Maternal and developmental toxicity of ayahuasca in Wistar rats

INTRODUCTION: Ayahuasca is a psychotropic plant beverage initially used by shamans throughout the Amazon region during traditional religious cult. In recent years, ayahuasca has also been used in ceremonies of a number of modern syncretic religious groups, including pregnant women. However, no documented study has been performed to evaluate the risk of developmental toxicity of ayahuasca. METHODS: In the present work, maternal and developmental toxicity was evaluated in Wistar rats. Ayahuasca was administered to pregnant rats in three different doses [the equivalent typical dose (TD) administered to humans, five‐fold TD and 10‐fold TD] during the gestational period (6–20 days). RESULTS: Dams treated with the highest ayahuasca dose showed maternal toxicity with decrease of weight gain and food intake. Visceral fetal findings were observed in all treatment groups. Skeletal findings were observed in the intermediate‐ and high‐dose groups. The fetuses deriving from the highest dose group also presented a decrease in body weight. CONCLUSIONS: From these results, it is possible to conclude that there is a risk of maternal and developmental toxicity following ayahuasca exposure and that the level of toxicity appears to be dose‐dependent. Birth Defects Res (Part B) 89:207–212, 2010. © 2010 Wiley‐Liss, Inc.     

Developmental toxicity evaluation of sodium thioglycolate administered topically to Sprague-Dawley (CD) rats and New Zealand White rabbits

BACKGROUND: Sodium thioglycolate, which has widespread occupational and consumer exposure to women from cosmetics and hair‐care products, was evaluated for developmental toxicity by topical exposure during the embryonic and fetal periods of pregnancy METHODS: Timed‐mated Sprague–Dawley rats (25/group) and New Zealand White (NZW) rabbits (24/group) were exposed to sodium thioglycolate in vehicle (95% ethanol:distilled water, 1:1) by unoccluded topical application on gestational days (GD) 6–19 (rats) or 6–29 (rabbits) for 6 hr/day, at 0, 50, 100, or 200 mg/kg body weight/day (rats) and 0, 10, 15, 25, or 65 mg/kg/day (rabbits). At termination (GD 20 rats; GD 30 rabbits), fetuses were examined for external, visceral, and skeletal malformations and variations. RESULTS: In rats, maternal topical exposure to sodium thioglycolate, at 200 mg/kg/day (the highest dose tested) on GD 6–19, resulted in maternal toxicity, including reduced body weights and weight gain, increased relative water consumption and one death. Treatment‐related increases in feed consumption and changes at the application site occurred at all doses, in the absence of increased body weights or body weight change. Fetal body weights/litter were decreased at 200 mg/kg/day, with no other embryo/fetal toxicity and no treatment‐related teratogenicity in any group. In rabbits, maternal topical exposure to sodium thioglycolate on GD 6–29 resulted in maternal dose‐related toxicity at the dosing site in all groups; no maternal systemic toxicity, embryo/fetal toxicity, or treatment‐related teratogenicity were observed in any group. CONCLUSIONS: A no observed adverse effect level (NOAEL) was not identified for maternal toxicity in either species with the dosages tested. The developmental toxicity NOAEL was 100 mg/kg/day (rats) and ≥65 mg/kg/day (rabbits; the highest dose tested). The clinical relevance of theses study results is uncertain because no data were available for levels, frequency, or duration of exposures in female workers or end users. Birth Defects Research Part B 68:144–161, 2003. © 2003 Wiley‐Liss, Inc.     

Occurrence and fate of fetal lumbar rib induced by Scutellariae radix in rats

BACKGROUND: This study was conducted to evaluate the occurrence and fate of fetal lumbar rib induced by Scutellariae radix (SR) in rats. METHODS: Water extracts of SR were orally administered to pregnant rats from day 7 to day 17 of gestation at a dose of 186 mg/kg/day, equivalent to 25 g/kg of starting material, representing a 100‐fold increase over typical human intake level. RESULTS: The incidence of fetal lumbar rib in the SR‐treated group was increased on gestational day 20 and then decreased on postnatal day 50. The weight of fetuses in the SR‐treated group tended to be less than that in the control group. Alkaline phosphatase in SR‐treated dams was increased on gestational day 20, but was decreased on postnatal day 50. There were no significant differences between the vehicle control and SR‐treated groups in maternal body weight, embryological, histopathological, hematological, and serum biochemical changes. CONCLUSIONS: The present data suggest that the appearance of lumbar rib induced by SR is a transient fetal variation rather than teratogenicity or maternal toxicity. Birth Defects Res (Part B) 89:201–206, 2010. © 2010 Wiley‐Liss, Inc.     

