Harmonization of criteria and terminology in fetal rat skeletal evaluations.

BACKGROUND: A survey of laboratories in North American and Europe that routinely conduct fetal skeletal examinations was performed with the purpose of (1) understanding current terminology used for classifying skeletal findings in developmental toxicity (DT) studies and (2) understanding the criteria used to identify relatively common findings that sufficiently deviate from normal. The goal was to promote terminology harmonization and improve interlaboratory consistency in the criteria used to identify developmental anomalies. METHODS: The survey, designed based on terminology for developmental anomalies recommended by an international collaboration (Makris et al., Congenital Anomalies, 2009;49(3):123-246), was conducted by a subgroup (authors of this publication) of the Royal Society of Biology's International Register of Fetal Morphologists (IRFM). RESULTS: Individual and summarized anonymized responses are provided here. The authors, who are expert fetal morphologists with experience performing fetal examinations, reviewed the responses and generated recommendations on preferred terminology and criteria for determining when morphological variations deviate from normal and warrant recording of the findings for skeletal observations in Sprague Dawley (SD) fetal rats. The objective of these recommendations is to complement Makris et al. (Congenital Anomalies, 2009;49(3):123-246). CONCLUSION: The broad application will improve interlaboratory harmonization of recording fetal skeleton findings in developmental toxicity studies intended for regulatory submissions, including SEND (Standard for Exchange of Nonclinical Data).

GSK2245035, a TLR7 agonist, Does Not Increase Pregnancy Loss in Cynomolgus Monkeys.

GSK2245035, a small molecule Toll-like Receptor 7 (TLR7) agonist developed for immunomodulatory treatment for allergic airways disease, aimed to reduce Th2 and enhance Th1/Treg responses to aeroallergens via the local induction of type I interferons (IFNs). GSK2245035 demonstrated selectivity for potent release of type I IFNs compared to TNF-α and IL-6, with dose dependent increases in the interferon inducible chemokine, IP-10, in the nasal compartment. Implantation and parturition require pro-inflammatory processes including IFNs, Interferon Stimulated Genes, TNFα and IP-10 while pregnancy requires immune regulation to maintain maternal fetal immune tolerance, and recombinant type I IFNs induced abortions in monkeys. Due to its mechanism of action, GSK2245035 was studied at pharmacologically and clinically relevant doses in a monkey pregnancy model. Monkeys received 0, 3 or 30 ng/kg/week GSK2245035 intranasally once weekly, from Day 20 postcoitum through Day 63 postpartum. Although systemic IFN-α and IP-10 levels were approximately 14.8 or 40 -fold (respectively) above predose levels at 3 or 30 ng/kg/week, respectively, there were no effects on pregnancy and infant outcome. Non-adverse effects included increased incidence of nasal discharge, increased maternal body temperature at 30 ng/kg/week and dose-dependent increases in maternal IP-10 and IFN-α and decreased infant anti-KLH IgM and IgG titers following KLH immunization at ≥3 ng/kg/week, relative to controls. Potentially, lower IFN-α and IP-10 levels as well as once-weekly intranasal dosing vs daily subcutaneous or intramuscular dosing with recombinant type I IFNs could explain the lack of pregnancy effects; however, there was an undesired impact on offspring immune function.

Benzofuranyl ureas with potent cardiovascular teratogenicity in rats.

Studies of embryo-fetal development in rats were conducted with two 5-lipoxygenase inhibitors. SB-202235 (1,000 mg/kg/day) or SB-210661 (50, 100, or 500 mg/kg/day) was administered orally by gavage to female rats on days 6-17 postcoitus (pc) or days 7-16 pc. SB-202235 (1,000 mg/kg/day) and SB-210661 (100 mg/kg/day) reduced maternal body weight gain for the treatment period by 16% and 21%, respectively, relative to controls. SB-202235 (1,000 mg/kg/day) or SB-210661 (50 or 100 mg/kg/day), did not affect numbers of resorptions, dead or live fetuses/litter, but 500 mg/kg/day of SB-210661 caused 100% embryo lethality. SB-202235 (1,000 mg/kg/day) and SB-210661 (50 and 100 mg/kg/day) reduced fetal body weight by 15-30% and produced extensive cardiovascular malformations, as well as diaphragmatic hernias. SB-210661 also caused thymic abnormalities and cryptorchidism. Cardiovascular defects included abnormalities in aorticopulmonary septation, the aortic arch, pulmonary trunk, and ventricular septal defects are discussed relative to comparable human syndromes of cardiovascular malformation.

Spontaneous and induced alterations in the cardiac membranous ventricular septum of fetal, weanling, and adult rats.

Alterations of the cardiac membranous ventricular septum were studied using macrodissection, scanning electron and light microscopy of fetal, weanling, and adult Sprague-Dawley rats. Membranous ventricular septal defects (VSDs) were observed in 2.0% of fetuses on day 21 postcoitus (pc) but not in weanling or adult rats. The most common observation was a nonpatent depression in the membranous septum with an incidence of 38.1, 10.5, 4.3% for fetuses on days 17, 19, or 21 pc, respectively, 11.8% for weanlings, and 9.1% for adults. VSDs were characterized by a split in the endocardial cushion cells in the interventricular component of the membranous septum. Nonpatent depressions were characterized by a split in the endocardial cushion cells in the atrioventricular component of the septum, and they persisted postnatally as a blind-ended diverticulum directed above the tricuspid valve. The cardiovascular teratogens, trimethadione and trypan blue, produced in fetuses nonpatent depressions and VSDs morphologically similar to untreated fetuses. Maternal diet restriction (25% of controls) lowered fetal (day 21 pc) body weight by 47% but did not affect the incidence of ventricular septal alterations, suggesting that intrauterine growth retardation is not necessarily associated with alterations in the development of the ventricular septum. We conclude that neither VSDs nor nonpatent depressions in Sprague-Dawley rats affect postnatal survival and that VSDs close spontaneously during neonatal life.