The Effect of Maternal Restraint on Developmental Toxicity of Aluminum in Mice

Both aluminum (Al) and maternal restraint have been reported to cause developmental toxicity in mammals. This study assessed in pregnant mice the potential interaction between Al and maternal restraint. Four groups of plug-positive female mice were given IP injections of AlCl₃ at 37.5 and 75 mg/kg/day on days 6–15 of gestation. Two of these groups were also subjected to restraint for 2 h/day during the same gestational days. Control groups included restrained and unrestrained pregnant mice nonexposed to Al. Cesarean sections were performed on gestation day 18, and the fetuses were weighed and examined for morphological defects. Maternal toxicity was significantly enhanced by restraint at 75 mg AlCl₃/kg/day. No increases in the number of resorptions or dead fetuses per litter were observed following exposure to Al, maternal restraint, or combined Al and restraint. However, a significant decrease in fetal body weight, as well as a significant increase in the number of litters with morphologic defects, was observed in the group exposed to 75 mg AlCl₃/kg/day plus maternal restraint. The current results suggest that maternal restraint could enhance the metal-induced developmental toxicity (reduced fetal body weight, increase in the number of litters with morphologic defects) only at high doses of the metal, which are also toxic to the dam.     

Combined effects of perfluorooctane sulfonate (PFOS) and maternal restraint stress on hypothalamus adrenal axis (HPA) function in the offspring of mice

Although it is known that prenatal exposure to perfluorooctane sulfonate (PFOS) can cause developmental adverse effects in mammals, the disruptive effects of this compound on hormonal systems are still controversial. Information concerning the effects of PFOS on hypothalamus adrenal (HPA) axis response to stress and corticosterone levels is not currently available. On the other hand, it is well established that stress can enhance the developmental toxicity of some chemicals. In the present study, we assessed the combined effects of maternal restraint stress and PFOS on HPA axis function in the offspring of mice. Twenty plug-positive female mice were divided in two groups. Animals were given by gavage 0 and 6 mg PFOS/kg/day on gestation days 12-18. One half of the animals in each group were also subjected to restraint stress (30 min/session, 3 sessions/day) during the same period. Five plug-positive females were also included as non-manipulated controls. At 3 months of age, activity in an open-field and the stress response were evaluated in male and female mice by exposing them to 30 min of restraint stress. Male and female offspring were subsequently sacrificed and blood samples were collected to measure changes in corticosterone levels at four different moments related to stress exposure conditions: before stress exposure, immediately after 30 min of stress exposure, and recuperation levels at 60 and 90 min after stress exposure. Results indicate corticosterone levels were lower in mice prenatally exposed to restraint. In general terms, PFOS exposure decreased corticosterone levels, although this effect was only significant in females. The recuperation pattern of corticosterone was mainly affected by prenatal stress. Interactive effects between PFOS and maternal stress were sex dependent. The current results suggest that prenatal PFOS exposure induced long-lasting effects in mice.     

Concurrent exposure to perfluorooctane sulfonate and restraint stress during pregnancy in mice: effects on postnatal development and behavior of the offspring.

The combined effects of maternal restraint stress and perfluorooctane sulfonate (PFOS) on postnatal development and behavior of the offspring were assessed in mice. Thirty-four plug positive females were randomly divided into two groups. Animals were given by gavage 0 and 6 mg PFOS/kg/day on gestation days 12-18. One-half of the animals in each group was subjected to restraint stress (30 min per session, three sessions per day) during the same period. Neither restraint nor PFOS exposure significantly modified maternal food or water consumption. Pups of dams exposed to 6 mg/kg of PFOS showed a reduced body weight on postnatal days 4 and 8. Moreover, PFOS exposure induced some delay in developmental landmarks and neuromotor maturation. Maternal restraint stress reduced activity in an open-field when combined with 6 mg PFOS/kg/day. In addition, in males prenatal restraint stress impaired motor coordination in a rotarod. The current results indicate that concurrent exposure to PFOS and restraint stress during pregnancy induces opposite effects on developmental parameters in the pups. These effects consist in a general delayed maturation trend induced by PFOS exposure, and a general accelerated maturation pattern induced by prenatal stress. Interactive effects between PFOS and maternal stress were observed in young adult mice. These effects consisted mainly in a diminished activity in an open-field test.     

