Maternal Water Consumption Research Articles

Evaluation of the Developmental Toxicity of Ethylene Glycol Aerosol in the CD Rat and CD-1 Mouse by Whole-Body Exposure

Evaluation of the Developmental Toxicity of Ethylene Glycol Aerosol in the CD Rat and CD-1 Mouse by Whole-Body Exposure. Tyl, R. W., Ballantyne, B., Fisher, L. C., Fait, D. L., Savine, T. A., Dodd, D. E., Klonne, D. R., and Pritts, I. M. (1995). Fundam. Appl. Toxicol.24, 57-75.Ethylene glycol (EG) is a major industrial chemical, shown to be teratogenic at high doses by gavage in rodents. Since one route of industrial exposure is to the aerosol at high concentrations, timed-pregnant CD rats and CD-1 mice were exposed, whole-body, to a respirable aerosol of EG (mass median aerodynamic diameter, 2.3 μm) on Gestational Days (GD) 6 through 15 for 6 hr per day at target exposure concentrations of 0, 150, 1000, or 2500 mg/m3 (analytical concentrations of 0, 119 ± 13, 888 ± 149, and 2090 ± 244 mg/m3, respectively), with 25 plug-positive animals per species per group. Clinical observations and maternal body weights were documented throughout gestation for both species. Maternal food and water consumption was measured in rats only throughout gestation. At scheduled necropsy (GD 21 for rats, GD 18 for mice), maternal animals were evaluated for body weight, liver weight, kidney weight, gravid uterine weight, number of ovarian corpora lutea, and status of implantation sites, i.e., resorptions, dead fetuses, live fetuses. Fetuses were dissected from the uterus, counted, weighed, sexed, and examined for external, visceral, and skeletal malformations and variations. All rat dams survived to scheduled termination. Minimal maternal toxicity was indicated by a significant increase in absolute and relative liver weight at 2500 mg/m3. Food and water consumption, maternal body weights and weight gain, and maternal organ weights (other than liver) were unaffected by exposure. Gestational parameters were unaffected by exposure, including pre- and post-implantation loss, live fetuses/litter, sex ratio, and fetal body weight/litter. There was no treatment-related increase in the incidence of any individual malformation, in the incidence of pooled external, visceral, or skeletal malformations, or in the incidence of total malformations by fetus or by litter. There were no increases in the incidence of external or visceral variations. Evidence of fetotoxicity, expressed as reduced ossification in the humerus, the zygomatic arch, and the metatarsals and proximal phalanges of the hind-limb, was observed at 1000 and 2500 mg/m3. All mouse dams survived to scheduled termination. One dam at 2500 mg/m3 was carrying a totally resorbed litter at termination. Maternal toxicity was observed at 1000 and 2500 mg/m3, expressed as reduced body weight and weight gain during and after the exposure period, and reduced gravid uterine weight. (Maternal effects may have been due, in part or in whole, to effects on the conceptuses; see below.) Embryo/fetal toxicity was also observed at 1000 and 2500 mg/m3, expressed as an increase in nonviable implantations/litter, a reduction in viable implantations/litter, and reduced fetal body weights (male, female, and total)/litter. The incidences of individual and pooled external, visceral, and skeletal malformations were increased at 1000 and 2500 mg/m3, as was the incidence of total malformations. Malformations were found in the head (exencephaly), face (cleft palate, foreshortened and abnormal face, and abnormal facial bones), and skeleton (vertebral fusions, and fused, forked, and missing ribs). The incidences of many fetal variations were also increased at 1000 and 2500 mg/m3 (and only a few at 150 mg/m3). The no observable adverse effect level (NOAEL) for maternal toxicity in rats was 1000 mg/m3 (analytical concentration 888 mg/m3) and in mice was 150 mg/m3 (analytical concentration 119 mg/m3). The NOAEL for development toxicity in rats was 150 mg/m3 and in mice was at or below 150 mg/m3, under the conditions of this study. Analysis of EG on the fur of rats and mice during and after the exposure period at 2500 mg/m3 indicated that much of the EG "dose" (∼65-95%) was potentially derived from ingestion after grooming and/or percutaneous absorption. This contribution of the ingested and/or absorbed chemical could have been sufficient, per se, to produce the teratogenic effects observed in mice. The definitive evaluation of the possible role of inhaled EG aerosol alone in teratogenesis requires an exposure regimen which limits or precludes exposure by any other route.

The developmental toxicity of boric acid in mice, rats, and rabbits.

