Teratogenic effects of acetaldehyde in the rat

Acetaldehyde, the proximal metabolite of ethanol, was administered intraperitoneally in single and triple doses (50, 75, 100 mg/kg) to pregnant CF rats on days 10, 11 and 12 of gestation and fetuses were collected on day 21. Besides significant fetal resorptions, malformations were found which included edema, microcephaly, micrognathia, micromelia, hydrocephaly, exencephaly, hemorrhages etc. Somatometric measurements of fetuses (i.e. crown rump length, transumbilical distance and tail length) revealed significant growth retardation. Alizarin red-stained skeletal preparations showed considerable stunting. The placental weight and umbilical cord length were also significantly reduced. The close similarity of the pattern of acetaldehyde-induced fetal malformations with those resulting from maternal alcohol consumption during pregnancy is suggestive of the possible implication of acetaldehyde in the fetal alcohol syndrome.     

Teratogenic potential of the mycotoxin, citreoviridin, in rats

Citreoviridin produced by the fungus Penicillium citreo-viride was administered by gavage to groups of 9–16 pregnant Fisher 344 rats either on days 8–11 (group A) or on days 12–15 (group B) of gestation. Doses of 0, 5, 10 or 15 mg/kg body weight were given daily in a constant volume of 1 ml/kg body weight in dimethylsulphoxide. Six rats in each high-dose group died during the dosing period. Compared with control groups, mean daily feed consumption was significantly reduced in the 10- and 15-mg/kg animals in both groups A and B. Weight gain during pregnancy in both groups was reduced with increasing dosage; dams in control groups gained an average of 75 g/rat compared with 30 g overall gain in group A, or 9 g overall gain in group B, both at a dose of 15 mg/kg. Male and female pup weights were reduced with increasing dosage for both groups A and B. The post-implantation foetal loss rate was significantly increased to 33% in group A high-dose animals. The main effect of citreoviridin on skeletal development in both groups A and B was one of retardation. No internal abnormalities were observed in group A pups. Some smaller than average pups from dams in group B that were treated with the high dose of citreoviridin had slightly dilated lateral ventricles of the brain and, in some cases, a palate defect. The foetotoxicity induced by citreoviridin was observed only at doses that also induced maternal toxicity.     

Teratogenic potential of noise in mice and rats.

The effect of noise on the developing embryo was studied in mice and rats. The first experiment was designed to determine whether noise associated with the routine husbandry in a large animal facility plays a role in producing “spontaneous” malformations. From Days 1 through 18 of gestation one group of mice was exposed only to self-generated noise [30–45 dB(A)] and another group, housed in regular animal quarters, was exposed to the usual noise level [50–60 dB(A)]. The reduction in noise level did not decrease the incidence of malformations detected but significantly decreased maternal weight gain through pregnancy. The second experiment involved exposure of mice on Days 3–6, 7–10, or 11–14 of gestation and of rats on Days 6–15 of gestation to 100 dB of white noise (20-20,000 Hz). Mice exposed on Days 3–6 and 11–14 gained significantly less weight through pregnancy (p < 0.01 and 0.05) and the incidence of resorptions was significantly increased (p < 0.01) upon comparison with the control mice. Neither fetal weight nor the incidence of malformed offspring was significantly affected by exposure to noise during gestation. In rats, maternal weight gain was significantly decreased but developmental toxicity was not observed in the experimental group. Results of this study indicated that white noise had maternal and fetotoxic effects in mice, little effect in rats, and was not teratogenic in either species.     

