RESUMEN
OBJECTIVES: Magnitudes of morphological integration may constrain or facilitate craniofacial shape variation. The aim of this study was to analyze how the magnitude of integration in the skull of Macaca fascicularis changes throughout ontogeny in relation to developmental and/or functional modules. MATERIALS AND METHODS: Geometric morphometric methods were used to analyze the magnitude of integration in the macaque cranium and mandible in 80 juvenile and 40 adult M. fascicularis specimens. Integration scores in skull modules were calculated using integration coefficient of variation (ICV) of eigenvalues based on a resampling procedure. Resultant ICV scores between the skull as a whole, and developmental and/or functional modules were compared using Mann-Whitney U tests. RESULTS: Results showed that most skull modules were more tightly integrated than the skull as a whole, with the exception of the chondrocranium in juveniles without canines, the chondrocranium/face complex and the mandibular corpus in adults, and the mandibular ramus in all juveniles. The chondrocranium/face and face/mandibular corpus complexes were more tightly integrated in juveniles than adults, possibly reflecting the influences of early brain growth/development, and the changing functional demands of infant suckling and later masticatory loading. This is also supported by the much higher integration of the mandibular ramus in adults compared with juveniles. DISCUSSION: Magnitudes of integration in skull modules reflect developmental/functional mechanisms in M. fascicularis. However, the relationship between "evolutionary flexibility" and developmental/functional mechanisms was not direct or simple, likely because of the complex morphology, multifunctionality, and various ossification origins of the skull.
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Macaca fascicularis/anatomía & histología , Macaca fascicularis/crecimiento & desarrollo , Cráneo/anatomía & histología , Cráneo/crecimiento & desarrollo , Animales , Antropología Física , Cefalometría , Cara/anatomía & histología , Femenino , Masculino , Desarrollo MaxilofacialAsunto(s)
Transferencia de Embrión/métodos , Macaca fascicularis/fisiología , Macaca mulatta/fisiología , Animales , Femenino , Macaca fascicularis/genética , Macaca fascicularis/crecimiento & desarrollo , Macaca mulatta/genética , Macaca mulatta/crecimiento & desarrollo , Especificidad de la EspecieRESUMEN
We assessed the variability of spleen and mesenteric lymph node (MLN) microscopic observations and the correlations of these observations with other study data from 478 control cynomolgus monkeys from 53 routine nonclinical safety studies. Spleen weight parameters (absolute and relative to body or brain weights) were highly variable both within a control group on an individual study (up to 5.11-fold) and among animals with the same light microscopic observation. Grades for microscopic observations were also highly variable. The most frequent microscopic observations for spleen were changes in the size and number of germinal centers (58%), acidophilic (hyaline) material in lymphoid follicles (52%), and compound lymphoid follicles (20%). The most frequent microscopic observations in the MLN were eosinophil infiltrates (90%), changes in size and number of germinal centers (42%), and brown pigment (21%). The only meaningful relationships ( r2 > 0.3) were positive correlations between reticuloendothelial hyperplasia and malarial pigment in the spleen and between each of these observations and spleen weight parameters. We conclude that determination of test article-related effects on the immune system in routine monkey toxicology studies requires careful consideration and a weight-of-evidence approach due to the low numbers of animals/group, the inherent variability in spleen and MLN parameters, and the infrequent correlation among immune system-related end points.
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Ganglios Linfáticos/anatomía & histología , Macaca fascicularis/inmunología , Bazo/anatomía & histología , Pruebas de Toxicidad/normas , Envejecimiento , Animales , Grupos Control , Centro Germinal , Ganglios Linfáticos/crecimiento & desarrollo , Ganglios Linfáticos/inmunología , Macaca fascicularis/anatomía & histología , Macaca fascicularis/crecimiento & desarrollo , Tamaño de los Órganos , Bazo/crecimiento & desarrollo , Bazo/inmunologíaRESUMEN
The present study aimed to specify the cerebral sulci developed by cortical expansion in cynomolgus monkey fetuses. The degree of sulcal infolding was evaluated by the gyrification index (GI), which was quantified using ex vivo magnetic resonance imaging. The correlation of cortical volume with the sulcal GI was most frequent during embryonic days (EDs) 100 to 120. Interestingly, the high correlation was marked during EDs 140 to 150 in restricted primary sulci in prefrontal, parietotemporal and medial temporal regions. The present results suggest that cortical expansion is involved in gyral demarcation by sulcal infolding, followed by the sulcal infolding progression in phylogenetically-newer cortices.
