Cadmium-induced forelimb ectrodactyly: a proposed mechanism of teratogenesis

We have attempted to elucidate the mechanism of cadmium teratogenesis utilizing inbred mouse strains sensitive (C57BL/6J) or resistant (SWV) to the embryotoxic effect of this common heavy metal contaminant. Carbonic anhydrase activity of whole-embryo homogenates was moderately depressed in C57BL/6J mice compared to a slight and transient decrease in the resistant SWV mice. Embryonic erythrocytes were similarly examined, and the cadmium did not have any effect on carbonic anhydrase activity in either strain. Likewise, histochemical examination of carbonic anhydrase activity did not reveal any effect of cadmium in the embryos of their strain. Generally, the zinc concentration of embryos was not affected by cadmium administration. However, increased levels of zinc were observed in cadmium-exposed yolk sacs of both strains suggesting that cadmium produces an adverse effect on yolk sac function. Untreated C57BL/6J units (embryo plus surrounding extraembryonic membranes), embryos, and yolk sacs had much lower hemoglobin concentrations than those observed in untreated SWV units, embryos, and yolk sacs. Additionally, cadmium exposure significantly decreased C57BL/6J embryonic hemoglobin levels on gestation day 10 (PM) and increased C57BL/6J yolk sac hemoglobin levels on gestation days 10 (AM) and 10 (PM). No difference in hemoglobin concentration was observed between untreated and cadmium-treated SWV embryos or yolk sacs. We propose that cadmium induces forelimb ectrodactyly by creating an acidotic embryonic environment and that the primary site at which cadmium exerts its teratogenic effect might be the yolk sac.     

The effect of ethylmercury on fetal development and some essential metals levels in fetuses and pregnant female rats

Ethylmercuric chloride (EtHg), at the dose of 2.5 mg Hg/kg, was administered by gavage every other day to pregnant rats from d 6 to 20 of gestation. On the 21st day of gestation, females were sacrificed to allow the evaluation of embryotoxicity and take the material for analytical determinations. Copper, zinc, iron, and calcium were determined by AAS in liver, kidneys, brain, intestines of fetal and pregnant female rats, as well as in maternal spleen, whole blood, placenta, and fetal carcass. Ethylmercury caused a decrease of the body weight gain during gestation and diminution of relative liver weight of intoxicated females. This compound also induced fetotoxic effects, evidenced by slight diminution of the length as well as the weight of fetuses. It was found that the effect of EtHg on the levels of endogenous metals is different in females and fetuses. In pregnant females, EtHg administration resulted in a significant increase of copper levels in kidneys, liver, and spleen: and in the decrease of zinc concentration in the kidneys, but an increase in placenta and blood compared with pregnant controls. EtHg induced slight decrease of iron concentration in kidneys and intestinal wall of pregnant females. The concentrations of iron in liver and kidney and of zinc in whole blood and liver were lower in control pregnant rats than those in control non-pregnant females. In fetuses of EtHg-exposed mothers, increases in kidney zinc and liver calcium levels were found, whereas tissue copper and iron concentrations were the same as in controls.     

The effect of methylmercury on prenatal development and trace metal distribution in pregnant and fetal rats

Methylmercuric chloride (MetHg) at the dose of 2.5 mgHg/kg was administered by gavage every other day to pregnant rats from the sixth to the twentieth day of gestation. On the 21st day of gestation, females were sacrificed to allow the evaluation of embryotoxicity and the taking of analytical material. Copper, zinc, iron, and calcium were determined4 by AAS in brain, liver, kidneys, intestine, whole blood, and spleen of pregnant MetHg-exposed, nonpregnant and pregnant control females, and in fetuses as well as in placenta. Exposure of pregnant rats to MetHg brought about a decrease in the concentration of intestinal iron and calcium compared with control pregnant animals. In whole fetuses where the mother had been exposed to MetHg, the concentrations of calcium and iron were significantly decreased. The skeletal examination showed developmental retardation of fetuses in the MetHg group, which was reflected in enhanced frequency of delayed ossification of the sternebrae, os occipitale, and vertebrae. The copper level in the brains of fetuses from intoxicated mothers was significantly lower and the absolute brain weights were higher than in controls.     