Influence of maternal restraint stress on the long-lasting effects induced by prenatal exposure to perfluorooctane sulfonate (PFOS) in mice

The behavioral effects of concurrent maternal exposure to restraint stress and perfluorooctane sulfonate (PFOS) were assessed in the offspring of mice at 3 months of age. Plug positive females were divided into two groups. Animals were given by gavage 0 and 6mg PFOS/kg/day on gestation days 12-18. One-half of the animals in each group were subjected to restraint stress (30min/session, three sessions per day) during the same period. At 3 months, mice were evaluated for general activity in an open-field, and for learning and memory in a water maze task. The group prenatally exposed to PFOS and restraint presented a reduced mobility in the open-field. In the water maze, an interaction between sex and restraint was observed. Delayed task learning was also detected in females prenatally exposed to PFOS and restraint. An overall effect of restraint was observed in mice on retention of the task, suggesting a better retention in restrained animals. On the other hand, corticosterone levels were lower in animals prenatally subjected to restraint stress. The current results suggest interactive effects between PFOS and maternal stress.     

Perinatal toxicity of endrin in rodents. I. Fetotoxic effects of prenatal exposure in hamsters

The potential of the insecticide endrin to induce fetal toxicity was determined in hamsters exposed to the compound on either day 8 or days 5--14 of gestation. Endrin was administered by oral gavage as a solution in corn oil. Doses used included 0.5--10.0 mg/kg on day 8 and 0.75 to 3.5 mg/kg/day on days 5--14. Exposure to a single dose of endrin resulted in significant incidences of fused ribs and meningoencephaloceles at levels of 5 mg/kg or greater. No significant effects were noted in either maternal mortality and weight gain or in fetal mortality or weight gain. The administration of multiple doses of endrin resulted in few fetal defects, although a significant dose-related increase in fetal mortality and decrease in fetal weight was seen. Significant maternal lethality and weight reductions were noted at doses of 1.5 mg/kg/day or greater. At sacrifice, maternal liver and fetal tissues were collected and subsequently analyzed for endrin and a major metabolite, 12-ketoendrin. Endrin was found to cross the placenta and 20 ppb were found in fetuses from litters exposed to 2.5 mg/kg/day. Maternal livers from this dose group contained an average of 2500 pbb of endrin.     

Effects of prenatal exposure to manganese on postnatal development and behavior in mice: influence of maternal restraint

Manganese (Mn) is an essential trace element whose deficiency and excess have been reported to cause central nervous system (CNS) disturbances. On the other hand, during pregnancy, maternal stress has been shown to enhance the developmental toxicity of a number of metals. In this study, the maternal toxicity and developmental effects of a concurrent exposure to Mn and restraint stress were evaluated in mice. Pregnant animals were divided into three groups and received subcutaneous injections of manganese chloride tetrahydrate (MnCl2.4H2O) at 0, 1 and 2 mg/kg/day on Gestation Days 6-18. Each group was divided into two subgroups. Mice in one subgroup were subjected to restraint for 2 h/day on Days 6-18 of gestation. Pregnant mice were allowed to deliver, and pups were evaluated for physical and neuromotor maturation. Subsequently, adult mice were also evaluated for activity and learning. A significant increase in perinatal mortality was observed at 2 mg/kg/day Mn. A delay in some developmental landmarks (eye opening, testes descent) due to Mn exposure (2 mg/kg/day) was also seen in both restrained and unrestrained animals. No differences in motor resistance and coordination, or in learning at the passive avoidance test, were noted in adult mice. At the current Mn doses, combined exposure to Mn and stress during the prenatal period did not produce long-lasting effects on adult mice.     