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Macaca fascicularis/anatomía & histología , Lóbulo Parietal/anatomía & histología , Corteza Prefrontal/anatomía & histología , Lóbulo Temporal/anatomía & histología , Animales , Mapeo Encefálico , Embrión de Mamíferos , Femenino , Feto , Interpretación de Imagen Asistida por Computador , Macaca fascicularis/crecimiento & desarrollo , Imagen por Resonancia Magnética , Masculino , Lóbulo Parietal/diagnóstico por imagen , Lóbulo Parietal/crecimiento & desarrollo , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/crecimiento & desarrollo , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/crecimiento & desarrolloRESUMEN
Callosal projection neurons (CPN) interconnect the neocortical hemispheres via the corpus callosum and are implicated in associative integration of multimodal information. CPN have undergone differential evolutionary elaboration, leading to increased diversity of cortical neurons-and more extensive and varied connections in neocortical gray and white matter-in primates compared with rodents. In mouse, distinct sets of genes are enriched in discrete subpopulations of CPN, indicating the molecular diversity of rodent CPN. Elements of rodent CPN functional and organizational diversity might thus be present in the further elaborated primate cortex. We address the hypothesis that genes controlling mouse CPN subtype diversity might reflect molecular patterns shared among mammals that arose prior to the divergence of rodents and primates. We find that, while early expression of the examined CPN-enriched genes, and postmigratory expression of these CPN-enriched genes in deep layers are highly conserved (e.g., Ptn, Nnmt, Cited2, Dkk3), in contrast, the examined genes expressed by superficial layer CPN show more variable levels of conservation (e.g., EphA3, Chn2). These results suggest that there has been evolutionarily differential retraction and elaboration of superficial layer CPN subpopulations between mouse and macaque, with independent derivation of novel populations in primates. Together, these data inform future studies regarding CPN subpopulations that are unique to primates and rodents, and indicate putative evolutionary relationships.
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Corteza Cerebral/metabolismo , Cuerpo Calloso/metabolismo , Macaca fascicularis/metabolismo , Ratones Endogámicos C57BL/metabolismo , Neuronas/metabolismo , Animales , Evolución Biológica , Movimiento Celular , Corteza Cerebral/citología , Corteza Cerebral/crecimiento & desarrollo , Cuerpo Calloso/citología , Cuerpo Calloso/crecimiento & desarrollo , Regulación del Desarrollo de la Expresión Génica , Inmunohistoquímica , Hibridación in Situ , Macaca fascicularis/anatomía & histología , Macaca fascicularis/crecimiento & desarrollo , Ratones Endogámicos C57BL/anatomía & histología , Ratones Endogámicos C57BL/crecimiento & desarrollo , Neuronas/citología , ARN Mensajero/metabolismoRESUMEN
The authors examined a large random sample of skulls from two species of macaques: rhesus monkeys and cynomolgus monkeys. The skulls were measured, divided into age and sex groups and thoroughly analysed using statistical methods. The analysis shows that skulls of young rhesuses are considerably more domed, i.e. have better-developed neurocrania, than their adult counterparts. Male and female skulls, on the other hand, were found to be very similar, which means that sexual dimorphism of the rhesus macaque was suppressed. Both of these patterns are known from the human evolutionary pattern. No such parallelism to the development of Homo sapiens was found in the cynomolgus monkeys. The authors conclude that mosaic hominisation trends may have featured in the evolution of all primates. This would mean that apes were not a necessary step on the evolutionary way leading to the development of Homo sapiens, who may have started to evolve at an earlier stage of monkeys.
