Prenatal developmental toxicity study of the basic rubber accelerator, 1,3-di-o-tolylguanidine, in rats

Pregnant rats were given 1,3-di-o-tolylguanidine (DTG) by gavage at 0, 10, 20 or 40 mg/kg bw/day on days 6–19 of pregnancy and the pregnancy outcome was determined on day 20 of pregnancy. At 40 mg/kg bw/day, deaths were observed in four out of 24 females. The incidences of females showing mydriasis at 20 and 40 mg/kg bw/day and showing decreased locomotor activity at 40 mg/kg bw/day were significantly increased. Alopecia, bradypnea, prone position and tremor were also observed at 40 mg/kg bw/day. The maternal body weight gain at 20 and 40 mg/kg bw/day and food consumption at 40 mg/kg bw/day were significantly reduced. A significantly decreased weight of the gravid uterus, increased incidence of postimplantation loss, decreased number of live fetuses, and lowered weights of fetuses and placentae were found at 40 mg/kg bw/day. The incidences of the total number of fetuses with external malformations at 40 mg/kg bw/day and with skeletal malformations at 20 and 40 mg/kg bw/day were significantly increased. Significantly higher incidences of fetuses with brachydactyly and short tail and defects of caudal vertebrae, phalanges and metacarpals were observed at 40 mg/kg bw/day. Delayed ossification was also noted at 40 mg/kg bw/day. The data indicate that DTG is teratogenic at maternal toxic doses and the NOAELs of DTG for maternal and developmental toxicity are 10 mg/kg bw/day in rats.     

In vivo and in vitro investigations of the effects of the antimalarial drug dihydroartemisinin (DHA) on rat embryos

Artemisinin derivatives are clinically effective and safe antimalarials, but are not recommended during the first trimester of pregnancy because of the resorptions and abnormalities seen in animal reproduction studies. Understanding how, when and what toxicity occurs is crucial to any assessment of clinical relevance. Previously, DHA has been shown in the rat whole embryo culture (WEC) to primarily affect primitive red blood cells (RBCs) causing subsequent tissue damage and dysmorphogenesis. To verify the primary target of DHA in vivo and to detect consequences induced by early damage on embryo development, pregnant female rats were orally treated on gestation days (GD) 9.5 and 10.5 with 7.5 or 15 mg/kg/day DHA and caesarean sectioned on GD11.5, 12.5, 13.5, 15 and 20. A parallel in vitro WEC study evaluated the role of oxidative damage and examined blood islands and primitive RBCs.

In accordance with the WEC results, primitive RBCs from yolk sac hematopoiesis were the target of DHA in vivo. The resulting anemia led to cell damage, which depending on its degree, was either diffuse or focal. Embryonic response to acute anemia varied from complete recovery to malformation and death, depending on the extent of cell death. Malformations occurred only in litters with embryonic deaths. DHA induced low glutathione levels in RBCs, indicating that oxidative stress may be involved in artemisinin toxicity; effects were extremely rapid, with altered RBCs seen as early as GD10.

In establishing the relevance of these findings to humans, one should consider differences in the development of rodents and humans. While yolk sac hematopoiesis occurs similarly in the two species, early placentation and extent of exposure differ. In particular, early hematopoiesis takes only 7 days in rats (during which RBCs expand in a clonal fashion) compared with 6 weeks in humans; thus the susceptible period in relation to the duration of exposure to an artemisinin-based treatment may be substantially different.     

宁泌泰胶囊对小鼠胚胎和胎仔发育毒性研究

摘 要 目的：评价口服给予宁泌泰胶囊对妊娠小鼠的母体毒性、胚胎 胎仔发育毒性和致畸性。方法: 将交配成功后的雌性小鼠于孕期第6～15天连续经口灌胃给予宁泌泰胶囊10 d,剂量为5.2,10.4,20.7 g·kg^-1·d^-1,对照组给予生理盐水。实验过程中定期记录体质量;于妊娠第18天解剖孕鼠,记录黄体数、活胎数、死胎数、吸收胎数;观察胎仔的外观形态,记录体重,并检查骨骼和内脏。结果: 孕鼠及胚胎、胎仔发育的上述各项观察指标未发现明显异常,与对照组比较差异无显著统计学意义。结论:在本实验条件下,宁泌泰胶囊未发现明显的母体毒性与胚胎 胎仔发育毒性。     