Evaluation of embryo-fetal development in rats housed in concrete or hwangto cages during pregnancy

BACKGROUND: Recently, it was reported that the 4‐week exposure of rats to a concrete building environment under cool temperatures (11.7–12.1°C) had adverse effects on the general health parameters. This study examined the potential effects of concrete and hwangto building environments on pregnant dams and embryo‐fetal development in Sprague‐Dawley rats. METHODS: Groups of 10 mated females were exposed to polycarbonate (control), concrete, or hwangto cages from gestational days (GD) 0 to 20 under cool temperatures (11.9–12.5°C). All the females underwent a caesarean section on GD 20, and their fetuses were examined for any morphological abnormalities. RESULTS: The temperatures in the cages were similar in all groups but the relative humidity in the concrete and hwangto groups were higher than in the control group. The concentration of volatile organic compounds in the hwangto group during the study period was lower than in the control group. In the concrete group, maternal effects manifested as an increase in the incidence of clinical signs, a lower body weight, and a decrease in the thymus and ovary weights. Developmental effects included increased post‐implantation loss and decreased litter size. In contrast, in the hwangto group, there were no exposure‐related adverse effects on the maternal and developmental parameters. CONCLUSIONS: Overall, the exposure of pregnant rats to a concrete building environment under cool temperatures has adverse effects on the clinical signs, body weight, organ weight, and embryo‐fetal development. On the other hand, exposure to a hwangto building environment does not have any adverse effects on pregnant dams or on embryo‐fetal development in rats. Birth Defects Res (Part B), 2008. © 2008 Wiley‐Liss, Inc.     

Different embryo-fetal toxicity effects for three VLA-4 antagonists

BACKGROUND: VLA‐4 (Very late antigen 4, integrin α₄β₁) plays an important role in cell‐cell interactions that are critical for development. Homozygous null knockouts of the α₄subunit of VLA‐4 or VCAM‐1 (cell surface ligand to VLA‐4) in mice result in abnormal placental and cardiac development and embryo lethality. Objectives of the current study were to assess and compare the teratogenic potential of three VLA‐4 antagonists. METHODS: IVL745, HMR1031, and IVL984 were each evaluated by the subcutaneous route in standard embryo‐fetal developmental toxicity studies in rats and rabbits. IVL984 was also evaluated in mice. Fetuses were examined externally, viscerally, and skeletally. RESULTS: IVL745 did not cause significant maternal or fetal effects at doses up to 100 or 250 mg/kg/day in rats or rabbits, respectively. HMR1031 treatment resulted in marked maternal toxicity and slight fetal toxicity at the highest tested doses of 200 and 75 mg/kg/day in rats and rabbits, respectively. HMR1031 embryo‐fetal effects consisted of slightly lower body weight and crown‐rump length in rats and minor sternebral defects in rabbits. IVL984 treatment resulted in minimal maternal effects at doses up to 40, 15, and 100 mg/kg/day in rats, rabbits, and mice, respectively (excluding abortions in rabbits). However, marked developmental effects were observed at the lowest tested IVL984 doses, 1, 0.2, and 3 mg/kg/day in rats, rabbits, and mice, respectively. IVL984 embryo‐fetal effects consisted of increased total post‐implantation loss due to early resorptions and high incidences of cardiac malformations and skeletal malformations and/or variations. Notably, spiral septal defects were observed in up to 76% of rat fetuses and up to 58% of rabbit fetuses. CONCLUSIONS: Dramatic differences in teratogenic potential were observed: IVL745 was not teratogenic, HMR1031 caused slight embryo‐fetal effects at maternally‐toxic doses, and IVL984 was a potent teratogen at doses where direct maternal toxicity was limited to abortions in rabbits. Prominent effects of IVL984 included embryo lethality and cardiac malformations including spiral septal defects in three species. Birth Defects Res B 71:55–68, 2004. © 2004 Wiley‐Liss, Inc.     