Teratogenic evaluation of mancozeb in the rat following inhalation exposure

Crl:CD rats were exposed (whole body) to mancozeb by inhalation at 0, 1, 17, 55, 110, 890, or 1890/500 mg/m3 for 6 hr/day from Day 6 through 15 of gestation (sperm-positive vaginal smear considered Day 1). Dams were killed 1 day prior to natural delivery and fetuses were examined externally, viscerally, and skeletally for any alterations. Maternal toxicity, as evidenced by significantly decreased body weight gain, hindlimb paralysis, general debilitation, and death or termination in extremis, was noted among rats exposed to mancozeb at concentrations of 500 to 1890 mg/m3. Dams from the 55 and 110 mg/m3 groups exhibited decreased body weight gain and hindlimb weakness. There was no maternal toxicity for dams exposed at a concentration of 17 mg/m3. Embryofetal toxicity, as evidenced by a significantly increased incidence of totally resorbed litters, external hemorrhage, and wavy ribs, was noted at concentrations of 55 mg/m3 and above. The embryofetal toxicity occurred only at concentrations toxic to the dam. Among the groups exposed to mancozeb, the incidence of major malformations was not dose related. Hence, under the test conditions of this study, mancozeb was not found to be teratogenic and produced no toxicity unique to the conceptus.     

Teratogenic assessment of three methylated hydrazine derivatives in the rat

The embryotoxicity and teratogenicity of methylhydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine were investigated with pregnant Fischer-344 rats. The compounds were administered ip on d 6-15 of pregnancy. A dose-dependent reduction in maternal weight gains occurred for all three compounds. A dose-related teratogenic effect did not occur for any of the three compounds. Embryotoxicity, manifested as reduced 20-d fetal weights, occurred only in the 1,1-dimethylhydrazine and 1,2-dimethylhydrazine high-dose treatment groups. The results indicate that none of the three methylated hydrazine derivatives are selectively embryotoxic or teratogenic in the rat.     

Teratogenic evaluation of 1,1,3,3-tetrabutylurea in the rat following dermal exposure

The teratogenic potential of 1,1,3,3-tetrabutylurea (TBU) was evaluated in the Crl:CD(SD)BR rat. Doses of 25, 50 or 100 mg TBU/rat/day in 0.5 ml dimethyl phthalate were applied to the shaven dorsal skin on days 6-15 of gestation, the day on which a sperm-positive vaginal smear was present being designated day 1. The rats were killed 1 day before natural delivery and the foetuses were examined for external development, structure and integrity of internal tissues and organs, and skeletal development. No maternal effects were seen in rats exposed to 25 mg TBU, but skin irritation and a reduction in maternal body-weight gains were seen in rats treated with either 50 or 100 mg/day, the effects being more pronounced in the 100-mg/day group. In the latter group, the number of pregnancies maintained was reduced and the number of resorptions per litter, calculated only on the litters with resorptions, was increased. Foetuses derived from the females treated with 100 mg/day were slightly smaller than the controls but were structurally normal. The outcome of pregnancy was unaltered in rats given either 25 or 50 mg TBU/day. No increase in malformed foetuses was observed in any of the test groups. Under the conditions of this study, TBU was not teratogenic when applied dermally to rats at doses up to 100 mg/day.     

Teratogenic effects of the endothelin receptor antagonist L-753,037 in the rat

The studies presented in this paper were undertaken to investigate the effects of L-753,037, a balanced endothelin receptor antagonist with similar affinity for the ET(A) and ET(B) receptors (Ki = 0.03 to 0.12 nM and 0.1 to 3.33 nM, respectively), when administered to pregnant female rats by oral gavage, on the development, growth, maturation, and reproductive performance of the F1 generation. Following embryonic exposure to L-753,037, profound craniofacial, cardiovascular, and viscerocranial malformations were noted in the F1 generation. All of the affected organs are derived, in part, from cranial neural crest cells predominantly originating from the posterior midbrain through the hindbrain and destined for the pharyngeal arches. In contrast, cranial structures derived from the paraxial mesoderm (i.e., basisphenoid) were of normal shape and size. There were no apparent effects on enteric neural crest cell derivatives. Based on the phenotype of affected fetuses and their similarity to fetuses with gene knockouts of ET-1 or the ET(A) receptor, the observed alterations are considered to be a pharmacologically mediated class effect on cranial neural crest cells. The phenotype observed suggests that ET(A) receptor antagonism may have specific effects on cranial neural crest cell migration and/or proliferation.     