Boric acid (BA) is a naturally occurring agent used in manufacturing processes and numerous consumer products. Because of the potential for both industrial and consumer exposure to boron-containing compounds, and the lack of developmental toxicity data, the National Toxicology Program evaluated the potential for boric acid to cause developmental toxicity in pregnant Swiss (CD-1) mice, Sprague-Dawley rats (n = 26-28/group), and New Zealand rabbits (n = 18-23/group). BA was provided in the feed to mice and rats at 0, 0.1, 0.2, or 0.4% throughout gestation to attain steady-state exposure as early as possible during development. Average doses (mg/kg/day) were 248, 452, or 1003 for mice, and 78, 163, or 330 in rats. A separate group of rats received 0.8% BA in the feed, or 539 mg/kg/day only on gestation days (gd) 6 to 15. Rabbits were given BA (0, 62.5, 125, or 250 mg/kg) by gavage administration on gd 6 to 19. Maternal body weight, food and/or water consumption and signs of toxicity were monitored at regular intervals. At termination, gd 17 (mice), 20 (rats), or 30 (rabbits), the uterus was examined to determine the number of resorptions, dead, or live fetuses. Fetuses were weighed and live fetuses were examined for external, visceral, and skeletal defects. Mouse dams exhibited mild renal lesions (> or = 248 mg/kg/day BA), increased water intake and relative kidney weight (1003 mg/kg/day BA), and decreased weight gain during treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased testis growth and sperm production in adult rats following transient neonatal goitrogen treatment: optimization of the propylthiouracil dose and effects of methimazole

Treatment of male rat pups with the reversible goitrogen 6-propyl-2-thiouracil (PTU), administered by adding 0.1% PTU to the mother's drinking water from birth to day 25, increases their testis size and daily sperm production (DSP) at 160 days of age by up to 80% and 140%, respectively. The purpose of this study was to examine the effectiveness of various concentrations of PTU and determine the PTU dose that would maximize testis growth while minimizing side effects such as decreased maternal water consumption and decreased pup growth. Whether this effect was specific to PTU was determined by evaluating the effects of another commonly used goitrogen, methimazole (MMI), in increasing adult testis size and sperm production. Dams were given PTU (0.1-0.0004% w/v) or 0.025% MMI (w/v) in their water from birth to day 25 post partum, then given no further treatment. Thyroxine concentrations were measured in all groups of pups at 25, 35 and 45 days, and testis weight and DSP were determined at 90 days of age. At 25 days of age, thyroxine concentrations were maximally decreased by PTU treatments of 0.0015% or greater; less severe decreases were produced by 0.0004% PTU or 0.025% MMI. Thyroxine concentrations increased in all treated groups at day 35 compared with day 25, and returned to normal by day 45. At 90 days of age, testis weight was increased by about 40% in rats whose mothers had been treated with doses of 0.006% PTU or greater, whereas testis weights in groups given 0.0015 and 0.0004% PTU or 0.025% MMI were increased 31, 15 and 18%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Prenatal cocaine exposure in the laboratory mouse: Effects on maternal water consumption and offspring outcome

Pregnant mice were given 50 mg/kg cocaine HCl (1% solution, sc) once daily from gestation days 7 through 18 (sperm positive = day 0; term = day 19). Pair-fed and untreated control groups were also used. The pregnant cocaine-treated females showed normal weight gain and food consumption but had significantly increased water consumption. The cocaine-treated group had a significant increase in embryonic resorptions but no significant effects on stillbirths or postnatal mortality. The offspring of cocaine-treated females had significantly reduced birth weights and postnatal weight gains up to the age of 28 days. There was also a delay in their ear opening but not in other maturational milestones. Increased water consumption following cocaine treatment has been reported by other studies. We speculate that cocaine has a diuretic effect. We discuss the implications of this effect during pregnancy.

The effects of water source on reproductive outcome in Fischer-344 rats.

To investigate the relation between maternal water consumption and pregnancy loss, we conducted a reproductive toxicology study using Fischer rats. On day 0 of gestation, dams were assigned to tapwater, commercial bottled water, or purchased high pressure liquid chromatography grade water. On day 20 of gestation, we killed the dams and removed their litters for examination. There were no marked effects of dietary water source on maternal body weight, number of implantation sites, number of live fetuses, sex of offspring or number of resorptions per litter. Fetal length and weight, placenta weight, and soft tissue and skeletal malformations were also similar among groups. The tapwater group had somewhat higher resorption frequency (5.3%) and frequency of affected fetuses (6.5%) than those fed bottled water (3.8% and 4.5%, respectively).