Glucocorticoids impair fetal beta-cell development in rats

In rats, poor fetal growth due to maternal food restriction during pregnancy is associated with decreased beta-cell mass at birth and glucose intolerance in adulthood. Overexposure to glucocorticoids in utero can induce intrauterine growth retardation in humans and animals and subsequent glucose intolerance in rodents. The aims of this study were to investigate whether glucocorticoid overexposure mediates the effect of undernutrition on beta-cell mass and to study their potential role in normally nourished rats. Undernutrition significantly increased maternal and fetal corticosterone levels. Twenty-one-day-old fetuses with undernutrition showed growth retardation and decreased pancreatic insulin content; adrenalectomy and subcutaneous corticosterone implants in their dams prevented the maternal corticosterone increase and restored fetal beta-cell mass. In fetuses with normal nutrition, fetal corticosterone levels were negatively correlated to fetal weight and insulin content; fetal beta-cell mass increased from 355 +/- 48 microg in sham to 516 +/- 160 microg after maternal adrenalectomy; inhibition of steroid production by metyrapone induced a further increase to 757 +/- 125 microg. Our data support the new concept of a negative role of glucocorticoids in fetal beta-cell development.     

Reproductive and Developmental Toxicity of Orally Administered Botanical Composition,UP446‐Part I: Effects on Embryo‐Fetal Development in New Zealand White Rabbits and Sprague Dawley Rats

The pharmacotoxicology impacts of dietary supplements taken at the time of pregnancy have remained alarming since women are the frequent herbal medicine users in many countries as a complement to the conventional pregnancy management. The use of herbal medicines and diet supplements in expectant mothers linked closely to the health of the childbearing mothers and the fetuses where the lack of developmental safety data imposes a challenge to make the right choices. Here, we describe the potential adverse effects of UP446, a standardized bioflavonoid composition from the roots of Scutellaria baicalensis and the heartwoods of Acacia catechu, on embryo‐fetal development following maternal exposure during the critical period of major organogenesis in rabbits and rats. Pregnant dams were treated orally with UP446 at doses of 250, 500, and 1000 mg/kg/day during gestation. The number of resorptions, implantations, litter size, body weights, and skeletal development was evaluated. Maternal food intake and body, tissue, and placenta weight were also assessed. There were no statistically significant differences in implantation, congenital malformation, embryo‐fetal mortalities, and fetuses sex ratios in all dosing groups of both species. Therefore, the no observed adverse effect level of UP446 was considered to be greater than 1000 mg/kg in both the maternal and fetus in both species     

Studies of the teratogenic potential of exposure of rats to 6000-MHz microwave radiation. I. Morphologic analysis at term

Thirty-six pregnant Wistar strain albino rats were exposed throughout pregnancy to 6000-MHz microwave radiation at a power density level of 35 mW/cm2 or were used as controls. The irradiation did not cause a significant increase in maternal body temperature as measured by a rectal thermocouple. The rats were randomly assigned to one of four groups: home cage control (5), anechoic chamber control (10), sham-irradiated concurrent control (10), and irradiated (11). All animals were killed on the 22nd day of gestation, and maternal tissues were removed and weighed and maternal blood samples were taken. The 384 resultant fetuses and their placentas were individually weighed, fixed, and dissected to determine normality. Teratologic evaluation included the following parameters: maternal weight and weight gain; mean litter size; maternal organ weight and organ weight/body weight ratios; body weight ratios of brain, liver, kidneys, and ovaries; maternal peripheral blood parameters including hematocrit, hemoglobin, and white cell counts; number of resorptions and resorption rate; number of abnormalities and abnormality rate; mean term fetal weight. The irradiated fetuses exhibited slight but statistically significant growth retardation at term. Term maternal monocyte count was also significantly depressed. No other parameters differed between the control groups and the irradiated group.     