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Macaca fascicularis/anatomía & histología , Macaca fascicularis/crecimiento & desarrollo , Macaca mulatta/anatomía & histología , Macaca mulatta/crecimiento & desarrollo , Cráneo/anatomía & histología , Cráneo/crecimiento & desarrollo , Animales , Femenino , Masculino , Caracteres Sexuales , Estadística como AsuntoRESUMEN
Terminal body weights (TBWs), thymus weight parameters, and thymus morphology were retrospectively evaluated in 453 cynomolgus monkeys assigned to control groups on nonclinical toxicity studies. Morphology of bone, ovary, and testis/epididymis were used to determine maturity status of individual animals. There was no correlation between TBW and thymus weight (absolute and/or relative to TBW or brain weight). Thymus weight parameters and grades of decreased lymphocytes in the thymus were highly variable in immature animals compared to mature animals. There was also high (up to 11-fold) variability of thymus weight parameters within a given control group on the same study (generally 3 or 4 animals per sex). Several parameters evaluated had more pronounced age-related changes in males when compared to females. Our results demonstrate the inherent variability of thymus weight parameters and morphologic observations for cynomolgus monkeys on toxicology studies. Changes in thymus parameters in cynomolgus monkeys are unreliable indicators of immunomodulation or immunotoxicity in the absence of other relevant findings. Therefore, the thymus parameters commonly evaluated in preclinical safety assessments should not be the primary data set used to determine the presence of a direct test article-related effect on the immune system.
Asunto(s)
Macaca fascicularis/crecimiento & desarrollo , Macaca fascicularis/inmunología , Timo/crecimiento & desarrollo , Timo/inmunología , Animales , Femenino , MasculinoRESUMEN
OBJECTIVE: To investigate the infection situation of blood parasitic protozoa in farmed Macaca fascicularis in an animal breeding ground in Nanning, Guangxi Zhuang Autonomous Region, so as to provide the evidence for the prevention and control of human blood parasitic protozoa. METHODS: A total of 993 blood samples from farmed M. fascicularis were collected and stored on FTA cards. Among them, 550 thin blood smears were made. Each 10 samples were mixed in groups, and then the Babesia spp. and Plasmodium spp. in the blood of M. fascicularis were detected by Nest-PCR and PCR, respectively. The positive groups were tested individually. The thin blood smears stained with Giemsa were examined microscopically when PCR reported the samples were positive. RESULTS: When detected by Nest-PCR, the positive rate of Babesia. microti was 6.95% (69/993); only 1 positive sample with Plasmodium inui was detected by PCR. Among the 22 positive thin blood smears detected by PCR, 16 were determined with B. microti by microscopic examinations, on which the ring forms could be observed in the erythrocytes, but no hemozoin. CONCLUSIONS: The positive rate of B. microti in M. fascicularis in Guangxi Zhuang Autonomous Region is high, and the animal may play a role as a reservoir host in the transmission of B. microti. In the screening of B. microti with low infection density, Nest-PCR has a higher sensitivity.
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Babesia microti/aislamiento & purificación , Babesiosis/parasitología , Macaca fascicularis/parasitología , Malaria/veterinaria , Enfermedades de los Monos/parasitología , Plasmodium/aislamiento & purificación , Animales , Babesia microti/genética , Babesiosis/epidemiología , China/epidemiología , Femenino , Macaca fascicularis/crecimiento & desarrollo , Malaria/epidemiología , Malaria/parasitología , Masculino , Enfermedades de los Monos/epidemiología , Plasmodium/genética , Reacción en Cadena de la PolimerasaRESUMEN
Testicular volume is one of several parameters that have been used in preclinical toxicology to facilitate the identification of sexually mature male cynomolgus macaques when semen evaluation is unavailable. Furthermore, testicular volume provides additional information to pathologists to aid in the interpretation of microscopic findings. Orchidometry has been proposed as a useful tool for assessing testicular volume. To assess its utility for this purpose, we used orchidometry to measure testicular volume in untreated control male cynomolgus macaques during preclinical toxicology studies. Additional parameters including age, body weight, testicular weight, serum testosterone, and testicular histology were also evaluated. Serum inhibin B and the diameter of histologic testicular sections were assessed to determine whether they might provide any additional corroborative evidence for differentiating stages of sexual maturity in males. Orchidometry was easy to use in sedated or awake macaques and, in combination with testicular histology, enabled the establishment of cut-off values by which sexually mature male cynomolgus macaques can be identified with a high degree of confidence. The relative utility of the parameters examined for discriminating sexually mature and immature males was testicular volume ≥ serum testosterone > body weight > age; for differentiation of sexually mature and peripubertal males the order was testicular volume ≥ body weight > serum testosterone > age. Testicular weight and the diameter of histologic testicular sections provided corroborative information for discriminating stages of sexual maturity. Serum inhibin B was of little value in helping to differentiate the different stages of sexual maturation evaluated in this study.