A teratologic evaluation of continuous‐wave, daily ultrasound exposure in unanesthetized pregnant rats

Pregnant Sprague-Dawley rats were trained to remain immobile when placed in water in an ultrasound exposure tank and exposed to 0, 0.1, 2.0, or 30.0 W/cm2 ISPTA (spatial peak, temporal average), 3.0-MHz continuous wave (cw) ultrasound on embryonic (E) days 4-19 for approximately 15 min/day. On E20 fetuses were removed; weighed; examined for external, skeletal, and visceral malformations; and uteri were examined for resorptions. Analyses revealed no increase in pre-implantation loss and no effects on maternal body weight, food, or water consumption. No increase in skeletal or visceral malformations was found, in fact exposed groups had a lower incidence of defects than controls. A significant increase in resorptions in the lowest exposure group (0.1 W/cm2) was obtained, but the effect was isolated, non-dose dependent and not credible as a treatment-related effect. No reduction in fetal weight was obtained, in fact the lowest (0.1-W/cm2) and middle (2.0-W/cm2) exposure level groups weighed slightly more than controls. The immobility procedure succeeded in avoiding anesthetization or forced restraint of the dams, thereby eliminating these factors as potential confounders. The results demonstrated that in unanesthetized, unrestrained rats in utero exposure to incident intensities of ultrasound of up to 30.0 W/cm2 cw ultrasound (or estimated internal exposures of 4-21 W/cm2, depending on body orientation to the incident beam) produced no evidence of embryotoxicity based on fetal necropsy data.

Interactive effects of prenatal alcohol and cocaine exposures on postnatal mortality, development and behavior in the Long-Evans rat

Polydrug abuse has increased substantially in recent years amongst obstetric patients. One of the most common drug combinations is alcohol and cocaine. To better understand the adverse consequences of this drug combination on pregnancy and the offspring, alcohol (2 g/kg, b.i.d.) and cocaine HCl (30 mg/kg, b.i.d.) were administered individually and in combination to separate groups of pregnant Long-Evans rats from gestation days 7–20. The pregnant dams were evaluated for maternal weight gain, food and water consumption, mortality, and gestational length. The offspring were evaluated for physical maturation, mortality, and behavior. The drug combination was found to have greater effects regarding decreased birth weight, increased postnatal mortality, and delayed physical maturation than either drug alone. Drug treatments also influenced activity monitor behavior in that prenatal cocaine exposure was associated with hypoactivity while the alcohol and the alcohol-plus-cocaine treatments were associated with hyperactivity in periweanling pups. Drug treatments had no significant effects on passive or active avoidance behaviors. These results suggest that combining alcohol and cocaine increases the risk to the offspring.

Maternal Water Consumption During Pregnancy and Congenital Cardiac Anomalies

This case-control study, conducted in a California county that had a local incident of water contamination in 1981, investigated the relation between a mother's reported consumption of tap water during pregnancy and congenital cardiac anomalies in their offspring born during 1981-1983. Data were obtained from telephone interviews with 145 mothers of children born with a severe cardiac anomaly and 176 mothers of children born without such an anomaly. A positive association between a mother's consumption of home tap water during the first trimester of pregnancy and cardiac anomalies in her infant was unrelated to the incident of water contamination, the mother's race, or her educational level. A negative relation was found between a mother's use of bottled water and cardiac anomalies among the infants. These findings corresponded primarily to births in 1981. These data could not fully distinguish between a potential causal agent in the water and differential reporting of exposure by study subjects.