The effect of heterologous antisera on embryonic development. XIII. Lack of effect of antisera to alpha fetoprotein.

This investigation was carried out to determine whether heterologous antisera to alpha fetoprotein (AFP) are embryotoxic to developing rat embryos. Homogeneous rat AFP was isolated and antisera directed against this glycoprotein were produced in rabbits, horse and goat. The effect of the antisera on embryonic development was examined by injecting the antisera intraperitoneally into pregnant rats on the ninth, eleventh and thirteenth days of gestation. The results demonstrated that there was no evidence of increased incidence of fetal abnormalities in 472 surviving fetuses of 42 injected rats. There was no evidence of increase embryonic death or retardation of intrauterine growth following administration of the antisera on the ninth, eleventh and thirteenth days of gestation. The localization of the injected antisera was examined by the indirect immunofluorescent method. The results showed that the heterologous AFP antibodies localized specifically in the visceral yolk sac placenta. No antibody localization was observed in the embryo proper or the chorioallantoic placenta. It is speculated that the localization of AFP antibodies in the visceral yolk sac does not interfere with the embryotrophic function of the visceral yolk sac placenta.     

Effect of 6-mercaptopurine on 65Zn distribution in the pregnant rat

The effect of 6-mercaptopurine (6-MP) on the distribution of gavaged 65Zn in maternal and embryonic tissues of Sprague-Dawley rats was examined 24 hr after injection of the drug on day 13 of pregnancy. 6-MP injection resulted in a significantly higher retention of counts of 65Zn in maternal liver and lower counts in maternal plasma, uterus, placenta, and embryo than in controls. Compared to controls, gel chromatography of maternal liver from 6-MP injected dams showed higher counts associated with a protein peak of molecular weight 6,000-8,000, the approximate molecular weight of the zinc-binding protein metallothionein. These results support the idea that the zinc deficiency, which is observed in day 21 fetuses from dams injected with 6-MP during midgestation, may be the result of a drug-induced sequestering of zinc into maternal liver followed by a decrease in maternal plasma zinc and subsequent reduction in fetal zinc uptake. We suggest that this 6-MP-associated redistribution of zinc into maternal liver may be due to induction of maternal metallothionein synthesis by the drug.     

Evaluation of heart malformations in B6C3F1 mouse fetuses induced by in utero exposure to methyl chloride

C57BL/6 female mice impregnated by C3H males mice to produce B6C3F1 fetuses were exposed daily for six hr to atmospheres containing 0, 250, 500, or 750 ppm methyl chloride, from gestation day 6 to gestation day 18. There were 74 to 77 females with copulation plugs per exposure concentration. Females exposed to 750 ppm ethyl chloride exhibited ataxia commencing on the seventh day of exposure (gestation day 12). They also showed hypersensitivity to touch or sound, tremors and convulsions. Six females in the 750 ppm group died and one was euthanized in extremis prior to scheduled sacrifice. On gestation day 18, all other females were euthanized for evaluation. Only dams exposed to 750 ppm exhibited significant decrease in body weight by gestation day 18, weight gain during the gestation period, and absolute weight gain (weight gain minus gravid uterine weight) versus controls. There were no treatment related-effects on these parameters in the other exposure groups. None of the groups exhibited exposure-related differences in pregnancy rate, gravid uterine weight, or maternal liver weight. There were no differences in the numbers of implantations, resorption, dead fetuses, nonlive (dead plus resorbed) fetuses, live fetuses, sex-ratio, or mean fetal body weight per litter. There was a significant exposure-related increase in the number and percentage of affected (nonlive plus malformed) fetuses per litter with the incidence of affected fetuses in the 750 ppm group significantly higher than controls. There was a statistically significant increase in the incidence of heart defects in the 500 and 750 ppm group relative to controls. Of the 37 fetuses in the study with heart defects, 23 were females, 14 were males. The heart defects observed included: absent or abnormal tricuspid valve, reduced number of papillary muscles and/or chordae tendineae on the right side, small right ventricle, globular heart, and white spots in the left ventricular wall. Multiple malformations were observed in one fetus from the 500 ppm group and in three fetuses in the 750 ppm group. It is concluded that methyl chloride inhalation exposure to pregnant C57BL/6 mice from gestation day 6 through gestation day 17 resulted in maternal toxicity only at the 750 ppm exposure concentration and was teratogenic to B6C3F1 conceptuses at exposure concentrations of 750 and 500 ppm, leading to fetal heart malformations. No evidence of embryo or fetotoxicity other than teratogenicity was seen at any of the exposure concentrations employed. No maternal, embryo or fetotoxicity or teratogenicity was associated with exposure of mice, during critical periods of embryo and fetal development, to 250 ppm of methyl chloride.     