Asunto(s)
Macaca fascicularis/crecimiento & desarrollo , Maduración Sexual/fisiología , Testículo/patología , Animales , Biomarcadores/sangre , Peso Corporal , Inhibinas/sangre , Macaca fascicularis/anatomía & histología , Masculino , Testosterona/sangreRESUMEN
An important aspect of the enhanced pre- and postnatal developmental (ePPND) toxicity study in nonhuman primates (NHP) is that it combines in utero and postnatal assessments in a single study. However, it is unclear if NHP ePPND studies are suitable to perform all of the evaluations incorporated into rodent PPND studies. To understand the value of including cognitive assessment in a NHP ePPND toxicity study, we performed a power analysis of object discrimination reversal task data using a modified Wisconsin General Testing Apparatus (ODR-WGTA) from two NHP ePPND studies. ODR-WGTA endpoints evaluated were days to learning and to first reversal, and number of reversals. With α = 0.05 and a one-sided t-test, a sample of seven provided 80% power to predict a 100% increase in all three of the ODR-WGTA endpoints; a sample of 25 provided 80% power to predict a 50% increase. Similar power analyses were performed with data from the Cincinnati Water Maze (CWM) and passive avoidance tests from three rat PPND toxicity studies. Groups of 5 and 15 in the CWM and passive avoidance test, respectively, provided 80% power to detect a 100% change. While the power of the CWM is not far superior to the NHP ODR-WGTA, a clear advantage is the routine use of larger sample size, with a group of 20 rats the CWM provides ~90% power to detect a 50% change. Due to the limitations on the number of animals, the ODR-WGTA may not be suitable for assessing cognitive impairment in NHP ePPND studies.
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Trastornos del Conocimiento/diagnóstico , Discriminación en Psicología , Desarrollo Embrionario , Macaca fascicularis/embriología , Macaca fascicularis/crecimiento & desarrollo , Estadística como Asunto , Animales , Animales Recién Nacidos , Reacción de Prevención , Femenino , Masculino , Aprendizaje por Laberinto , Ratas , Ratas Sprague-Dawley , Tamaño de la Muestra , Análisis y Desempeño de TareasRESUMEN
We previously reported on a histological classification of cynomolgus monkey testis into six grades (1, immature; 2, prepuberty; 3, onset of puberty; 4, puberty; 5, early adult; 6, adult) based on spermatogenesis development. In this investigation, the accessory reproductive organs from the same animals underwent histomorphometric examination, in addition to being examined histologically and weighed, to evaluate relationships between these parameters and the six grades. Seminiferous tubule diameter increased corresponding to the testicular maturity grade and was notably increased at grade 6. Beginning from grade 3, increases in the areas of the ductus epididymis were noted, and reserved sperm was visible in the lumen. In the prostate, the glandular lumen area per unit area showed an increase beginning from grade 3 but no clear differences between grades 4 and 6; advanced development of epithelial height was observed at grade 6. In the seminal vesicle, development of the epithelial cell layer was markedly increased at grade 6. It was concluded that development of the male accessory reproductive organs began after reserved sperm was observed in the lumen of the ductus epididymis (grade 3) and that these organs were developed notably when the testis reached sexual maturity (grade 6).
Asunto(s)
Genitales Masculinos/crecimiento & desarrollo , Macaca fascicularis/crecimiento & desarrollo , Animales , Genitales Masculinos/anatomía & histología , Genitales Masculinos/citología , Histocitoquímica , Macaca fascicularis/anatomía & histología , Masculino , Maduración Sexual/fisiologíaRESUMEN
The testes from 136 male cynomolgus monkeys were examined histopathologically in order to investigate the relationship between the development of spermatogenesis and testis weight, age, and body weight. At Grade 1 (immature), Sertoli cells and spermatogonia were the only cell classes in the testis. At Grade 2 (pre-puberty), no elongated spermatids were observed in the testis, although a few round spermatids and small lumen formation were observed. At Grade 3 (onset of puberty), all classes of germ cells were observed in the testis, although seminiferous tubule diameters and numbers of germ cells were small. Slight debris in the epididymis was observed in almost all animals. At Grade 4 (puberty), almost complete spermatogenesis was observed in the seminiferous tubules and it was possible to ascertain the spermatogenesis stage as described by Clermont, although tubule diameters and numbers of germ cells were small. There was less debris in the epididymis than at Grade 3. At Grade 5 (early adult), complete spermatogenesis was observed in the seminiferous tubules. At Grade 6 (adult), complete spermatogenesis in the seminiferous tubules and a moderate or large number of sperm in the epididymis were observed. Moreover, sperm analysis using ejaculated sperm was possible. Logistic regression analysis showed that testis weight is a good indicator of testicular maturity.