The developmental toxicity of orally administered theophylline in rats and mice

Theophylline (THEO), a widely prescribed anti-asthmatic, was evaluated for developmental toxicity. It was administered continuously on Gestational Days 6 through 15 to pregnant Sprague-Dawley (CD) rats in the feed (0, 0.15, 0.30, or 0.40%) and to pregnant Swiss (CD-1) mice in the drinking water (0, 0.075, 0.15, or 0.20%). Estimated intake of THEO for rats was 0, 124, 218, or 259 mg/kg/day, while for mice it was 0, 282, 372, or 396 mg/kg/day. In rats, maternal weight gain parameters (weight gain during gestation and treatment, as well as corrected weight gain) decreased at 0.40%. While food consumption was lower only in the 0.40% treatment group, water consumption was higher in all treated groups. There was a dose-related decreasing trend in gravid uterine weight. The number of live fetuses per litter decreased at 0.40% and the average male and female fetal weight per litter decreased at 0.30 and 0.40%. There was no increase in malformations. In mice, maternal corrected body weight and weight gain during gestation decreased at 0.15 and 0.20%, and weight gain during treatment and gravid uterine weight decreased at 0.20%. Water consumption was reduced by as much as 30–45% of controls at 0.15 and 0.20%, respectively, while food consumption did not change with THEO treatment. There was an increase in percentage resorptions per litter and a decrease in the average male and female fetal weight per litter at 0.15 and 0.20%. An increasing trend was noted for percentage malformed fetuses per litter, and percentage litters with externally malformed fetuses were slightly increased in the mid- and high-dose groups. However, these increases were not statistically significant. In summary, there were developmental effects seen in rats at a dose (0.30%) that did not produce overt maternal toxicity, but the adverse developmental effects in mice were observed at doses that caused reduced maternal water consumption and body weight gain. It is possible that water deprivation contributed to the effects seen in mice after THEO treatment. For maternal toxicity, no observable adverse effect levels (NOAELs) were 218 mg/kg for rats and 282 mg/kg for mice. NOAELs for developmental toxicity were 124 mg/kg for rats and 282 mg/kg for mice. These NOAELs are approximately 10- to 30-fold greater than doses required to maintain humans on serum THEO concentrations that are clinically useful.

Inhalation developmental toxicity study of propylene oxide in Fischer 344 rats

The developmental toxicity potential of propylene oxide (PO) was evaluated in Fischer 344 rats following inhalation exposure. Four groups of 25 mated female rats were exposed to 0, 100, 300, and 500 ppm of PO for 6 hr per day on Gestation Days 6 through 15, inclusive. Cesarean sections were performed on all females on Gestation Day 20 and the fetuses removed for morphological evaluation. Exposure to propylene oxide did not adversely affect survival, appearance, or behavior at any of the exposure levels tested. Maternal body weight gain and food consumption were reduced significantly among the females at the 500 ppm level during the exposure period. No exposure-related effects were noted with respect to maternal water consumption, organ weights, cesarean section, or fetal morphological observations with the sole exception of increased frequency of seventh cervical ribs in fetuses at the maternally toxic exposure level of 500 ppm. In summation, the no-observable-adverse-effect level (NOAEL) of propylene oxide, when administered to Fischer 344 rats via whole-body inhalation exposure, was considered to be 300 ppm.

The effects of inhalation exposure to sulfuryl fluoride on fetal development in rats and rabbits

Sulfuryl fluoride is a fumigant insecticide used for soils and permanent structures. Pregnant Fischer 344 rats and New Zealand White rabbits were exposed to 0,25, 75, or 225 ppm of sulfuryl fluoride vapor via inhalation for 6 hr/day on Days 6–15 and 6–18 of gestation, respectively. Among rats, maternal water consumption was increased in the 225 ppm exposure group, but there were no indications of embryotoxicity, fetotoxicity, or teratogenicity in any of the exposed groups. Among rabbits, maternal weight loss during the exposure period (Days 6–18) was observed in the 225 ppm group. Decreased fetal body weights, considered secondary to maternal weight loss, were also observed at 225 ppm. However, no evidence of embryotoxicity or teratogenicity was observed among rabbits in any exposure group. Thus, inhalation exposure to sulfuryl fluoride was not teratogenic in either rats or rabbits exposed to levels of up to 225 ppm, and fetotoxic effects (reduced body weights) were observed among fetal rabbits only at an exposure level that produced maternal weight loss.

Quantitative measurement of water consumption patterns in lactating female and neonatal Fischer 344 rats employing [ 14C]methylcellulose

Lactating female and neonatal Fischer 344 rats were given water containing [ 14C]methylcellulose, a nonabsorbed marker, over a 24-hr interval on Days 13, 15, 18, 21, 24, and 27 postpartum. The amount of water consumed was calculated based on the 14C activity recovered in the feces and gastrointestinal tract. Maternal water consumption during the first 28 days postpartum, when expressed as g/kg/day, averaged 2.5 times the level consumed by nonlactating female rats. Maternal water consumption peaked on Day 21 postpartum at 3.3 times the level measured in nonlactating female rats of comparable age. Neonatal water consumption began on Day 18 postpartum and by Day 28 postpartum was 1.9 times the level observed in nonlactating females. Average neonatal water consumption between Days 21 and 28 postpartum was 1.3 times the level for nonlactating female rats. These data indicate that when the test material is administered via the drinking water the dose levels received by the maternal and neonatal rats have been routinely underestimated, and that conclusions concerning the dose-response relationship or increased sensitivity during this period must be tempered by these results.