Combined embryotoxic action of toluene, a widely used industrial chemical, and acetylsalicylic acid (aspirin)

CFY rats were exposed to inhalation of fresh air at days 10-13 of gestation; at day 12 the dams were given 0, 125, 250, 500, or 1,000 mg/kg acetylsalicylic acid (ASA) by gavage. During the same period of gestation (days 10-13) further groups of rats were exposed to toluene at 1,000, 2,000, and 3,600 mg/m3 atmospheric concentration and were given 250 mg/kg ASA by gavage; two subgroups of animals treated with 250 mg/kg ASA in combination with 3,600 mg/m3 toluene inhalation were given 0, 2.5, or 5 gm/kg glycine 2 hours before the ASA dose. At day 21 the animals were killed and examined for teratogenic effects and histological changes. After 48 hours toluene exposure other groups of rats were treated with ASA or with ASA plus glycine (administered 2 hours earlier) on day 20 of gestation. These animals were killed 2 hours later and the salicylic acid concentration in maternal and embryonic plasma and in amniotic fluid was measured by gas chromatography. With the rising ASA doses both maternal toxicity (increased mortality, decreased food consumption, and weight gain) and embryonic toxicity (postimplantation loss, increased incidence of weight-retarded fetuses, increased minor anomalies and malformations, decreased average weight of fetuses) increased. Toluene was found to potentiate the toxic effect of ASA and to increase both maternal and embryonic toxicity. The type of ASA-induced minor anomalies and malformations was also found to be altered under the effect of toluene pretreatment. By raising the toluene concentration the salicylic acid level in the maternal and embryonic plasma and in the amniotic fluid was increased above the expected concentration. The mechanism of the potentiating interaction should be looked for in the depletion of the glycine pool by toluene (and its metabolites) and in the resultant increase of salicylic acid level. Increasing ASA embryotoxicity caused by toluene can be warded off by glycine administration.     

Ameltolide. II: Placental transfer of radiocarbon following the oral administration of a novel anticonvulsant in rats

The placental transfer of orally administered ameltolide was evaluated to confirm embryonic exposure in the rat developmental toxicity study (Higdon et al., '91). Dissection techniques were used to determine the amount of total radiocarbon that traversed the placenta and distributed within the embryo in pregnant CD rats 0.75, 2, 5, 12, and 24 h after a single oral gavage dose of 50 mg/kg [14C]ameltolide on gestation day 12. Quantification of radiocarbon within placental and embryonic tissues and amniotic fluid was determined and compared with maternal plasma, liver, kidney, uterus, and ovary. Highest concentrations of radiocarbon occurred at 5 h postdose in all tissues sampled (maternal and embryonic) and then declined steadily over the 24-h time course of the study. Maternal liver contained the highest concentrations of radiocarbon at all time points and peaked at 5.86% of dose at 5 h. Embryonic tissues accounted for less than 0.2% of the administered dose at all time points. Tissue-to-maternal plasma ratios indicated that maternal liver and kidney concentrations were higher than maternal plasma concentrations at all time points. Uterine and ovarian concentrations were approximately equal to maternal plasma concentrations at 5, 12, and 24 h postdose. Although placental, embryonic, and amniotic fluid tissue-to-maternal plasma ratios were less than or equal to 1.0, ratios increased slightly throughout the time course of this study. Results from this study confirm embryonic exposure to radiocarbon associated with [14C]ameltolide and/or its metabolites in the rat developmental toxicity study, which has demonstrated the lack of observable teratogenic effects.     