Maternal exposure to multi-wall carbon nanotubes does not induce embryo-fetal developmental toxicity in rats

BACKGROUND: Although the potential risk of carbon nanotubes (CNTs) to humans has recently increased due to expanding production and widespread use, the potential adverse effects of CNTs on embryo–fetal development have not yet been determined. METHODS: This study investigated the potential effects of multi‐wall CNTs (MWCNTs) on pregnant dams and embryo–fetal development in rats. MWCNTs were administered to pregnant rats by gavage at 0, 40, 200, and 1,000 mg/kg/day. All dams were subjected to Cesarean section on day 20 of gestation, and the fetuses were examined for any morphological abnormalities. RESULTS: All animals survived to the end of the study. A decrease in thymus weight was observed in the high dose group in a dose‐dependent manner. However, maternal body weight, food consumption, and oxidant–antioxidant balance in the liver were not affected by treatment with MWCNTs. No treatment‐related differences in gestation index, fetal deaths, fetal and placental weights, or sex ratio were observed between the groups. Morphological examinations of the fetuses demonstrated no significant difference in incidences of abnormalities between the groups. CONCLUSIONS: The results show that repeated oral doses of MWCNTs during pregnancy induces minimal maternal toxicity and no embryo–fetal toxicity at 1,000 mg/kg/day in rats. The no‐observed‐adverse‐effect level of MWCNTs is considered to be 200 mg/kg/day for dams and 1,000 mg/kg/day for embryo–fetal development. In this study, the dosing formulation was not analyzed to determine the degree of reaggregation (or not), nor were blood levels of CNT's measured in the dosed animals to verify or characterize absorption. Birth Defects Res (Part B) 92:69–76, 2011. © 2011 Wiley‐Liss, Inc.     

Pharmacology and placental transfer of a human αv integrin monoclonal antibody in rabbits

BACKGROUND: Intetumumab is a human IgG1 anti‐αv‐integrin monoclonal antibody that inhibits angiogenesis. Integrin binding and angiogenesis are important in reproduction including fertilization, implantation, and embryofetal development. These studies were designed to determine the pharmacological relevance of the rabbit for the evaluation of potential effects on embryofetal development and to evaluate the placental transfer of intetumumab in rabbits. METHODS: In vitro pharmacology studies evaluated the binding of intetumumab to rabbit cells and the inhibition of vessel sprouting from rabbit aorta. For the evaluation of placental transfer, pregnant rabbits (8/group) were injected intravenously with intetumumab 50 or 100 mg/kg every 2 days from Gestation Day (GD)7 to GD19. Maternal sera, fetal homogenates/sera, and amniotic fluid were collected at necropsy on GD19 or GD28 for evaluation of intetumumab concentrations. Clinical condition of the dams was monitored and fetuses were screened for abnormalities. RESULTS: Intetumumab (5–40 µg/mL) inhibited aortic cell adhesion to vitronectin and vessel sprouting from rabbit aortic rings. Immunohistochemical staining of rabbit tissues demonstrated binding of intetumumab to placenta. Administration of intetumumab to pregnant rabbits was well tolerated by the dams and the fetuses did not show major abnormalities. Fetal exposure to intetumumab relative to maternal exposure was <0.1% on GD19 and 100–130% on GD29. CONCLUSIONS: The rabbit is a pharmacologically relevant species for evaluation of potential developmental effects of intetumumab. Intetumumab crosses the rabbit placenta during the fetal period (GD 19–28). Birth Defects Res (Part B) 89:116–123, 2010. © 2010 Wiley‐Liss, Inc.     

Effects of eflornithine hydrochloride (DFMO) on fetal development in rats and rabbits

Eflornithine hydrochloride (DFMO) is a highly selective, enzyme-activated, irreversible inhibitor of the enzyme L-ornithine decarboxylase (ODC). Because of its role in the biosynthetic pathway of polyamines, ODC is essential for the growth and development of newly implanted embryonic tissue. In order to assess its effect on embryonic growth and fetal development, at various stages of gestation, DFMO was administered in the drinking water to pregnant rats and rabbits at several concentrations (from 0.03% to 3.0%) and times (from days 7, 10, or 11 through days 18 or 19). Rats were killed on day 21 and rabbits on day 29 of pregnancy (day 1 = day of insemination), and the implantations and fetuses were examined. At a concentration of 1.0% (approximately 1,270 mg/kg/day) in rats and 3.0% (approximately 915 mg/kg/day) in rabbits, maternal food and water consumption and body weight gain were significantly reduced during the treatment period, and all implantations were aborted or resorbed. At lower doses (approximately 200-600 mg/kg/day) fetuses survived to term, though in reduced numbers, and a marked reduction in average fetal weight was seen. At levels of 60 mg/kg/day or lower, there were no deleterious effects to the dams or their offspring. Few malformations were detected at any dose level by gross teratologic examination; nor were any considered to have been drug induced because of their sporadic incidence. The embryotoxicity and severe growth retardation demonstrated by these studies verify that adequate polyamine levels are essential for normal embryonic and fetal development.     