Neonatal mortality from in utero exposure to perfluorooctanesulfonate (PFOS) in Sprague-Dawley rats: dose-response, and biochemical and pharamacokinetic parameters

Perfluorooctanesulfonate (PFOS) is a widely distributed, environmentally persistent acid found at low levels in human, wildlife, and environmental media samples. Neonatal mortality has been observed following PFOS exposure in a two-generation reproduction study in rats and after dosing pregnant rats and mice during gestation. Objectives of the current study were to better define the dose-response curve for neonatal mortality in rat pups born to PFOS-exposed dams and to investigate biochemical and pharmacokinetic parameters potentially related to the etiology of effects observed in neonatal rat pups. In the current study, additional doses of 0.8, 1.0, 1.2, and 2.0 mg/kg/day were included with original doses used in the two-generation study of 0.4 and 1.6 mg/kg/day in order to obtain data in the critical range of the dose-response curve. Biochemical parameters investigated in dams and litters included: (1) serum lipids, glucose, mevalonic acid, and thyroid hormones; (2) milk cholesterol; and (3) liver lipids. Pharmacokinetic parameters investigated included the interrelationship of administered oral dose of PFOS to maternal body burden of PFOS and the transfer of maternal body burden to the fetus in utero and pup during lactation, as these factors may affect neonatal toxicity. Dosing of dams occurred for 6 weeks prior to mating with untreated breeder males, through confirmed mating, gestation, and day four of lactation. Dose levels for the dose-response and etiological investigation were 0.0, 0.4, 0.8, 1.0, 1.2, 1.6, and 2.0 mg/kg/day PFOS. Statistically significant decreases in gestation length were observed in the 0.8 mg/kg and higher dose groups. Decreases in viability through lactation day 5 were observed in the 0.8 mg/kg and higher dose groups, becoming statistically significant in the 1.6 and 2.0 mg/kg dose groups. Reduced neonatal survival did not appear to be the result of reductions in lipids, glucose utilization, or thyroid hormones. The endpoints of gestation length and decreased viability were positively correlated, suggesting that late-stage fetal development may be affected in pups exposed to PFOS in utero and may contribute to the observed mortality. Benchmark dose (BMD) estimates for decreased gestation length, birth weight, pup weight on lactation day 5, pup weight gain through lactation day 5, and viability resulted in values ranging from 0.27 to 0.89mg/kg/day for the lower 95% confidence limit of the BMD5 (BMDL5). Results of analyses for PFOS in biological matrices indicate a linear proportionality of mean serum PFOS concentration to maternal administered dose prior to mating and through the first two trimesters of gestation. However, at 21 days of gestation, mean serum PFOS concentrations were notably reduced from values measured earlier in gestation. Urinary and fecal elimination was low as expected from prior observations in adult rats. Significant transfer of PFOS from dam to fetus in utero was confirmed, and results suggest that dam and corresponding fetal body burdens, as indicated by serum and liver PFOS levels, correlate with neonatal survival.     

Prenatal toxicity of Ascaris pepsin inhibitor in mice

The developmental toxicity of pepsin inhibitor isolated from Ascaris suum, a gastrointestinal nematode parasite, was evaluated. An embryo–fetal development study was conducted in BALB/c mice. Groups of 21 mated females were treated by intraperitoneal injection (0.3 ml/30 g body weight) with 0.9% NaCl solution vehicle or isolated Ascaris pepsin inhibitor (API) at dose levels of 50, 100, 150 or 200 mg/kg body weight/day on gestation days (GD) 6–15. Maternal food consumption, body weight, and clinical signs were monitored throughout gestation. Cesarean sections were performed on GD 18 and gravid uterine weight, implantation sites, early and late resorptions, live and dead fetuses were collected. Live fetuses were weighed and examined for external, visceral and skeletal variations and malformations. Maternal body weight gain, gravid uterine weight, food consumption were significantly decreased after injection of higher doses of API (100–200 mg/kg/day). All doses of API exhibited an embryotoxic effect (high rate of intrauterine resorption). The percentage of postimplantation loss in the groups with administered API was higher (over 4–11 times) than that in control group. Fetotoxicity was observed in all treatment groups in a dose-related manner and it was evidenced by increased dead fetuses, decreased fetal weight, increased visceral variations and reduced skeletal ossification. Fetal hydronephrosis and internal hydrocephalus were noted at 150, and 200 mg/kg/day. In summary, the maternal toxicity no-observed-adverse-effect level (NOAEL) was 50 mg/kg/day and the low-observed-adverse-effect level (LOAEL) was 100 mg/kg/day under the conditions of this study. However, the developmental toxicity LOAEL was 50 mg/kg/day based on decreased fetal body weight and prenatal mortality.     