Pregnancy and progeny in rats treated with prostaglandin E2

Prostaglandin E₂ (300 μg) did not terminate pregnancy in rats when administered intraperitoneally from day 12 through 15 of gestation. All fetuses were alive on recovery near term and showed no developmental defects. However, extensive edema and hemorrhagic lesions were detected in 18.2% of the offspring. Fetal resorption was not significantly increased. Embryotoxic effects, in the form of fetal death and resorption, occurred in all fetuses following intra-amniotic administration of 100 μg prostaglandin E₂ on day 15 of gestation. Premature labor and expulsion of the dead fetuses were not induced.     

Inducibility and amounts of metallothionein as influenced by cadmium and zinc in the developing rat

Information on the accumulation and/or depletion of Zn in metallothionein (MT) of rat fetus, rat pup, and maternal rat liver at various ages was obtained with pregnant rats fed a basal casein diet or this diet plus either 100 ppm Zn or 50 ppm Cd. Rats fed each of the respective diets were sacrificed on 12, 16, and 20 d of gestation and 0, 7, 14, and 28 d post-partum. No Cd was detected in the placenta or fetal tissue and the Cd did not affect the accumulation of Zn in the fetal MT, but it did increase the Zn content in liver MT of the dams. Very little Zn in MT was found on day 12 of gestation, but Zn rapidly increased in MT to a maximum at time of birth. The accumulation of Zn in MT was independent of the diet for the fetuses, but the Zn accumulation in the dam and pup tissues was diet dependent. In order to study age-dependent difference in the inducibility of MT, newborn, 5-week-old, or 24-week-old rats were injected with zinc at the levels of 0, 3, 6, or 9 mg/kg and 5 h later injected with³⁵S-cystine. In rats sacrificed 1 h later, the amount of radioactivity in liver MT demonstrated that this protein in older animals was more readily induced by Zn than in younger animals.     

Low iron diet and parenteral cadmium exposure in pregnant rats: the effects on trace elements and fetal viability

The effects of latent iron deficiency combined with parenteral subchronic or acute cadmium exposure during pregnancy on maternal and fetal tissue distribution of cadmium, iron and zinc, and on fetal viability were evaluated. Timed-pregnant Sprague-Dawley rats were fed on semisynthetic test diets with either high iron (240 mg kg) or low iron (10 mg kg), and concomitantly exposed to 0, 3 or 5 mg cadmium (as anhydrous CdCl₂) per kilogram body weight. Animals were exposed to cadmium from gestation day 1 through 19 by subcutaneously implanted mini pumps (Subchronic exposure) or on gestation day 15 by a single subcutaneous injection (Acute exposure). All rats were killed on gestation day 19. Blood samples, selected organs and fetuses were removed and prepared for element analyses by atomic absorption spectrometry. Low iron diet caused decreases in maternal body weight, maternal and fetal liver weights, placental weights and tissue iron concentrations. By cadmium exposure, both subchronic and acute, tissue cadmium concentrations were increased and the increase was dose-related, maternal liver and kidney zinc concentrations were increased, and fetal zinc concentration was decreased. Cadmium concentration in maternal liver was additionally increased by low iron diet. Acute cadmium exposure caused lower maternal body and organ weights, high fetal mortality, and decreased fetal weights of survivors. In conclusion, parenteral cadmium exposure during pregnancy causes perturbations in essential elements in maternal and fetal compartments. Acute cadmium exposure in the last trimester of gestation poses a risk for fetal viability especially when combined with low iron in maternal diet.     