Strontium-85 in the fetuses of pregnant rats and mice

Pregnant SPF Wistar rats and ICR/Swiss albino mice were injected in the tail vein with 85SrCl2 with 0.05 mM inactive carrier (SrCl2) given in volumes of 0.1 ml. The activity in the injected volume was about 14 MBq per kg of rat and 13 MBq per kg of mouse. The animals were injected at 2 or 13 days of gestation. The activity retained by the fetuses was quantitatively determined at three stages of the fetal intrauterine development: in rats at 14, 16 and 21 days of gestation, in mice at 14, 16 and 20 days of gestation. The activity of fetuses and/or placentas with fetal membranes was measured using a TESLA automatic gamma counter. Results indicate that fetuses of mice retained a significantly (P less than 0.01) greater percent of strontium activity than fetuses of rats. The highest specific activities (the percentage of total activity retained per gram of fetal tissue) were found in the late pregnancy period (at 21 days of gestation in rats and 20 days of gestation in mice) in animals that were injected with the radionuclide at 13 days of gestation.     

Toxicity of bryostatin‐1 on the embryo‐fetal development of Sprague‐Dawley rats

BACKGROUND: Bryostatin‐1, a highly oxygenated marine macrolide with a unique polyacetate backbone isolated from the marine animal Bugula neritina (Linnaeus), is now being developed as an anti‐cancer drug for treating malignancy. In the present study, developmental toxicity of bryostatin‐1 was evaluated in Sprague–Dawley rats. METHODS: Bryostatin‐1 was intravenously administered to rats on gestation days 6–15 at 4.0, 8.0, and 16.0 µg/kg on a daily basis. Then the reproductive parameters were determined in animals, and fetuses were examined for external, visceral, and skeletal malformations. RESULTS: The total weight gains were significantly different in animals between the control group and 8.0 and 16.0 µg/kg bryostatin‐1 groups during and after treatment. The resorption and death fetus rates were significantly different between the bryostatin‐1 group (16 µg/kg) and the control group. The fetal weight and fetal crown‐rump length in the bryostatin‐1 groups were significantly lower than that in the control group. CONCLUSIONS: Our results indicated that maternal toxicity occurred when the dose of bryostatin‐1 was at 8.0 µg/kg, embryotoxicity at 16.0 µg/kg, and fetotoxicity at 4.0 µg/kg; but bryostatin‐1 showed no teratogenic effect in rats. In light of our findings, bryostatin‐1 should be used with caution in pregnant women with cancer, if they would like to continue the pregnancy. Birth Defects Res (Part B) 89:171–174, 2010. © 2010 Wiley‐Liss, Inc.     

The influence of moderate exercise in diabetic and normal pregnancy on maternal and fetal outcome in the rat

The effect of treadmill exercise prior to and during pregnancy on maternal and fetal outcome was studied in nondiabetic and streptozotocin-induced diabetic rats. Animals were exercised daily on a motorized treadmill (16.1 m/min, 45 min/d) for three weeks prior to mating and throughout gestation. The catabolic state of diabetes was evidenced by changes in maternal body composition. Overall, fetuses of diabetic dams were smaller, lighter, had less calcified skeletons and had more malformations compared to control fetuses. Exercise in the nondiabetic dams resulted in a retardation of skeletal ossification compared to fetuses from sedentary controls. However, exercise improved fetal outcome in diabetic rats, resulting in increased fetal weight and a lower frequency of malformations compared to fetuses from sedentary diabetic dams.     

