-1, ET-2, and ET-3, the proliferation of p/p melanoblasts was stimulated by them. These results suggest for the first time that p gene exerts its influence on the proliferative activities of mouse epidermal melanoblasts by affecting the regulatory mechanisms dependent on the function of ETs.     

Paternal inheritance of egg traits in mice: a case of genomic imprinting

Eggs from reciprocal hybrids between the C57BL/6By and BALB/cBy strains were tested for their susceptibility to attack by hyaluronidase and pronase. There were significant reciprocal differences between the F1 females in the responses of their unfertilized eggs to both enzymes. The F1 hybrids from BALB mothers showed the increased susceptibility characteristic of C57BL whilst the F1 hybrids with C57BL mothers were more resistant to both enzymes, like BALB mice. Eggs from the four kinds of reciprocal F2 hybrid females also showed patroclinous patterns of susceptibility. A patroclinous difference was found between reciprocal crosses of the CXBD and CXBE recombinant inbred strains but not in crosses between recombinant inbred strains with similar phenotypes. Cross fostering did not alter the phenotypes of the C57BL and BALB females or those of their reciprocal F1 hybrids. The findings are interpreted in terms of differential genomic imprinting of paternally inherited information. The possible general usefulness of patroclinous differences between reciprocal F1 females in revealing differences in imprinting is noted.     

Time-response and dose-response to acetazolamide in the WB/ReJ and C57BL/6J mouse strains: genetic interaction in the ectrodactyly response

The WB/ReJ and C57BL/6J strains were compared in their time and dose responses to acetazolamide administered in a single subcutaneous injection regime. WB/ReJ has a genetically determined, high-frequency, transient fetal edema that has maximum expression on day 14 and is resolved by day 18. Acetazolamide, at 1,000 mg/kg, appears to induce edema in WB/ReJ with a time of response on days 9 and 10, and the induced edema follows the same time course of appearance and disappearance as the spontaneous trait. The dose-response analysis is not interpretable in the WB/ReJ and C57BL/6J strains and their reciprocal F1 fetuses because there was significant response only at the highest dose (2,000 mg/kg) used in this study. The time of ectrodactyly response is maximal on day 9 in both WB/ReJ and C57BL/6J strains. The dose-response analysis demonstrates that, for the usual measure of total fetuses with ectrodactyly (or penetrance), the Wb/ReJ and C57BL/6J strains and the WB/ReJ x C57BL/6J F1 (WB.B6F1) have the same slope of the dose-response curve and the strain difference in response can be interpreted as a difference in dosage tolerance. The tolerance of WB/ReJ is twofold greater than that of C57BL/6J. This overdominance of relative resistance to acetazolamide ectrodactyly supports the general finding of directional dominance of relative resistance among genetically different strain pairs. The median effective dose for penetrance of the ectrodactyly response of the reciprocal B6.WBF1 embryo is similar to the WB.B6F1, but the slope of the dose-response curve is significantly different, and a different teratogenic mechanism of response may be involved. Ectrodactyly was predominantly right sided in all genotypes, and, in bilaterally affected fetuses, the right forelimb was more severely affected. An unexpected difference between WB/ReJ and C57BL/6J was found when the laterality of ectrodactyly was analyzed further. There is a significant increase with dosage in bilaterally affected fetuses (a measure of expressivity) in C57BL/6J but not in WB/ReJ, even though the dose-response of total affected fetuses (penetrance) is similar in both strains. In C57BL/6J, the left and right forelimbs are correlated in their responses with the left, requiring approximately a threefold greater dose. The left and right forelimbs are symmetrical in response, and the difference can be interpreted in terms of a developmental (or teratogenic) gradient. In WB/ReJ, the right forelimb has the same dose response as C57BL/6J and requires a twofold greater dose than the right forelimb of C57BL/6J, but the left forelimb has a very flat slope and is not correlated with the response of the right.(ABSTRACT TRUNCATED AT 400 WORDS)