Cocaine as a cause of congenital malformations of vascular origin: experimental evidence in the rat

Cocaine hydrochloride was administered to pregnant Sprague-Dawley rats as a single intraperitoneal dose or as two doses 1-4 hours apart. A single dose administered on day 16 of gestation was teratogenic in a dose-dependent manner, with 40 mg/kg being a no-effect dose and 50 mg/kg the lowest teratogenic dose; 80 mg/kg was lethal to the dam. Forty-eight hours after exposure to a teratogenic dose on day 16 of pregnancy, the fetuses showed severe hemorrhage and edema in the their extremities, particularly the footplates, tail, genital tubercle, and upper lip/nose. When the fetuses were examined on day 21 of gestation, the main externally visible malformations were reduction deformities of the limbs and tail. When two doses of cocaine were administered 1-4 hours apart, the incidence of affected fetuses increased as the time interval between the two doses decreased. Two doses of cocaine administered 2 hours apart were not teratogenic on day 9, 10, 11, 12, 13, or 14 of gestation but did induce reduction deformities on days 15, 16, 17, 18, or 19. The same dose administered 1 hour apart was teratogenic on days 14-19. In general, cocaine administration on gestational days 14, 15, or 16 induced more severe and more widespread hemorrhage and edema than administration on days 17, 18, or 19. In the latter cases, damage was restricted to the distal parts of the hindlimb digits and the tail. The results show that in the rat cocaine is only teratogenic during the late organogenic or postorganogenic period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mammary gland growth in the hypophysectomized pregnant rat (38522).

Sprague-Dawley-Rolfsmeyer rats were hypophysectomized on days 11, 12 or 15 of pregnancy and sacrificed on day 20 to determine the extent of mammary development, as assessed by determination of nucleic acid content. The DNA of six abdominal-inguinal glands in the hypophysectomized groups was not significantly different from that in the sham-operated pregnant or intact pregnant control groups. All groups maintaining pregnancy had significantly higher DNA contents in mammary glands than virgin control or hypophysectomized aborted groups. In order to determine the minimal numbers of placental-fetal units required to maintain pregnancy and mammary gland growth, fetuses and placentas were removed on day 12 of pregnancy in addition to the pituitary so that only one fetus and one placenta remained in the uterus of a group of 6 rats with other groups having 2, 3, 4, 5 remaining. Pregnancy was maintained with only one placental-fetal unit, but mammary gland proliferation was significantly lower than the control group on day 20 of pregnancy. Three to five conceptuses supported mammary proliferation during the latter half of pregnancy at a level not significantly different from intact or sham-operated control groups. Removal of placental units on day 12 in rats having pituitaries intact resulted in no mammary DNA change when 1-5 units remained. Removal of pitutaries on day 12 and placental-fetal units on day 14 also resulted in no change in mammary DNA with as little as two placentas (minus all fetuses),while only one placenta remaining resulted in a significantly lower mammary DNA than in groups wtih 2 or more placentas.     

Influence of endogenous growth hormone-releasing factor (GRF) on the secretion of GH during the perinatal period in the rat

Passive immunization of pregnant rats with a specific antiserum to rat GRF (GRF-AS) is followed by a decrease in fetal serum GH on the 19th day of gestation. A significant reduction in serum GH is still observed in older fetuses and newborn rats. Pituitary GH content increases in 19- and 20-day-old fetuses after GRF-AS administration to their mothers. These results suggest that endogenous fetal hypothalamic GRF (or placenta GRF) play a physiological role in the secretion of pituitary GH as early as the 19th day of fetal life and may be responsible for the peak of GH release that occurs in fetuses at the end of gestation.     