Oxytocin and vasopressin in the rat do not readily pass from the mother to the amniotic fluid in late pregnancy

In order to see whether the mother contributes to the vasopressin or oxytocin levels of amniotic fluid, these peptides were measured under conditions (1) in which the fetus lacks vasopressin (Brattleboro strain) and (2) where high maternal oxytocin and vasopressin plasma levels were induced by means of a controlled-delivery Accurel-collodion device. No vasopressin could be demonstrated in amniotic fluid of vasopressin-deficient fetuses present in a heterozygous (i.e., vasopressin-synthetizing mother). High peptide levels on the maternal side of Wistar rats generally failed to affect the amniotic fluid levels. The increase that was occasionally seen in amniotic vasopressin was probably due to fetal release concomitant with growth retardation. Amniotic vasopressin is derived from the fetus. Since amniotic fluid oxytocin is neither derived from the mother nor from the fetal brain, other fetal sources should be considered.     

Assessment of immunization against recombinant human bone morphogenetic protein-2 (dibotermin alpha) on reproduction and development in rabbits

BACKGROUND: To determine if the fetus was affected by maternal antibodies to BMP‐2, the antibody response and developmental effects in fetuses from does immunized against recombinant human BMP‐2 were evaluated. METHODS: Female New Zealand White rabbits received four intramuscular injections (on premating days 1, 8, 22, and 43 [3 days before mating]) of saline and adjuvant (TiterMax^® Gold [control]) or recombinant human BMP‐2 (2 mg/dose) and adjuvant (treated). On GD 29, fetuses were examined, and maternal and fetal anti‐BMP‐2 titer levels and neutralizing activity were assessed. RESULTS: Anti‐BMP‐2 antibodies were detected in 17 of 18 treated does (127 of 151 fetuses), and low levels were detected in 2 of 16 control does (no fetal exposure observed). In general, levels of fetal anti‐BMP‐2 antibodies were similar to those in the does, and pregnancy did not boost the immune response to BMP‐2. There were no effects of immunization or anti‐BMP‐2 antibody titer levels on embryo–fetal viability, fetal weight, or fetal external, visceral, or skeletal development. Only a small number of fetuses (n = 4) displayed detectable neutralizing anti‐BMP‐2 antibodies, but there were no treatment‐related effects in those fetuses. CONCLUSIONS: The lack of embryo–fetal effects may be due to dosage effects of neutralizing anti‐BMP‐2 antibodies, timing of exposure (stage and duration) to neutralizing anti‐BMP‐2 antibodies, and/or redundancy of effects of the various BMPs. Birth Defects Res (Part B) 92:543–552, 2011. © 2011 Wiley Periodicals, Inc.     

Developmental toxicity assessment of thermoresponsive poly(N-isopropylacrylamide-co-acrylamide) oligomers in CD-1 mice

BACKGROUND: Although polymers and hydrogels are used successfully in biomedical applications, including implants and drug delivery devices, smaller molecular weight oligomers, such as those investigated here, have not been extensively studied in vivo. Poly(N‐isopropylacrylamide‐co‐acrylamide), or P(NIPAAm‐co‐AAm), has a unique thermoresponsive behavior and is under investigation as a novel drug delivery system for metastatic cancer treatment. To date, no studies have been published regarding the safety of P(NIPAAm‐co‐AAm) to the conceptus. METHODS: From gestation days (GD) 6–16, pregnant CD‐1 mice were dosed via i.p. injection with aqueous solutions containing 500, 750, or 1,000 mg/kg/d P(NIPAAm‐co‐AAm). Dams were sacrificed on GD 17 and their litters were examined for abnormalities. RESULTS: P(NIPAAm‐co‐AAm) caused no statistically significant difference in maternal weight gain or percent resorbed or dead fetuses compared to control values, but fetal weight was significantly decreased in the two highest dosage groups. CONCLUSIONS: At the highest dosages employed, maternal exposure to P(NIPAAm‐co‐AAm) was associated with decreased fetal weight. However, as the estimated human exposure levels for persons using this system would be some 1,500‐fold lower than the lowest dosage administered in this study, the authors feel that this oligomer was not shown to pose a biologically significant risk at relevant human dosages. Birth Defects Res (Part B), 2008. © 2008 Wiley‐Liss, Inc.     