Prevention of valproic acid-induced neural tube defects by sildenafil citrate

This study was undertaken to test the effects of sildenafil citrate (SC), a type 5 phosphodiesterase inhibitor, on valproic acid (VPA)-induced teratogenesis. On gestation day (GD) 8, ICR (CD-1) mice were treated by gastric intubation with SC at 0 (vehicle), 1.0, 2.5, 5.0 or 10 mg/kg. One hour later, animals received a teratogenic dose of VPA (600 mg/kg) or vehicle. Developmental endpoints were evaluated near the end of gestation. Twenty-eighth percent of fetuses exposed to VPA had neural tube defects (exencephaly). Pretreatment with SC at 2.5, 5.0 or 10 mg/kg significantly reduced the rate of VPA-induced exencephaly to 15.9%, 13.7%, and 10.0%, respectively. Axial skeletal defects were observed in 75.8% of VPA-exposed fetuses. Pre-treatment with SC at 10 mg/kg, but not at lower doses, significantly decreased the rate of skeletally affected fetuses to 61.6%. These results show that SC, which prolongs nitric oxide (NO) signaling action protects from VPA-induced teratogenesis.     

First trimester exposure to topiramate and the risk of oral clefts in the offspring: A systematic review and meta-analysis

Topiramate (TPM) is an increasingly used drug during childbearing ages for treatment of epilepsy, migraine, and appetite suppression as well as for off-label indications such as sleep and psychiatric disorders. Presently, while some reports suggested an increased risk of oral cleft (OC), these reports are balanced by studies that could not confirm such association. We conducted a meta-analysis of all studies reporting on women exposed to TPM during pregnancy. Of the 2327 publications reviewed, 6 articles met the inclusion criteria including 3420 patients and 1,204,981 controls. The odd ratio (OR) of OC after the first trimester exposure to TPM exposure was 6.26 (95% confidence interval: 3.13–12.51; P = 0.00001). This study provides strong evidence that TPM is associated with an increased risk of OC in infants exposed to TPM during embryogenesis and should lead to a careful review of TPM use in women of reproductive ages.     

Folic acid reduces the ethanol-induced morphological and behavioral defects in embryonic and larval zebrafish (Danio rerio) as a model for fetal alcohol spectrum disorder (FASD)

The objective of this work was to determine whether folic acid (FA) reduces the embryonic ethanol (EtOH) exposure induced behavioral and morphological defects in our zebrafish fetal alcohol spectrum disorder (FASD) model. Teratogenic effects, mortality, the excitatory light-dark locomotion (ELD), sleep (SL), thigmotaxis (TH), touch sensitivity (TS), and optomotor response (OMR) tests were evaluated in larvae (6–7 days post-fertilization) using four treatment conditions: Untreated, FA, EtOH and EtOH + FA. FA reduced morphological defects on heart, eyes and swim bladder inflation seen in EtOH exposed fish. The larvae were more active in the dark than in light conditions, and EtOH reduced the swimming activity in the ELD test. EtOH affected the sleep pattern, inducing several arousal periods and increasing inactivity in zebrafish. FA reduces these toxic effects and produced more consistent inactivity during the night, reducing the arousal periods. FA also prevented the EtOH-induced defects in thigmotaxis and optomotor response of the larvae. We conclude that in this FASD model, EtOH exposure produced several teratogenic and behavioral defects, FA reduced, but did not totally prevent, these defects. Understanding of EtOH-induced behavioral defects could help to identify new therapeutic or prevention strategies for FASD.     

Sequence of articles

Endocrine disrupting chemicals (EDCs) have been emphasized due to their threats in fertility, intelligence, and survival. For the last decade, many researchers have investigated EDC-health outcome. However, EDC responses in human were not clearly clarified through experimental and epidemiological data. Therefore, considering particular status of EDC endpoints, we suggest that one of the best ways to prevent unknown health risks from EDCs is to perform exposure monitoring or to do surveillance for EDC release into the environment. For this purpose, this review considers exposure status of EDCs, and EDC-related health risks, focusing on the mainly highlighted EDCs, such as dioxins/PCBs, DDT/DDE, bisphenol A, phthalates, alkylphenols, and phytoestrogens. We also reviewed tobacco, a mixed source of EDC-related endocrine disorders.     