Developmental toxicity of perfluorooctane sulfonate (PFOS) is not dependent on expression of peroxisome proliferator activated receptor-alpha (PPAR alpha) in the mouse

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are members of a family of perfluorinated compounds. Both are environmentally persistent and found in the serum of wildlife and humans. PFOS and PFOA are developmentally toxic in laboratory rodents. Exposure to these chemicals in utero delays development and reduces postnatal survival and growth. Exposure to PFOS on the last 4 days of gestation in the rat is sufficient to reduce neonatal survival. PFOS and PFOA are weak agonists of peroxisome proliferator activated receptor-alpha (PPAR alpha). The reduced postnatal survival of neonatal mice exposed to PFOA was recently shown to depend on expression of PPAR alpha. This study used PPAR alpha knockout (KO) and 129S1/SvlmJ wild type (WT) mice to determine if PPAR alpha expression is required for the developmental toxicity of PFOS. After mating overnight, the next day was designated gestation day (GD) 0. WT females were weighed and dosed orally from GD15 to 18 with 0.5% Tween-20, 4.5, 6.5, 8.5, or 10.5mg PFOS/kg/day. KO females were dosed with 0.5% Tween-20, 8.5 or 10.5mg PFOS/kg/day. Dams and pups were observed daily and pups were weighed on postnatal day (PND) 1 and PND15. Eye opening was recorded from PND12 to 15. Dams and pups were killed on PND15, body and liver weights recorded, and serum collected. PFOS did not affect maternal weight gain or body or liver weights of the dams on PND15. Neonatal survival (PND1-15) was significantly reduced by PFOS in both WT and KO litters at all doses. WT and KO pup birth weight and weight gain from PND1 to 15 were not significantly affected by PFOS exposure. Relative liver weight of WT and KO pups was significantly increased by the 10.5mg/kg dose. Eye opening of PFOS-exposed pups was slightly delayed in WT and KO on PND13 or 14, respectively. Because results in WT and KO were comparable, it is concluded that PFOS-induced neonatal lethality and delayed eye opening are not dependent on activation of PPAR alpha.     

Fetal toxicity of kepone in rats and mice.

Doses of 10, 6, and 2 mg/kg/day of Kepone in CD rats and 12, 8, 4, and 2 mg/kg/day in CD-1 mice were administered to pregnant animals by gastric intubation during the major period of organogenesis, Days 7–16 of gestation. Fetal toxicity was produced in both rats and mice at doses which caused significant reductions in maternal weight gains during gestation and increased liver/body weight ratios. In rats, fetuses from dams receiving the highest dose (which also resulted in 19% maternal mortality) exhibited significant incidences of reduced fetal weight, reduced degree of ossification, edema, undescended testis, enlarged renal pelvis, and enlarged cerebral ventricles. Lower dose levels which also produced maternal weight loss and liver/body weight ratio increase, but no mortality, caused only reduced fetal weight and reduced degree of ossification. Male rats born to dams treated with Kepone during gestation showed no reproductive impairment. In the mouse, fetotoxicity only occurred in the highest dose group and was manifested by increased fetal mortality and clubfoot.     

