Search

This update Version 2 of the Terminology of Developmental Abnormalities in Common Laboratory MammalsVersion 1 by Wise et al. 1997 incorporates improvements and enhancements to both content and organization of the terminology, to enable greater flexibility in its application, while maintaining a consistent approach to the description of findings. The revisions are the result of an international collaboration among interested organizations, advised by individual experts and the outcomes of several workshops. The terminology remains organized into tables under the broad categories of external, visceral, and skeletal observations, following the manner in which data are typically collected and recorded in developmental toxicity studies. This arrangement of the tables, as well as other information provided in appendices, is intended to facilitate the process of specimen evaluation at the laboratory bench level. Only the commonly used laboratory mammals i.e., rats, mice, rabbits are addressed in the current terminology tables. The inclusion of other species that are used in developmental toxicity testing, such as primates, is considered outside the scope of the present update. Similarly, categorization of findings as, for example, “malformation” or “variation” remains unaddressed, in accordance with the overall principle that the focus of this document is descriptive terminology and not diagnosisinterpretation. The skeletal terms have been augmented to accommodate cartilage findings. Birth Defects Res Part B86:227–327, 2009. © 2009 WileyLiss, Inc.

BACKGROUND: Lasofoxifene is a nonsteroidal selective estrogen receptor modulator (SERM) with greater than 100‐fold selectivity against all other steroid receptors and is a potentially superior treatment for postmenopausal osteoporosis. The purpose of this study was to evaluate the effects of lasofoxifene on male reproduction in rats in light of the known effects of estrogen modulating compounds on male reproductive ability. METHODS: Lasofoxifene was administered to adult male rats at doses of 0.1, 1, 10, and 100 mg/kg for 66–70 consecutive days. After 28 days of dosing, male rats were cohabited with untreated female rats. Female rats were euthanized on gestation day 14 and a uterine examination was carried out for evaluation of reproductive parameters and embryo viability. Male rats were euthanized after 66–70 days of dosing and epididymal sperm motility and concentration were assayed. The testes, epididymides, prostate, and seminal vesicles were weighed and microscopically examined. RESULTS: The duration of cohabitation was increased for 100 mg/kg males by 0.7 days. The number of males copulating and the number of implantation sites produced per copulation were reduced in the 10 and 100 mg/kg groups. Weights of the seminal vesicles and epididymides were reduced for all groups, although the testes weight and epididymal sperm motility and concentration were not affected by treatment. There were no microscopic findings in the male reproductive tissues. CONCLUSION: The changes in male fertility and reproductive tissue weights after exposure to lasofoxifene are consistent with those previously described for estrogen receptor‐modulating compounds. Birth Defects Res B 71:142–149, 2004. © 2004 Wiley‐Liss, Inc.