Developmental toxicity evaluation of dietary di(2-ethylhexyl)phthalate in Fischer 344 rats and CD-1 mice

Di(2-ethylhexyl)phthalate (DEHP), a widely used plasticizing agent, was evaluated for developmental toxicity in timed-pregnant Fischer 344 rats (22–25 dams/dose) and CD-1 mice (24–30 dams/dose). DEHP was administered in the diet on gestational Days (gd) 0 through 20 at 0.0, 0.5, 1.0, 1.5, or 2.0% (rats) and on gd 0 through 17 at 0.00, 0.025, 0.05, 0.10, or 0.15% (mice). At termination (gd 20, rats; gd 17 mice), al fetuses were examined for external, visceral, and skeletal malformations and variations. In rats, maternal toxicity and reduced fetal body weight per litter were observed at 1.0, 1.5, and 2.0%. Increased resorptions and decreased number of live fetuses/litter were observed at 2.0%. Maternal food consumption was reduced and water consumption was increased in all DEHP groups. The number and percentage of fetuses malformed per litter were unaffected by treatment. In mice, maternal toxicity, increased resorptions and late fetal deaths, decreased number of live fetuses, and reduced fetal body weight per litter were observed at 0.10 and 0.15%. Maternal food and water consumption exhibited a dose-related upward trend with food consumption significantly increased at 0.15%. The number and percentage of fetuses malformed per litter (open eye, exophthalmia, exencephaly, short, constricted, or no tail, major vessel malformations, fused or branched ribs, and fused or misaligned thoracic vertebral centra) were elevated at 0.05, 0.10, and 0.15% DEHP. In conclusion, DEHP was not teratogenic at any dose tested in Fischer 344 rats when administered in the feed throughout gestation but did produce maternal and other embryofetal toxicity at 1.0, 1.5, and 2.0%. In contrast, DEHP administration throughout gestation in CD-1 mice resulted in an increased incidence of malformations at doses which produced maternal and other embryofetal toxicity (0.10 and 0.15%) and at a dose (0.05%) which did not produce significant maternal toxicity. No treatment-related embryofetal toxicity including teratogenicity was observed in mice at 0.025% or in rats at 0.5% DEHP.

Endogenous vasopressin and the weaning period in brattleboro rats

Vasopressin, which is important for behavior and brain development, begins to influence osmoregulation with the onset of weaning. We studied the role of vasopressin in the development of feeding behavior since its mechanisms might be essential for the age determination of the suckling and weaning periods. Radionuclide methods were employed to follow maternal milk, solid food and water consumption in developing Brattleboro rats. The appearance of solid food intake and the spontaneous extinction of maternal milk intake indicated the onset and the end of weaning. The absence of endogenous vasopressin did not influence the onset and/or the duration of the weaning period. Both vasopressin-deficient homozygous Brattleboro rats and their heterozygous littermates (with preserved vasopressin synthesis) began to consume solid food and water at the age of 16 days and their intake of maternal milk was terminated about the 27th day of age. Thus, the maturation of feeding behavior in the suckling and weaning periods is vasopressin-independent.

Cadmium-induced fetal growth retardation: Protective effect of excess dietary zinc

Reproductive performance and fetal cellular growth and development were investigated in laboratory rats chronically fed low drinking water levels (0, 1.0, 10.0, and 100 μg/ml) of cadmium (Cd), a known embryotoxic trace element, through gestation. Maternal daily food and water consumption, total weight gain, maternal weight gain, and feed efficiency all decreased with increasing Cd consumption. Term fetal weight was significantly less than that of control subjects only in the group fed 100 μg Cd/ml drinking water. Total litter weight, however, gradually decreased with increasing Cd concentration due to reduced litter size. Fetal growth retardation was a result of decreased cell division (DNA) and cell growth (protein/DNA ratio). When dams were pair-fed the average daily amount of food consumed by those fed 100 μg Cd/ml drinking water, maternal weight gain and fetal weight, DNA, and protein/DNA ratio were increased, but not to control levels. Dietary zinc (Zn) supplementation (5.0 μg/ml drinking water) of Cd-fed dams increased maternal food consumption and fetal weight, DNA, and protein/DNA ratio to control levels. Fetal levels of Cd were extremely low (0.038 to 0.095 μg/gm fetus) and did not increase with increasing Cd consumption, while placental Cd increased more than 10-fold. Fetal Zn was decreased in Cd-fed dams, and Zn supplementation increased fetal Zn levels, but not to control levels. These results suggest that Cd-induced fetal growth retardation is an indirect rather than a direct effect, resulting from reduced maternal food consumption and metabolism. Since dietary Zn blocks these effects, Cd may be a result of induced Zn deficiency.