Developmental toxicity assessment of arsenic acid in mice and rabbits

To evaluate potential effects of exposure to inorganic arsenic throughout major organogenesis, CD-1 mice and New Zealand White rabbits were gavaged with arsenic acid dosages of 0, 7.5, 24, or 48 mg/kg/d on gestation days (GD) 6 through 15 (mice) or 0, 0.19, 0.75, or 3.0 mg/kg/d on GD 6 through 18 (rabbits) and examined at sacrifice (GD 18, mice; GD 29, rabbits) for evidence of toxicity. Two high-dose mice died, and survivors at the high and intermediate doses had decreased weight gains. High-dose-group fetal weights were decreased; no significant decreases in fetal weight or increases in prenatal mortality were seen at other dosages. Similar incidences of malformations occurred in all groups of mice, including controls. At the high dose in rabbits, seven does died or became moribund, and prenatal mortality was increased; surviving does had signs of toxicity, including decreased body weight. Does given lower doses appeared unaffected. Fetal weights were unaffected by treatment, and there were no effects at other doses. These data revealed an absence of dose-related effects in both species at arsenic exposures that were not maternally toxic. In mice, 7.5 mg/kg/d was the maternal No-Observed-Adverse-Effect-Level (NOAEL); the developmental toxicity NOAEL, while less well defined, was judged to be 7.5 mg/kg/d. In rabbits, 0.75 mg/kg/d was the NOAEL for both maternal and developmental toxicity.     

Neonatal death of mice treated with perfluorooctane sulfonate

Pregnant mice exposure to perfluorooctane sulfonate (PFOS) causes neonatal death. Ten pregnant ICR mice per group were given 1, 10 or 20 mg/kg PFOS daily by gavage from gestational day (GD) 0 to the end of the study. Five dams per group were sacrificed on GD 18 for prenatal evaluation, the others were left to give birth. Additional studies were conducted for histopathological examination of lungs and heads of fetuses and neonates at birth. PFOS treatment (20 mg/kg) reduced the maternal weight gain and feed intake but increased the water intake. The liver weight increased in a dose-dependent manner accompanied by hepatic hypertrophy at 20 mg/kg. PFOS reduced the fetal body weight in a dose-dependent manner and caused a bilateral enlargement in the neck region in all fetuses at 20 mg/kg and mild enlargement in some fetuses at 10 mg/kg, in addition to skeletal malformations. Almost all fetuses at 20 mg/kg were alive on GD18 and showed normal lung structure; but at parturition, all neonates were inactive and weak, showed severe lung atelectasis and severe dilatation of intracranial blood vessel, and died within a few hours. At 10 mg/kg, all neonates were born alive, 27% showed slight lung atelectasis, all of them had mild to severe dilatation of the intracranial blood vessel, and 45% of neonates died within 24 hr. The cause of neonatal death in mice exposed to PFOS may be attributed either to the intracranial blood vessel dilatation or to respiratory dysfunction. The former might be a cause of the latter.     

Developmental toxicity of orally administered thiabendazole in ICR mice.

Thiabendazole (TBZ) is a potent anthelmintic and fungicide used in the treatment of parasitic infections in humans and domestic animals and post-harvest protection of agricultural commodities. TBZ is not teratogenic or selectively foetotoxic in rats or rabbits, in contrast to several other benzimidazole derivatives. However, when administered orally to pregnant (Jcl:ICR) mice at lethal dosages, malformations were observed in treated fetuses. To assess whether the effects found in this previous study were attributable to maternal toxicity or TBZ the present study was conducted. TBZ doses of 25, 100 or 200 mg/kg/day were selected based on a preliminary range-finding study in which maternotoxicity was evident at doses of 200 mg/kg/day or above. The compound was administered during gestation days 6-15 as a solution in olive oil. Caesarean sections were completed on gestation day 18 and complete fetal examinations conducted. Decreases in maternal weight gain relative to controls were found at doses of 100 mg/kg/day or above, which paralleled decreases in foetal weights in these same dose groups. However, there were no treatment-related external, visceral or skeletal anomalies in any treatment group. Therefore, TBZ was not teratogenic or selectively foetotoxic in mice, with no-observed-effect levels (NOEL) of 25 and greater than 200 mg/kg/day for maternal and fetal weight effects and teratogenicity, respectively. These results indicate that foetal effects noted in previous studies in mice were probably secondary to severe maternal toxicity.     