Teratogenic evaluation of 1,4-dichlorobutene-2 in the rat following inhalation exposure

The teratogenic potential of 1,4-dichlorobutene-2 (1,4-DCB) was evaluated in the rat. From inhalation toxicity studies, particularly ongoing lifetime studies, exposure levels of 0, 0.5, and 5.0 ppm were selected. Rats were exposed for 6 hr per day on Days 6 through 15 of gestation (sperm-positive vaginal smear considered Day 1). Female rats were killed 1 day prior to natural delivery and fetuses were examined for external development, structure and integrity of internal tissues and organs, and skeletal development. The only clinical sign of toxicity observed among rats exposed to 1,4-DCB, was a significantly-reduced rate of weight gain seen at the 5.0-ppm level. 1,4-DCB exposure did not change either the number of pregnant rats or the number of implantation sites, resorption sites, and fetuses per female. Treatment did not affect embryonal development as measured by fetal weight and crown-rump length, or by gross external, visceral, and skeletal examination of the fetuses. Under the test conditions of this study, 1,4-DCB was neither embryotoxic nor teratogenic.     

Action of quercetin on glycogen catabolism in the rat liver

1. The influence of quercetin on glycogen catabolism and related parameters was investigated in the isolated perfused rat liver and subcellular systems. 2. Quercetin stimulated glycogenolysis (glucose release). This effect was already evident at a concentration of 50 µ M maximal at 300 µ M and declined at higher concentrations. Quercetin also stimulated oxygen consumption, with a similar concentration dependence. 3. Lactate production from endogenous glycogen (glycolysis) was diminished by quercetin without significant changes in pyruvate production. 4. Quercetin did not inhibit glucose transport into cells but decreased intracellular sequestration of [5- 3 H]glucose under conditions of net glucose release. 5. In isolated mitochondria, quercetin diminished the energy transduction efficiency. It also inhibited several enzymatic activities, e.g. the K + -ATPase/Na + -ATPase of plasma membrane vesicles and the glucose 6-phosphatase of isolated microsomes. 6. No significant changes of the cellular contents of AMP, ADP and ATP were found. The cellular content of glucose 6-phosphate, however, was increased (3.12-fold). 7. Some of the effects of quercetin (glycogenolysis stimulation) can be attributed to its action on mitochondrial energy metabolism, as, for example, uncoupling of oxidative phosphorylation. However, the multiplicity of the effects on several enzymatic systems certainly produces an intricate interplay that also generates complex and apparently contradictory effects.     

Action of quercetin on glycogen catabolism in the rat liver

1. The influence of quercetin on glycogen catabolism and related parameters was investigated in the isolated perfused rat liver and subcellular systems. 2. Quercetin stimulated glycogenolysis (glucose release). This effect was already evident at a concentration of 50 microM maximal at 300 microM and declined at higher concentrations. Quercetin also stimulated oxygen consumption, with a similar concentration dependence. 3. Lactate production from endogenous glycogen (glycolysis) was diminished by quercetin without significant changes in pyruvate production. 4. Quercetin did not inhibit glucose transport into cells but decreased intracellular sequestration of [5-(3)H]glucose under conditions of net glucose release. 5. In isolated mitochondria, quercetin diminished the energy transduction efficiency. It also inhibited several enzymatic activities, e.g. the K(+)-ATPase/Na(+)-ATPase of plasma membrane vesicles and the glucose 6-phosphatase of isolated microsomes. 6. No significant changes of the cellular contents of AMP, ADP and ATP were found. The cellular content of glucose 6-phosphate, however, was increased (3.12-fold). 7. Some of the effects of quercetin (glycogenolysis stimulation) can be attributed to its action on mitochondrial energy metabolism, as, for example, uncoupling of oxidative phosphorylation. However, the multiplicity of the effects on several enzymatic systems certainly produces an intricate interplay that also generates complex and apparently contradictory effects.     