Cadmium exposure on day 12 of gestation in the Wistar rat: distribution, uteroplacental blood flow, and fetal viability

The effects of cadmium exposure (40 mumole CdCl2/kg, s.c.) on day 12 of gestation were evaluated in the Wistar rat. At 16-18 hours following such cadmium exposure, blood flow (as determined by radiolabeled microspheres) to the chorioallantoic placenta (CAP) was significantly reduced by 35%; at 24-26 hours, blood flow to the CAP had returned to control levels and was still unaffected at 38-43 hours. Uterine blood flow was not significantly altered at any of these timepoints. Between 16-18 and 24-26 hours after cadmium exposure, the concentration of cadmium in the placenta decreased significantly, while total cadmium content did not change. By 38-43 hours after cadmium exposure, total cadmium content of the placenta had increased significantly, although cadmium concentration was unchanged. There were no adverse effects on fetal viability or growth, as determined on day 20 of gestation. In sharp contrast, near-term (day 18) exposure to 40 or 50 mumole CdCl2/kg (s.c.) resulted in 53% and 82% mean incidences of fetolethality, respectively, within 24 hours. Administration of 50 mumole CdCl2/kg (sc) on day 12 also had no effect on fetal growth but resulted in increased fetolethality (12%). Thus midgestational cadmium exposure and its accompanying alterations in placental blood flow do not compromise fetal viability or growth. The differential response to cadmium at mid- and late gestation, in terms of fetolethality, is not due to maternal cadmium dose.     

Teratogenic potentially of single dose of thalidomide in JW-NIBS rabbits

A single dose (500 mg/kg) of thalidomide was administered orally to pregnant JW-NIBS rabbits in various stages of organogenesis. Head anomalies in fetuses (anencephaly, holoprosencephaly and hydrocephaly) were induced at a high frequency by the maternal administration of thalidomide on day 7, and also in a few fetuses on day 8. These fetuses included those with an abnormal skull such as hypoplasia of cerebral and facial skull. Microphthalmia in fetuses was observed with a single administration from day 7 to 12 of gestation. Contracture of forearms and club foot in fetuses resulted from the maternal administration of thalidomide on day 8 or 9 of gestation, respectively. With a single administration on day 8 or 9 of gestation, kinky tail in fetuses resulted, and brachyury was observed with a high frequency from day 8 to 11 of gestation. Skeletal anomalies such as fusion or displacement of coccygeal vertebral bodies were observed at a high frequency with a single treatment from day 8 to 10 of gestation. Among the internal anomalies observed was abnormal lobation of the lung, resulting from a single treatment from day 6 to 15 of gestation (except for day 13), and abnormal lobation of the liver, induced from day 7 to 10. The cardiovascular anomalies were induced at a high frequency with a single treatment from day 7 to 9 of gestation. In the present experiment, the critical period for each anomaly produced by thalidomide in JW-NIBS rabbits was determined.     

Developing embryo and cyclic changes in the uterus of Peripatus (Macroperipatus) acacioi (Onychophora,Peripatidae)