Developmental toxicity of perfluorooctane sulfonate (PFOS) is not dependent on expression of peroxisome proliferator activated receptor-alpha (PPARα) in the mouse

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are members of a family of perfluorinated compounds. Both are environmentally persistent and found in the serum of wildlife and humans. PFOS and PFOA are developmentally toxic in laboratory rodents. Exposure to these chemicals in utero delays development and reduces postnatal survival and growth. Exposure to PFOS on the last 4 days of gestation in the rat is sufficient to reduce neonatal survival. PFOS and PFOA are weak agonists of peroxisome proliferator activated receptor-alpha (PPARα). The reduced postnatal survival of neonatal mice exposed to PFOA was recently shown to depend on expression of PPARα. This study used PPARα knockout (KO) and 129S1/SvlmJ wild type (WT) mice to determine if PPARα expression is required for the developmental toxicity of PFOS. After mating overnight, the next day was designated gestation day (GD) 0. WT females were weighed and dosed orally from GD15 to 18 with 0.5% Tween-20, 4.5, 6.5, 8.5, or 10.5 mg PFOS/kg/day. KO females were dosed with 0.5% Tween-20, 8.5 or 10.5 mg PFOS/kg/day. Dams and pups were observed daily and pups were weighed on postnatal day (PND) 1 and PND15. Eye opening was recorded from PND12 to 15. Dams and pups were killed on PND15, body and liver weights recorded, and serum collected. PFOS did not affect maternal weight gain or body or liver weights of the dams on PND15. Neonatal survival (PND1–15) was significantly reduced by PFOS in both WT and KO litters at all doses. WT and KO pup birth weight and weight gain from PND1 to 15 were not significantly affected by PFOS exposure. Relative liver weight of WT and KO pups was significantly increased by the 10.5 mg/kg dose. Eye opening of PFOS-exposed pups was slightly delayed in WT and KO on PND13 or 14, respectively. Because results in WT and KO were comparable, it is concluded that PFOS-induced neonatal lethality and delayed eye opening are not dependent on activation of PPARα.     

The Developmental Toxicity of Bisphenol A in Rats and Mice

The Developmental Toxicity of Bisphenol A in Rats and Mice.MORRISSEY, R. E., GEORGE, J. D., PRICE, C. J., TYL, R. W., MARR,M. C., AND KIMMEL, C. A. (1987). Fundam. Appl. Toxicol. 8, 571–582.Bisphenol A (BPA) was evaluated for developmental toxicity inCD rats (0, 160, 320, or 640 mg/kg/day) and CD-1 mice (0, 500,750, 1000, or 1250 mg/kg/day) dosed daily by gastric intubationon Gestational Days 6 through 15. Timed-pregnant dams were sacrificed1 day prior to parturition, the uterine contents were examined,and all fetuses were examined for external, visceral, and skeletalmalformations. In rats, maternal weight gain during gestation,weight gain corrected for gravid uterine weight, and weightgain during treatment were significantly reduced at all BPAdoses. Gravid uterine weight and average fetal body weight perlitter were not affected by BPA. No increase in percentage resorptionsper litter or percentage fetuses malformed per litter was detected.In mice, maternal mortality occurred at all BPA doses, reaching18% at the high dose, which also produced a significant decreasein maternal body weight gain during gestation and treatment.Weight gain corrected for gravid uterine weight was not affectedby BPA. Reductions in gravid uterine weight and average fetalbody weight were observed with the 1250 mg/kg dose of BPA. Relativematernal liver weight was increased at all doses of BPA. Therewas a significant increase in the percentage of resorptionsper litter with 1250 mg BPA/kg/day. Malformation incidence wasnot altered by BPA. Thus, BPA treatment at maternally toxicdose levels during organogenesis produced fetal toxicity inmice but not in rats and did not alter fetal morphologic developmentin either species.     