Teratogenic potential of purified pentachlorophenol and pentachloroanisole in subchronically exposed Sprague-Dawley rats

Male and female Sprague-Dawley (Spartan) rats were exposed to dietary levels of 0, 60, 200 or 600 ppm purified pentachlorophenol (PCP) or pentachloroanisole (PCA) for 181 days, through mating and pregnancy. The daily intakes of PCP were 0, 4, 13 or 43 mg/kg body weight and of PCA were 0, 4, 12 or 41 mg/kg body weight. Animals exposed to PCP generally consumed more food than control animals during pregnancy. Dams at the high-dose level of both compounds showed evidence of toxicity, weighing less on day 0 of gestation and gaining less throughout pregnancy than did the controls. Dams exposed to the high dose of PCP gained less weight during pregnancy (exclusive of the gravid uterus) than control dams. At the 43 mg/kg/day dose level PCP was embryolethal. Foetuses at the lower dose levels of PCP exhibited dose-related decreases in body weights. A reduction in crown-rump length and an increase in foetal skeletal variations were seen at 13 mg/kg/day in PCP animals only. An intake of 41 mg PCA/kg/day was associated with a decrease in the number of corpora lutea and in embryolethality. PCA exposure also resulted in reductions in foetal body weight and crown-rump lengths of males at 4 and 41 mg/kg/day. Female foetuses were unaffected.     

葛花对大鼠胚胎致畸作用的观察

目的 观察葛花对SD大鼠胚胎的致畸作用.方法 受孕的雌性SD大鼠随机不分为低、中、高剂量组及对照组,称重并编号.大鼠受孕第7 ～16天,以葛花受试物灌胃,第20天处死,分析大鼠胚胎发育指标与胎仔发育指标,观察胎鼠外观和骨骼有无异常.结果 样品各剂量组孕鼠体重、体重增重、子宫连胎重与对照组比较,差异均无统计学意义（P＞0.05）;样品各剂量组活胎率、死胎率、吸收胎率与对照组比较,差异均无统计学意义（P＞0.05）;样品各剂量组胎仔胎盘重、体重、身长、尾长与对照组比较,差异均无统计学意义（P＞0.05）;样品各剂量组胎仔外观畸形率、内脏畸形率、骨骼畸形率与对照组比较,差异均无统计学意义（P＞0.05）.结论 安全剂量的葛花对大鼠无母体毒性、胚胎毒性和致畸作用,人体每天葛花摄入量7.5g,属安全推荐量.     

Neuro-protective potential of quercetin during chlorpyrifos induced neurotoxicity in rats

Chlorpyrifos (CPF) has been considered as one of the most potent organophosphates and is linked to several neurological disorders. On the other hand, Quercetin is a vital plant flavanoid and has been reported to regulate a number of physiological processes in the central nervous system. The present study was conducted to investigate the protective potential of quercetin during chlorpyrifos induced neurotoxicity. Female Wistar rats weighing 150–200?g were divided into four different groups viz: Normal control, CPF treated (13.5?mg/kg.b.wt. every alternate day), Quercetin treated (50?mg/kg.b.wt./day) and combined CPF and quercetin-treated. All the treatments were carried out for a total duration of eight weeks. Chlorpyrifos treatment showed significant alterations in the cognitive behavior and motor activities of rats, which were appreciably improved upon simultaneous supplementation with quercetin. Further, CPF treatment caused a significant inhibition in the enzyme activities of acetylcholinesterase and choline acetyltransferase, but caused an increase in the levels of acetylcholine in the brain. Further, chlorpyrifos exposure significantly elevated the levels of lipid peroxidation and protein carbonyl contents as well as the activities of catalase, superoxide dismutase, which were interestingly found to be decreased following co-treatment with quercetin. In contrast, CPF treatment decreased the activities of glutathione reductase, transferase, as well as levels of reduced and total glutathione in both the cerebrum and cerebellum but co-administration of quercetin, increased these levels. Chlorpyrifos treatment altered the neuro-histoarchitecture, which showed improvement upon quercetin supplementation. Hence, this study suggests that quercetin can be used as a prophylactic intervention to prevent CPF induced neurotoxicity.     