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Macaca fascicularis/crecimiento & desarrollo , Maduración Sexual/fisiología , Testículo/crecimiento & desarrollo , Factores de Edad , Animales , Peso Corporal , Epidídimo/crecimiento & desarrollo , Histocitoquímica , Modelos Logísticos , Masculino , Tamaño de los Órganos/fisiología , Espermatogénesis/fisiología , Testículo/fisiologíaRESUMEN
Tubular anomalous bones were found in both thighs of a 6-year-old male long-tailed macaque (Macaca fascicularis) bred in captivity. The bones had jagged ends and protruded from the skin. Radiographs showed that they developed in the femurs at the middle and elongated. They were removed with surgery under anesthesia. Histological analysis revealed that these bones had the same histological structure as the femur, though they were composed of primary and secondary osteon regions. This finding indicated that the new bones developed from the old bone piece(s), acquired a tubular shape, and elongated. It is suggested that the anomalous bones were produced not by the congenital deformity but by regeneration from fragments of the fractured femur that were embedded in the bone marrow; these acquired a tubular pattern and elongated.
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Fracturas del Fémur/veterinaria , Fémur/anomalías , Animales , Regeneración Ósea , Fracturas del Fémur/diagnóstico por imagen , Fracturas del Fémur/patología , Fracturas del Fémur/cirugía , Fémur/anatomía & histología , Fémur/diagnóstico por imagen , Fémur/cirugía , Macaca fascicularis/anomalías , Macaca fascicularis/anatomía & histología , Macaca fascicularis/crecimiento & desarrollo , Masculino , RadiografíaRESUMEN
Cynomolgus macaques, frequently used in drug metabolism studies, are bred mainly in the countries of Asia; however, comparative studies of drug metabolism between cynomolgus macaques bred in these countries have not been conducted. In this study, hepatic gene expression profiles of cynomolgus macaques bred in Cambodia (mfCAM), China (mfCHN), and Indonesia (mfIDN) were analyzed. Microarray analysis revealed that expression of most hepatic genes, including drug-metabolizing enzyme genes, was not substantially different between mfCAM, mfCHN, and mfIDN; only 1.1% and 3.0% of all the gene probes detected differential expression (>2.5-fold) in mfCAM compared with mfCHN and mfIDN, respectively. Quantitative polymerase chain reaction showed that the expression levels of 14 cytochromes P450 (P450s) important for drug metabolism did not differ (>2.5-fold) in mfCAM, mfCHN, and mfIDN, validating the microarray data. In contrast, expression of CYP2B6 and CYP3A4 differed (>2.5-fold, p < 0.05) between cynomolgus (mfCAM, mfCHN, or mfIDN) and rhesus macaques, indicating greater differences in expression of P450 genes between the two lineages. Moreover, metabolic activities measured using 14 P450 substrates did not differ substantially (<1.5-fold) between mfCAM and mfCHN. These results suggest that gene expression profiles, including drug-metabolizing enzyme genes such as P450 genes, are similar in mfCAM, mfCHN, and mfIDN.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Expresión Génica , Macaca fascicularis/metabolismo , Microsomas Hepáticos/metabolismo , Animales , Cambodia , China , Sistema Enzimático del Citocromo P-450/genética , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica , Indonesia , Hígado/enzimología , Hígado/metabolismo , Macaca fascicularis/crecimiento & desarrollo , Macaca mulatta/crecimiento & desarrollo , Macaca mulatta/metabolismo , Masculino , Microsomas Hepáticos/enzimología , Análisis de Secuencia por Matrices de Oligonucleótidos , Filogenia , ARN Mensajero/metabolismo , Caracteres Sexuales , Especificidad de la Especie , Regulación hacia ArribaRESUMEN
Cynomolgus CYP2C76, not orthologous to any human cytochrome P450, partly accounts for species differences in drug metabolism between cynomolgus macaques and humans. To discover the CYP2C76 variants, we previously surveyed cynomolgus macaque genomes and found several non-synonymous variants, including a null allele. However, the analysis was limited to cynomolgus macaques, and the number of genomes was relatively small. In this study, therefore, further screening was conducted using 74 cynomolgus and 30 rhesus macaques. A total of 18 non-synonymous variants was found, among which 7 were in substrate recognition sites, important for protein function, and 14 (74%) were shared by both macaque lineages. In cynomolgus macaques, 3 (16%) non-synonymous variants were unique to Indochinese animals, whereas all the variants found in Indonesian animals were shared by Indochinese animals. Among the 18 variants, as compared with the wild type, in progesterone 16α-hydroxylation, L65F, M310L, and N364S variants showed lower metabolic activity and lower intrinsic clearance by kinetic analysis. Molecular modeling indicated that the reduced catalytic activity of the L65F variant in progesterone 16α-hydroxylation possibly resulted from a longer distance of progesterone to the heme in the active site of the CYP2C76 protein. L65F, M310L, and N364S variants might partly influence inter-animal variations of CYP2C76 metabolic activities.