Exposure of pregnant rats to uranium and restraint stress: effects on postnatal development and behavior of the offspring

The effects on postnatal development and behavior were assessed in the offspring of female rats concurrently exposed to uranium (U) and restraint stress. Adult female rats were administered uranyl acetate dihydrate (UAD) in the drinking water at doses of 0, 40 and 80 mg/(kg day) for 4 weeks before mating with untreated males, as well as during pregnancy and lactation. One-half of female rats in each group were concurrently subjected to restraint (2h/day). On gestation day 14, one-half of restrained and unrestrained rats were sacrificed in order to evaluate maternal toxicity and gestational parameters. Pups were evaluated for physical development, neuromotor maturation, and behavior. Uranium concentrations were also determined in various tissues of dams and fetuses. In all uranium-treated groups, the highest concentrations of this element were found in kidney and bone, being considerably higher than those in brain. Uranium levels in tissues of dam or fetuses were not significantly affected by restraint. No significant interactions between uranium and restraint could be observed in maternal toxicity. Moreover, no relevant effects of uranium, maternal restraint, or their combination were noted on developmental landmarks in the offspring. In the passive avoidance test, at 40 and 80 mg UAD/(kg day) restraint significantly modified passive avoidance acquisition (T1) and retention time (T2) 24h later. However, no significant differences were observed on the Morris water maze test. The results of the present study indicate that, in general terms, exposure of female rats to UAD before mating with untreated males, as well as during gestation and lactation, did not cause relevant dose-related adverse effects on postnatal development and behavior of the offspring. The influence of stress was very limited.     

Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. I: maternal and prenatal evaluations.

The maternal and developmental toxicities of perfluorooctane sulfonate (PFOS, C8F17SO3-) were evaluated in the rat and mouse. PFOS is an environmentally persistent compound used as a surfactant and occurs as a degradation product of both perfluorooctane sulfonyl fluoride and substituted perfluorooctane sulfonamido components found in many commercial and consumer applications. Pregnant Sprague-Dawley rats were given 1, 2, 3, 5, or 10 mg/kg PFOS daily by gavage from gestational day (GD) 2 to GD 20; CD-1 mice were similarly treated with 1, 5, 10, 15, and 20 mg/kg PFOS from GD 1 to GD 17. Controls received 0.5% Tween-20 vehicle (1 ml/kg for rats and 10 ml/kg for mice). Maternal weight gain, food and water consumption, and serum chemistry were monitored. Rats were euthanized on GD 21 and mice on GD 18. PFOS levels in maternal serum and in maternal and fetal livers were determined. Maternal weight gains in both species were suppressed by PFOS in a dose-dependent manner, likely attributed to reduced food and water intake. Serum PFOS levels increased with dosage, and liver levels were approximately fourfold higher than serum. Serum thyroxine (T4) and triiodothyronine (T3) in the PFOS-treated rat dams were significantly reduced as early as one week after chemical exposure, although no feedback response of thyroid-stimulating hormone (TSH) was observed. A similar pattern of reduction in T4 was also seen in the pregnant mice. Maternal serum triglycerides were significantly reduced, particularly in the high-dose groups, although cholesterol levels were not affected. In the mouse dams, PFOS produced a marked enlargement of the liver at 10 mg/kg and higher dosages. In the rat fetuses, PFOS was detected in the liver but at levels nearly half of those in the maternal counterparts, regardless of administered doses. In both rodent species, PFOS did not alter the numbers of implantations or live fetuses at term, although small deficits in fetal weight were noted in the rat. A host of birth defects, including cleft palate, anasarca, ventricular septal defect, and enlargement of the right atrium, were seen in both rats and mice, primarily in the 10 and 20 mg/kg dosage groups, respectively. Our results demonstrate both maternal and developmental toxicity of PFOS in the rat and mouse.     