Teratogenic effects of nitrofen on cellular and functional maturation of the rat lung

The herbicide nitrofen was administered to pregnant Sprague-Dawley and Fischer-344 rats on Days 10-13 of gestation (po, 20 or 40 mg/kg daily) and the effects of maturation of the perinatal lung were evaluated. Nitrofen interfered with the ontogenetic acquisition of lung cells as DNA, RNA, and protein content were subnormal. The hypoplastic lungs in the newborns were associated with structural deficits, resulting in a profound reduction of surface area available for gas exchange and depressed lung compliance. Other factors which influence pulmonary function and systemic delivery of oxygen were also considered. Adrenal catecholamines, which play an important role in surfactant production and fluid resorption in the lung during the transition to air-breathing, were markedly reduced. In addition, red blood cell concentration was significantly diminished. Taken together, these results suggest that the neonatal mortality observed in the nitrofen-treated rats is likely associated with respiratory distress caused by a number of cellular and functional aberrations. These include (a) hypoplasia and structural defects in the lung leading to deficient pulmonary function, (b) deficits in adrenal catecholamines potentially impeding the transition of the lung to air-breathing, and (c) impaired systemic delivery of oxygen due to reduced hemoglobin concentration.     

Teratogenic potential of third-generation antiepileptic drugs: Current status and research needs

The aim of this review was to scrutinize the current literature available on teratogenic safety of third-generation antiepileptic drugs (TGAEDs) considering their clinical implications and to highlight for further research need in the interest of the diseased population in general and women with epilepsy in particular. For evaluation of the teratogenic potential of TGAEDs, this review summarized the existing information on controlled clinical trials conducted by the pharmaceutical companies, case reports, scholarly articles (prospective and retrospective studies), and experimental tests carried out so far. Firstly, clinical reports have reviewed on each drug followed by non-clinical studies reported hitherto. The Pub-Med and Google search engine was used to explore the relevant articles with pertinent keywords like pregnancy, epilepsy, seizures, women with epilepsy, antiepileptic or anticonvulsant drugs, first-second/new and third/ newest generation antiepileptic drugs, teratogenicity, teratological potential, birth defects, congenital anomalies, epilepsy and pregnancy registries, malformation surveillance program. The search was also carried out by the individual name of 20 third-generation AEDs. This review declared that although much research has been carried out on clinical and non-clinical implications for the assessment of the teratogenic potential of FGAEDs and SGAEDs, reports on the teratogenic safety of TGAEDs are still limited. It is concluded that there is an urgent need to exaggerate a large number of clinical intervention trials/reports and experimental studies to draw a definite conclusion for the teratogenic safety of TGAEDs. This is a pioneer attempt by our laboratory to review the teratogenic potential of third-generation antiepileptic drugs.     

Inhibitory effect of quercetin on rat trachea contractility in vitro

Objectives The effect of quercetin, a naturally occurring flavonoid traditionally used to treat airway diseases such as bronchial asthma, on the contractile response elicited by electrical field stimulation or carbachol in rat isolated trachea was investigated. Methods Isolated tracheal tissue was subjected to contractions by an electrical field stimulation of 5 Hz for 30 s, 400 mA, and the responses in the presence of cumulative concentrations of quercetin (10^?6?3 × 10^?4 M) were observed. The effect of quercetin was also evaluated after administration of phentolamine plus propranolol (to block α‐ and β‐adrenergic receptors), N^G‐nitro‐L‐arginine methyl ester (to block nitric oxide synthesis), capsaicin (to desensitise sensory C fibres), α‐chymotrypsin (a proteolytic enzyme that rapidly degrades vasoactive intestinal peptide), SR140333 and SR48968 (tackykinin NK₁ and NK₂ receptor antagonists, respectively). Key findings Quercetin produced a concentration‐dependent inhibition of contractions induced by both carbachol and electrical field stimulation. However, quercetin was more active in inhibiting the contractions produced by electrical field stimulation than those induced by carbachol, suggesting a presynaptic site of action (in addition to a postsynaptic effect, as revealed by the inhibitory action of quercetin on carbachol‐induced contractions). The inhibitory effect of quercetin on contractions induced by electrical field stimulation was unaffected by phentolamine plus propranolol, SR 140333 and SR 48968, capsaicin treatment or by the proteolytic enzyme α‐chymotrypsin. In contrast, the nitric oxide synthase inhibitor N^G‐nitro‐L‐arginine methyl ester significantly reduced the inhibitory effect of quercetin on contractions induced by electrical field stimulation. Conclusions Quercetin inhibits rat tracheal contractility through a presynaptic (involving nitric oxide) and a postsynaptic site of action.     