Female reproductive tracts of the viviparous neo-tropical onychophoran Peripatus acacioi have been examined at different times throughout the year, and the altering relationship between the developing embryo and the uterus is described. Depending on her age and time of year, the female may have one or two generations of embryos within her uterus. The uterine wall consists of a thin outer epithelium and basal lamina, three layers of muscles, and a thick basal lamina beneath an inner epithelium lining the uterus lumen. These layers are consistent along the length of the uterus apart from the inner epithelial lining, which varies according to position in the uterus and the developmental stage of embryos contained in the uterus. Early embryos are positioned along the length of the uterus and therefore have space in which to grow. During cleavage and segment formation, each embryo is contained within a fluid-filled embryo cavity that increases in size as the embryo grows. Morulae and blastulae are separated by lengths of empty uterus in which the epithelial lining appears vacuolated. Until the process of segment formation is complete, the embryos are attached to a placenta by a stalk and remain in the same part of the upper region of the uterus. As these embryos grow, the lengths of vacuolated cell-lined uterus between them decrease. Each embryo cavity is surrounded by the epithelial sac, the maternal uterine epithelium, which becomes overlaid by a thin layer of cells, the embryo sac, which is believed to be of embryonic origin. The placenta is a syncytial modification of the epithelial sac located at the ovarian end of each embryo cavity covered by the embryo sac and is analogous to the mammalian noninvasive epitheliochorial placenta. Segment-forming embryos have their heads directed toward the ovary. As the embryo gets longer during segment formation, its posture changes from coiled to flexed. Once segment formation is complete, the embryo loses contact with its stalk, an embryonic cuticle forms, and the embryo turns around so that its head is directed toward the vagina. The embryo escapes from its embryo sac and moves to the lower part of the uterus. In the lower part of the uterus, the straightened fetuses are first unpigmented but subsequently become pigmented as the secondary papillae on the body surface form and an adult-type cuticle forms beneath the embryonic cuticle. While the embryos are contained within their embryo cavities, nutrients are supplied by the placenta. Throughout development the mouth is open and in the mature fetus the gut is lined by peritrophic membrane and material is present in the gut lumen. Trachea have been observed only in fetuses that were ready for birth. Insemination, cyclical changes in the uterine epithelium, and the nature of the cuticle shed at parturition are discussed. © 1995 Wiley-Liss, Inc.     

Contragestational action of hyperthermia on rat pregnancy. Effect on ornithine decarboxylase.

In the rat, there are marked changes in ornithine decarboxylase activity in the fetuses and reproductive tissues during gestation. Exposure of pregnant rats to moderate hyperthermia (40 degrees C, 60 min) produced a marked decrease (about 80%) of ornithine decarboxylase activity in fetuses, uterus and ovaries, while this change was more moderate in placenta (about 20%). This effect was observed in different stages of pregnancy. Ornithine decarboxylase activity was returned to control values within a few hours after the end of the hyperthermic treatment. Hyperthermia produced marked contragestational effects if given sequentially on days 8, 9 and 10 of gestation, but only a decrease in the weight of viable fetuses was observed when given on days 11, 12 and 13. These results indicate that part of the harmful effects produced by hyperthermia on pregnant rats may be mediated by the sustained fall of ornithine decarboxylase activity during critical periods of gestation.     

Cadmium and lead toxicity effects on zinc, copper, nickel and iron distribution in the developing chick embryo

The teratologic effects on chicken embryos induced by the load of 100 micrograms of cadmium or lead nitrate salts injected into the yolk on day 5 of incubation as well as their effects upon zinc, copper, nickel and iron distribution were studied. Despite a significant teratologic influence of lead, cadmium administration did not induce significant effects. A week after injections, embryo lead content, but not cadmium concentration, increased; this differential action suggested an active uptake of lead by the embryo, not observed for cadmium. Both cadmium and lead affected significantly the iron, copper and zinc homeostasis in the egg. Cadmium induced these changes probably through alterations in the metallic ion transport processes towards the embryo.     

Relationship of dietary zinc to 6-mercaptopurine teratogenesis and DNA metabolism in the rat

The possible interaction between the level of maternal dietary zinc and the teratogenic activity of 6-mercaptopurine was investigated. Pregnant Sprague-Dawley rats were fed diets containing 9,100 or 1,000 ppm zinc from day zero of pregnancy and were given a single intraperitoneal injection of 6-MP (55mg/kg) on day 11. At term, females in the group fed 1,000 ppm zinc (a high intake) showed less pronounced effects on reproduction and embryogenesis than did those fed 9 ppm (marginally deficient) or 100 ppm (normal) zinc. Embryos examined on day 12 of gestation had similar concentrations of protein and RNA; however, the DNA content was lower and the incorporation of 3H-thymidine was greater in the drug treated groups than in non-drug treated controls. These results indicate that 6-mercaptopurine is acting to alter embryonic DNA metabolism and that high levesl of dietary zinc may ameliorate some of the deleterious effects of this drug on embryonic and maternal toxicity.