Evaluation of the developmental toxicity of 2,3-dimercapto-1-propanesulfonate (DMPS) in mice. Effect on mineral metabolism

The sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS), a potent chelating agent used in the treatment of inorganic and organic heavy metal intoxications was evaluated for developmental toxicity in pregnant Swiss mice. DMPS was administered by gavage at doses of 0, 75, 150 and 300 mg/kg per day on gestational days 6-15. Females were evaluated for body weight gain, food consumption, appearance and behavior, survival rates and reproduction data. Cesarean sections were performed on gestation day 18. There were no maternal toxic effects, and no treatment-related changes were recorded in the number of total implants, resorption, the number of live and dead fetuses, fetal body weight or fetal sex distribution data. Gross external, soft tissue and skeletal examination of the DMPS-treated fetuses did not show significant differences at any dose in comparison with the controls. Mineral analysis of maternal and fetal tissues revealed slight effects of DMPS on metabolism of calcium, magnesium, zinc, copper and iron. The results of this study in mice indicate that DMPS is not a developmental toxicant at levels up to 300 mg/kg per day.     

Skin absorption of hexafluoroacetone: teratogenic and lethal effects in the rat fetus.

Hexafluoroacetone trihydrate (HFA) was applied to the skin of pregnant rats from Day 6 through 16 of gestation. All rats were killed on Day 21 with uterine weights, fetal survival, number of resorptions, live fetal weights plus crown-rump lengths, and gross abnormalities by external examination determined at necropsy. The fetuses were processed for examination of visceral/neural anomalies and skeletal abnormalities. In a range-finding study, doses were from 2.3 to 90 mg/kg/day. At 90 mg/kg/day signs of maternal toxicity were observed. At 40 mg/kg/day and above, all but one of 36 fetuses were resorbed. At all doses nonlethal to fetuses, teratogenic effects were suggested. Based on maternal toxicity and embryolethality observed in the range-finding study, doses of either 1, 5, or 25 mg/kg/day were used in the main study. Fetal toxicity, measured by number of resorptions and live fetuses per litter, was evident at 25 mg/kg/day. At 5 and 25 mg/kg/day the mean fetal weights and crown-rump lengths were significantly lower than those of the controls and maternal weight gain was adversely affected. Teratogenic effects consisting of gross external, internal soft-tissue, and skeletal abnormalities were observed at 5 and 25 mg/kg/day. At 1 mg/kg/day a possible treatment-related increase in fetal gross external and internal soft-tissue abnormalities was observed.     

The developmental toxicity of uranium in mice

To evaluate the developmental toxicity of uranium, 5 groups of 20 pregnant Swiss mice were given by gavage daily doses of 0, 5, 10, 25 and 50 mg/kg of uranyl acetate dihydrate on gestational days 6-15. Cesarean sections were performed on all females on gestation day 18. Fetuses were examined for external, visceral, and skeletal abnormalities. The results indicated that such exposure resulted in maternal toxicity as evidenced by reduced weight gain and food consumption during treatment, and increased relative liver weight. There were no treatment-related effects on the number of implantation sites per dam, or on the incidence of postimplantation loss (resorptions plus dead fetuses). The number of live fetuses per litter and the fetal sex ratio were not affected by the treatment. However, dose-related fetal toxicity, consisting primarily of reduced fetal body weight and body length, and an increased incidence of abnormalities was observed. Malformations (cleft palate, bipartite sternebrae) and developmental variations (reduced ossification and unossified skeletal variations) were noted at the 25 and 50 mg/kg per day test levels. Therefore, administration of uranyl acetate dihydrate during organogenesis in mice produced maternal toxicity at 5, 10, 25 and 50 mg/kg per day. The "no observable effect level" (NOEL) for fetotoxicity including teratogenicity was below 5 mg/kg per day, as some anomalies were observed at this dose. There was no evidence of embryolethality at any dosage level used in this study.