Actions of quercetin on gluconeogenesis and glycolysis in rat liver

1. The action of quercetin on glucose catabolism and production was investigated in the perfused rat liver. 2. Quercetin inhibited lactate production from glucose: 80% inhibition was found at a quercetin concentration of 100 µM, and at higher concentrations inhibition was complete. 3. Pyruvate production from glucose presented a complex pattern, but stimulation was evident at 100 and 300 µM quercetin. Oxygen uptake tended to be increased. 4. Glucose synthesis from lactate and pyruvate was inhibited. Inhibition was already evident at 50 µM quercetin and almost complete at 300 µM. Concomitantly, the increment in oxygen uptake caused by lactate plus pyruvate was stimulated by 50 µM quercetin, but clearly inhibited by higher concentrations (100-500 µM). 5. Glucose phosphorylation in the high-speed supernatant fractions of liver homogenates was inhibited by quercetin, but only at concentrations above 150 µM. 6. It is concluded that quercetin can inhibit both glucose degradation and production and increase the cytosolic NAD + /NADH ratio. 7. These effects are likely to arise from many causes. Reduction of oxidative phosphorylation, inhibition of Na + -K + -ATPase, inhibition of glucokinase and inhibition of glucose 6-phosphatase could all contribute to the overall action of quercetin.     

Actions of quercetin on gluconeogenesis and glycolysis in rat liver

1. The action of quercetin on glucose catabolism and production was investigated in the perfused rat liver. 2. Quercetin inhibited lactate production from glucose: 80% inhibition was found at a quercetin concentration of 100 micro M, and at higher concentrations inhibition was complete. 3. Pyruvate production from glucose presented a complex pattern, but stimulation was evident at 100 and 300 micro M quercetin. Oxygen uptake tended to be increased. 4. Glucose synthesis from lactate and pyruvate was inhibited. Inhibition was already evident at 50 micro M quercetin and almost complete at 300 micro M. Concomitantly, the increment in oxygen uptake caused by lactate plus pyruvate was stimulated by 50 micro M quercetin, but clearly inhibited by higher concentrations (100-500 micro M). 5. Glucose phosphorylation in the high-speed supernatant fractions of liver homogenates was inhibited by quercetin, but only at concentrations above 150 micro M. 6. It is concluded that quercetin can inhibit both glucose degradation and production and increase the cytosolic NAD(+)/NADH ratio. 7. These effects are likely to arise from many causes. Reduction of oxidative phosphorylation, inhibition of Na(+)-K(+)-ATPase, inhibition of glucokinase and inhibition of glucose 6-phosphatase could all contribute to the overall action of quercetin.     

Teratogenic effect of busulfan on testis cells of the rat (postnatal development)]

10-mg/kg of 1,4-bis-(methanesulfonyloxy)-butane (busulfan) are administered on various days of gestation to Wistar rats. The testes of the male pubs of these litters are examined histologically. Depending on the time of application of busulfan the cells of spermiogenesis are dimished and the meiosis is delayed. The Leydig cells are unchanged. In a second experiment, the weight of the seminal vesicles, LH and FSH in the serum show no differences versus the control group.     

Sulphation of the flavonoids quercetin and catechin by rat liver.

1. The isolated perfused rat liver forms three sulphated metabolites from each of the flavonoids, quercetin and catechin: these are secreted into the bile and the perfusate. 2. Quercetin gives two double conjugates, containing sulphate and glucuronic acid, and one sulphate: catechin gives one such double conjugate and two sulphates. 3. This sulphation is not inhibited by 60 microM 2,6-dichloro-4-nitrophenol which almost completely inhibits the sulphation of harmol in this perfused liver system. 4. The sulphation of harmol by the perfused liver is not inhibited by the flavonoids. 5. Unfractionated sulphotransferases from rat liver catalyse sulphate conjugation of quercetin and catechin in vitro by a reaction inhibited by pentachlorophenol or dichloronitrophenol: the flavonoids inhibit the sulphation of 4-nitrophenol by this system. 6. The results with the two systems are discussed and shown to be compatible.