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Macaca fascicularis/metabolismo , Macaca mulatta/metabolismo , Polimorfismo Genético , Esteroide 16-alfa-Hidroxilasa/genética , Sustitución de Aminoácidos , Animales , Asia Sudoriental , China , Estudio de Asociación del Genoma Completo , Hidroxilación , Indonesia , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Cinética , Macaca fascicularis/sangre , Macaca fascicularis/crecimiento & desarrollo , Macaca mulatta/sangre , Macaca mulatta/crecimiento & desarrollo , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Progesterona/metabolismo , Conformación Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Especificidad de la Especie , Esteroide 16-alfa-Hidroxilasa/química , Esteroide 16-alfa-Hidroxilasa/metabolismoRESUMEN
The neural processes that underlie executive function begin to develop in infancy. However, it is unclear how the behavior manifested by these processes are related or if they can be differentiated early in development. This study seeks to examine early emerging executive functioning skills in monkeys (Macaca fascicularis) by using an error analysis approach where traditional measures of the tasks, as well as identification of major error patterns are related. Results show that during the infancy and early juvenile period, two processes that help support set-maintenance could be differentiated: modulation of responses to novelty and persistence despite negative feedback. The results suggest that these two aspects of set-maintenance were largely independent. Modulation of responses to novelty was most prominent in the infancy and early juvenile period. The ability to persist with a response set despite negative feedback emerged in the early juvenile period and was related to task performance until the end of the study.
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Función Ejecutiva/fisiología , Factores de Edad , Animales , Cognición/fisiología , Discriminación en Psicología/fisiología , Femenino , Macaca fascicularis/crecimiento & desarrollo , Macaca fascicularis/fisiología , Masculino , Pruebas Neuropsicológicas , Aprendizaje Inverso/fisiologíaRESUMEN
INTRODUCTION: The identification and use of mature male non-human primates in nonclinical toxicology studies could be important for evaluating candidate drugs for which the profile of toxicity may differ depending on sexual maturity. This investigation sought to establish operational criteria to complement the current standard of histological evaluation for defining sexual maturity in male cynomolgus monkeys (Macaca fascicularis) used for toxicology studies, and to identify a practical non-invasive measure to select mature males for study. METHOD: Retrospectively, the relationships between body weight, testicular weight and testis histology were established in control males (n=126) used in previous toxicology studies. Prospectively, testicular volumes were measured in-life by orchidometry using comparative scrotal palpation (n=23 males used for study), then compared to testicular weights measured at necropsy. RESULTS: Consistent with previous literature, a weak relationship was observed between body weight and testicular weight. There was, however, a very good relationship between testicular weight and histological maturation level, which was based upon microscopic examination of testes, epididymides and prostates. Orchidometric measurement of testicular volume was found to be a reasonable predictor of testicular weight and served to rapidly select sexually mature males for study, and a total testicular volume (left and right combined) of >20 ml correlated with the histological appearance of maturity. CONCLUSION: Based upon this preliminary exploratory study, the initial simple measurement of testicular volume by orchidometry may provide a non-invasive alternative approach for assessing the sexual maturity of male cynomolgus monkeys in research colonies or during toxicology studies that will require more thorough validation.