Epididymal sperm was examined using the Hamilton-Thorne Sperm analyzer (HTM-IVOS, version 10.6) in male rats treated with known male reproductive toxicants that act by different mechanisms to detect effects on sperm motion. Three agents known to produce changes in sperm motion at high exposure levels were administered at lower levels. Ethylene glycol monoethyl ether (EGEE), sulfasalazine (SASP), and 2,5-hexandione (2,5-HD) were administered by oral gavage to adult male Sprague-Dawley rats at 250 or 500 mg/kg/day, at 300 or 600 mg/kg/day, or at 100 or 250 mg/kg/day, respectively. The males were treated with EGEE, SASP, and 2,5-HD for 35, 28, and 28 days, respectively. The males treated with EGEE and SASP were mated with untreated females to assess male fertility. All males were examined for body weight, testicular and epididymal weight, epididymal sperm count, and sperm motion. The sperm motion parameters included percentage of motile sperm, percentage of progressively motile sperm (progressive motility), curvilinear velocity (VCL), average path velocity (VAP), straight line velocity (VSL), amplitude of lateral head displacement (ALH), beat cross frequency (BCF), linearity (LIN), and straightness (STR). For the male rats treated with SASP, no treatment-related effects on percentages of motile sperm or sperm count were observed despite impaired male fertility. However, abnormal motion of epididymal sperm from the SASP treated males was detected by a significant reduction in mean progressive motility, VAP, and ALH, and an increase in BCF and STR. For the males treated with 2,5-HD for 4 weeks, most parameters generated by the HTM-IVOS indicated decreased sperm motion despite no remarkable changes in testicular weight, epididymal weight, or sperm count. In the EGEE-treated males at 250 mg/kg/day for 5 weeks, abnormal motion of epididymal sperm was detected by decreased progressive motility and increased BCF, although there were no treatment-related effects on testicular weight or male fertility. Progressive motility was decreased in all treated groups and the difference from the control value was of the greatest magnitude among the sperm motion parameters generated by the HTM-IVOS. Velocity parameters (VAP, VSL, VCL) responded sensitively to abnormal sperm motion in the SASP and 2,5-HD studies. In spite of decreased sperm motion, BCF values were significantly increased in all treated groups except the 7-week EGEE high-dose group, where there were no motile sperm to evaluate. ALH was significantly decreased in the treated groups in which remarkable effects on sperm motion were noted. There were no significant changes in ALH at the low-dose of EGEE at which only mild effects on sperm motion were observed. STR was increased for epididymal sperm from the males treated with SASP when compared with the controls. For the males treated with EGEE and 2,5-HD, however, STR was decreased when compared with the controls. There were no significant differences in LIN in any of the groups treated with SASP, in which remarkably reduced sperm motion was detected by the other parameters. In conclusion, among the parameters generated by the HTM-IVOS, progressive motility was significantly decreased in all treated groups and the most valuable for detecting slight changes in sperm motion induced by these three different target toxicants. Further investigation with a larger set of compounds is needed to evaluate which IVOS parameters are the most sensitive in detecting motion changes.

Abstract: This paper is the first version of a Japanese glossary of terms for structural developmental abnormalities in laboratory animals, mainly rats, mice and rabbits. This is a translation of the glossary entitled Terminology of Developmental Abnormalities in Common Laboratory Mammals that was edited by the International Federation of Teratology Societies (IFTS) Committee on International Harmonization of Nomenclature in Developmental Toxicology (IFTS glossary). The purpose of the present Japanese glossary is to provide a common vocabulary, terms and definitions in the description of abnormalities observed in reproductive and developmental toxicity studies. The glossary contains 868 observations, synonyms, related terms, definitions of the abnormalities and non‐preferred terms for external, visceral and skeletal abnormalities in fetuses or neonates of laboratory animals. Modifying terms used repeatedly in the glossary (e. g., absent, atresia) are listed separately in Appendix A, and syndrome names that are generally known are listed in Appendix B. Translation was made into Japanese based on the following: 1) Observations are translated in order of organ/finding (e. g., thymus/absent, maxilla/fused) with exception of the terms in common use, 2) Words are appended where appropriate, when literal translation does not provide an adequate description, 3) A supplementary explanation is appended as an “annotation”, where appropriate, 4) Among the synonyms or related terms, the terms listed in Appendix A or the same Japanese translations as the observations are not described repeatedly, and 5) Non‐preferred terms are not literally translated, and only those terms which are considered as adequate as Japanese are described. Suggestions, questions, and additions are welcomed on the Japanese terms and translations in the glossary. Revisions of the Japanese glossary are planned based on the comments received.

ABSTRACTThe Non‐Clinical Evaluation Subcommittee of the Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA) collected historical control data from developmental and reproductive toxicity studies, which were conducted by the member companies and associated contract laboratories between 1986 and 1993. The data include spontaneous incidences of fetal morphological alterations and other observations made at terminal cesarean sections in rats, rabbits and mice. In addition, mating and natural delivery data in rats are also provided. There were strain differences as well as inter‐laboratory variations in the incidences of fetal visceral and skeletal alterations for both rats and rabbits. These inter‐laboratory variations were attributed to differences in the selection of observation parameters, observation criteria and classification of the findings.