Epoxiconazole‐Induced Degeneration in Rat Placenta and the Effects of Estradiol Supplementation

Epoxiconazole (CAS‐No. 133855‐98‐8) was recently shown to cause both a marked depletion of maternal estradiol blood levels and a significantly increased incidence of late fetal mortality when administered to pregnant rats throughout gestation (GD 7–18 or 21); estradiol supplementation prevented this epoxiconazole effect in rats (Stinchcombe et al., 2013), indicating that epoxiconazole‐mediated estradiol depletion is a critical key event for induction of late fetal resorptions in rats. For further elucidation of the mode of action, the placentas from these modified prenatal developmental toxicity experiments with 23 and 50 mg/kg bw/d epoxiconazole were subjected to a detailed histopathological examination. This revealed dose‐dependent placental degeneration characterized by cystic dilation of maternal sinuses in the labyrinth, leading to rupture of the interhemal membrane. Concomitant degeneration occurred in the trophospongium. Both placentas supporting live fetuses and late fetal resorptions were affected; the highest degree of severity was observed in placentas with late resorptions. Placental degeneration correlated with a severe decline in maternal serum estradiol concentration. Supplementation with 0.5 and 1.0 μg of the synthetic estrogen estradiol cyclopentylpropionate per day reduced the severity of the degeneration in placentas with live fetuses. The present study demonstrates that both the placental degeneration and the increased incidence of late fetal resorptions are due to decreased levels of estrogen, since estrogen supplementation ameliorates the former and abolishes the latter. Birth Defects Res (Part B) 98:208–221, 2013. © 2013 Wiley Periodicals, Inc.     

Fetal lung development in streptozotocin-induced experimental diabetes: cytidylyl transferase activity, disaturated phosphatidyl choline and glycogen levels

The influence of streptozotocin-induced maternal diabetes on choline phosphate cytidylyltransferase activity (EC.2.7.7.15) glycogen content and disaturated phosphatidyl choline in fetal lung was studied between 19 and 21 days of gestation. In this experimental model, induction of maternal diabetes two days after mating, resulted in fetal hyperglycemia and hyperinsulinemia; the fetuses were neither macrosomic nor showed any evidence of fetal growth retardation. The glycogen content of lungs on days 19 and 20, but not on day 21 of gestation was significantly higher in fetuses of diabetic rats than in controls. The pulmonary cytosol cytidylyltransferase activity was similar in the two groups of fetuses on days 19 and 20. On day 21 of gestation the enzyme activity was significantly lower in fetuses of diabetic rats than in those of controls. On day 21 of gestation and in newborns of diabetic mothers, although there was no difference in the total pulmonary phospholipids, the levels of disaturated phosphatidyl cholines were significantly lower than in controls.     

Oxidative stress and diabetes in pregnant rats

A considerable amount of clinical and experimental evidence now exists suggesting the involvement of free radical-mediated oxidative processes in the pathogenesis of diabetic complications. If the diabetic state is associated with a generalized increase in oxidative stress, it might well be reflected in the alterations in embryonic and fetal development during pregnancy. In the present study, incidence of the malformed fetuses, biochemical parameters and antioxidant system activity of streptozotocin (STZ)-induced diabetic pregnant rats was investigated and the results obtained were compared with those of the control group (non-diabetic). Virgin female Wistar rats were injected with 40 mg/kg streptozotocin (STZ) before mating. All the females were killed on Day 21 of pregnancy and the fetuses were analyzed. A maternal blood sample was collected by venous puncture and the maternal liver was removed for biochemical measurement. The diabetic dams presented hyperglycemia, hyperlipemia, hypertriglyceridemia, hypercholesterolemia, hyperuricemia, decreased reduced glutathione (GSH), hepatic glycogen and superoxide dismutase (SOD) determinations. There was an increased incidence of skeletal and visceral malformation in fetuses from diabetic rats. Our findings suggest that oxidative stress occurs in the diabetic pregnant state, which might promote maternal homeostasis alterations. These diabetic complications might be a contributory factor to conceptus damage causing embryonic death (abortion/miscarriage) or the appearance of malformations in the fetuses of diabetic dams. Antioxidant treatment of women with diabetes may be important in future attempts to prevent congenital malformations.