Developmental toxicity of albendazole and its three main metabolites in zebrafish embryos

Albendazole (ABZ) is used as an anthelmintic drug in humans and animals. ABZ has been shown to cause developmental toxicity in experimental animals, however it is not clear if this is caused by the parent compound or a metabolite. Zebrafish embryos were exposed from 1 to 144 hpf (hours post fertilization) to investigate the developmental toxicity of ABZ, the first metabolite albendazole sulphoxide and the subsequent metabolites albendazole sulphone (ABZSO₂) and albendazole-2-aminosulphone (ABZSO₂NH₂). The results showed that ABZ caused malformations of head and tail and embryonic lethality from 0.3 μM. In contrast, the metabolites did not display developmental toxicity at any tested concentration. Dechorionation did not influence the developmental toxic potential of ABZ and ABZSO, indicating that bioavailability was not a limiting factor. Chemical analysis showed that at sublethal concentrations, most of ABZ was metabolized to ABZSO. The results demonstrate that in zebrafish embryos ABZ rather than ABZSO displays developmental toxicity.     

Anticonvulsant profile and teratogenicity of 3,3-dimethylbutanoylurea: a potential for a second generation drug to valproic acid

Purpose: The purpose of this study was to evaluate the anticonvulsant activity and teratogenic potential of branched aliphatic acylureas represented by isovaleroylurea (IVU), pivaloylurea (PVU) and 3,3‐dimethylbutanoylurea (DBU), as potential second‐generation drugs to valproic acid (VPA). Methods: The anticonvulsant activity of IVU, PVU, and DBU was determined in mice and rats utilizing the maximal electroshock seizure (MES) and the pentylenetetrazole (scMet) tests. The ability of DBU to block electrical‐, or chemical‐induced seizures was further examined in three acute seizure models: the psychomotor 6 Hz model, the bicuculline and picrotoxin models and one model of chronic epilepsy (i.e., the hippocampal kindled rat model). The induction of neural tube defects (NTDs) by IVU, PVU, and DBU was evaluated after i.p. administration at day 8.5 of gestation to a mouse strain highly susceptible to VPA‐induced teratogenicity. The pharmacokinetics of DBU was studied following i.v. administration to rats. Results: DBU emerged as the most potent compound having an MES‐ED ₅₀ of 186 mg/kg (mice) and 64 mg/kg (rats) and an scMet‐ED ₅₀ of 66 mg/kg (mice) and 26 mg/kg (rats). DBU underwent further evaluation in the hippocampal kindled rat (ED ₅₀ = 35 mg/kg), the psychomotor 6 Hz mouse model (ED ₅₀ = 80 mg/kg at 32 mA and ED ₅₀ = 133 mg/kg at 44 mA), the bicuculline‐ and picrotoxin‐induced seizure mouse model (ED ₅₀ = 205 mg/kg and 167 mg/kg, respectively). In contrast to VPA, DBU, IVU, and PVU did not induce a significant increase in NTDs as compared to control. DBU was eliminated by metabolism with a half‐life of 4.5 h. Conclusions: DBU's broad spectrum and potent anticonvulsant activity, along with its high safety margin and favorable pharmacokinetic profile, make it an attractive candidate to become a new, potent, and safe AED.     

Fetal cartilage malformation by intravenous administration of indium trichloride to pregnant rats

The effects of indium on bone and cartilage development in rat fetuses were examined. Pregnant Sprague Dawley (SD) rats were treated with indium trichloride (0.1, 0.2, or 0.3 mg/kg) by single intravenous administration on Day 10 of gestation, and their fetuses were examined on Day 21. Half of each litter was prepared for skeletal examinations using a skeletal double-staining technique to allow evaluation of cartilage as well as bone. Dose-related increased incidences of external and skeletal fetal malformations occurred at doses of 0.2 mg/kg or more. The incidences of cartilage malformations in the vertebrae, ribs, and forepaw phalanges were significantly increased at 0.3 mg/kg. Malformations of the axial bone were accompanied by cartilage malformations. It was concluded from these results that indium produced cartilage malformations, that were considered to be the underlying cause for the majority of fetal skeletal malformations observed in rats in this study.