Asunto(s)
Ciencia de los Animales de Laboratorio/métodos , Macaca fascicularis/crecimiento & desarrollo , Maduración Sexual , Testículo/anatomía & histología , Animales , Peso Corporal , Epidídimo/anatomía & histología , Epidídimo/crecimiento & desarrollo , Ciencia de los Animales de Laboratorio/instrumentación , Macaca fascicularis/anatomía & histología , Masculino , Tamaño de los Órganos , Palpación , Próstata/anatomía & histología , Próstata/crecimiento & desarrollo , Estudios Retrospectivos , Desarrollo Sexual , Pruebas de Toxicidad Aguda/veterinariaRESUMEN
Belimumab is a fully human monoclonal antibody antagonist for soluble B-lymphocyte stimulator, and is a potential therapeutic for various autoimmune disorders. To support clinical use, belimumab was administered intravenously to pregnant cynomolgus monkeys every 2 weeks throughout gestation at dosages of 5 and 150 mg/kg. Fetuses were delivered by C-section on Gestation Day 150 from one-half of the mothers, and evaluated for teratologic effects (external, visceral, skeletal, and heart), pharmacodynamics (PD) and toxicokinetics (TK). Remaining mothers delivered their infants naturally, enabling extensive assessment of PD and TK during a 1-year postnatal period. Effects attributed to belimumab were limited to the expected pharmacology, primarily decreased numbers of B-lymphocytes in peripheral blood of mothers and infants, and in fetal lymphoid tissues. Infants demonstrated full recovery upon cessation of exposure. In conclusion, belimumab was well tolerated at pharmacologically active dose levels in pregnant cynomolgus monkeys and their infants after exposure throughout pregnancy.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Factor Activador de Células B/inmunología , Feto/efectos de los fármacos , Macaca fascicularis/embriología , Macaca fascicularis/crecimiento & desarrollo , Animales , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Área Bajo la Curva , Linfocitos B/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Inmunosupresores/inmunología , Inmunosupresores/farmacología , Activación de Linfocitos/efectos de los fármacos , Intercambio Materno-Fetal/efectos de los fármacos , Intercambio Materno-Fetal/inmunología , Tasa de Depuración Metabólica , Embarazo , Factores de TiempoRESUMEN
BACKGROUND: Natalizumab is a humanized monoclonal IgG4 antibody to human alpha4 integrin that blocks the interaction of alpha4beta1 and alpha4beta7 integrins with their ligands, including fibronectin, vascular cell adhesion molecule-1, and mucosal addressin cellular adhesion molecule-1. Because alpha4 integrins and their ligands are widely involved in mammalian development, lymphopoeisis, and hematopoiesis, natalizumab may interfere with these processes. METHODS: The effects of prenatal exposure to natalizumab on postnatal development were assessed in cynomolgus monkeys at doses of 0 and 30 mg/kg administered intravenously every other day from gestational day (GD) 20 to 70 or GD 20 to term. Infants were delivered by natural birth and evaluated for general health, survival, development, and immunological structure and function at 12 or 18 months. RESULTS: An increase in abortions was seen in the first cohort of natalizumab-treated dams (39.3 vs. 7.1% in the controls) but not in the second cohort (33.3, 37.5%). Infants in the term treatment group had elevated lymphocyte ( approximately 150%) and nucleated red blood cell counts ( approximately 400%), consistent with the pharmacological effect of natalizumab, and reductions in platelet counts ( approximately 28%), which were reversible following clearance of natalizumab. No anemia was observed. Infants in the term treatment group had significantly increased spleen weights at 12 months but not at 18 months. All other experimental observations in infants from natalizumab-treated dams were comparable with those of controls. CONCLUSION: Natalizumab had no adverse effects on the general health, survival, development, or immunological structure and function of infants born to dams treated with natalizumab during pregnancy.