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R J Kavlock

Publications and source records attributed to R J Kavlock.

At least 91 records · Page 5Linked to original sources
PubMed1987

The potential relationship of maternal toxicity, general stress, and fetal outcome.

Standard teratology bioassays generally call for a top dose level which is sufficient to induce some form of overt maternal toxicity such as death or weight loss. The presence of such maternal toxicity is often a confound in the interpretation of experimental results, especially at those dose levels producing the toxicity. While the physiological bases for the toxicity vary widely in a compound-related fashion, one underlying factor that remains constant for most induced toxicity is the presence of generalized stress in the affected animals. Previous studies have indicated that pregnant animals treated acutely with toxic levels of a variety of pharmacologically unrelated chemicals produced litters without a recognizable syndrome of defects, except for an increased incidence of supernumerary ribs (SNR). The present study reports on the effects of immobilization stress on the production of SNR in the Sprague-Dawley rat and the CD-1 mouse. Pregnant animals were immobilized in the supine position for 12-hour periods during the day of greatest sensitivity to SNR production (days 9 and 10 in the mouse and rat, respectively). Animals were killed immediately before term and the fetuses were examined. An increase in SNR was noted in immobilized mice but not rats. These results suggest that such fetal effects may be the result of general agent-induced maternal stress.

Abnormalities, Drug-Induced↗
PubMed1987

Developmental toxicity of dinocap in the mouse is not due to two isomers of the major active ingredients.

Technical-grade dinocap, a complex-mixture fungicide, is teratogenic in the CD-1 mouse, causing cleft palate and otolith defects. In this study we compared the developmental toxicities of 2,4-dinitro-6-(1-methylheptyl)phenyl crotonate and 2,6-dinitro-4-(1-methylheptyl)phenyl crotonate, model isomers of the major active ingredients of technical dinocap, to the known teratogenicity of the technical compound. Individual isomers, both isomers combined, or technical dinocap were administered to pregnant mice on days 7-16 of gestation. Some dams were killed at term and litters were removed, dead fetuses and resorptions were counted, and live fetuses were weighed and preserved in Bodian's fixative for examination for cleft palate. Other treated dams were allowed to give birth: postnatal viability and growth, development of swimming behavior, and otolith formation were evaluated. As in previous studies, technical-grade dinocap caused cleft palate and weight deficits in fetuses at term and increased neonatal mortality and abnormal swimming behavior, torticollis, and deficient otolith formation in surviving pups. Neither of the purified isomers exhibited any developmental toxicity when administered under identical conditions. Thus, it is concluded that these isomers are not the active teratogenic component(s) in technical-grade dinocap.

Animals↗
PubMed1987

Benomyl-induced craniocerebral anomalies in fetuses of adequately nourished and protein-deprived rats.

Benomyl, a benzimidazole fungicide, produced craniocerebral and systemic malformations in fetal rats when administered by gavage in doses of 31.2, 62.5, and 125 mg/kg of maternal body weight on days 7-21 of gestation. Malformations increased in incidence and severity with increasing benomyl dosage and nearly doubled when coupled with a protein-deficient diet. Protein deficiency alone produced only decreased fetal weight. High benomyl doses produced higher percentages of fetal resorptions and late fetal deaths, and these percentages also increased with protein deficiency. A benomyl dose of 62.5 mg/kg in protein-deficiency dams, the optimal combination for a high incidence of anomalies and low fetal wastage, produced hydrocephalus in 69.4% of fetuses, meningocele in 8.2%, encephalocele in 14.3%, exencephaly in 44.9%, anencephaly in 14.3%, corpus callosum agenesis in 26.5%, periventricular necrosis in 26.5%, and periventricular cellular "overgrowth" in 55.1%. The most common combination of anomalies was hydrocephalus, exencephaly, and periventricular "overgrowth." Common systemic malformations included cleft palate, micromelia, hydroureter, and misshapen tails. No fetus was entirely normal at the highest benomyl dose. Benomyl has been shown by others to bind tubulin and inhibit the formation of microtubules that are important in neurulation, mitosis, and cell migration during early brain development. Thus, it is suggested that benomyl, coupled with a protein-deficient diet, offers a teratogenic model with a spectrum of abnormalities similar to hypervitaminosis A but with a higher yield of specific craniocerebral anomalies.

Animals↗
PubMed1987

Fate of adriamycin-induced dilated renal pelvis in the fetal rat: functional and morphological effects in the offspring.

Previously we reported that gestational exposure to Adriamycin, an anthracycline antibiotic used in the treatment of neoplasms, reduced renal function in the neonatal rat, and we suggested that alterations in the development of the renal papilla might be responsible for the dysfunction. In this study we exposed groups of Sprague-Dawley rats to 0, 1.0, 1.25, or 1.5 mg/kg of Adriamycin on gestation days 10-12, a period previously shown to be effective in altering postnatal renal function with this compound. Offspring were evaluated at several developmental periods in order to 1) precisely define the morphological status of the urogenital system in Adriamycin-treated offspring; 2) replicate the finding of a decreased renal concentrating ability in the neonates; 3) determine the transience/permanence of any morphological effect; and 4) correlate any permanent alterations in urogenital morphology with our indicator of neonatal functional competence. Maternal Adriamycin treatment induced alterations in the development of the renal papilla that persisted well into the postnatal life of the offspring. The first appearance of the morphological alteration occurred in the absence of other general indicators of developmental toxicity such as growth retardation. The determination of the ultimate fate and functional consequences of the structural alterations required postnatal evaluations of the renal system. Finally, a relatively simple test of renal function in the neonate proved to be predictive of the permanence of the morphological effect, and the absolute test result showed a strong correlation with the incidence of the morphological effect in the overall population.

Abnormalities, Drug-Induced↗
PubMed1987

Critical prenatal periods for chlorambucil-induced functional alterations of the rat kidney.

Previous studies have demonstrated that exposure of rats to chlorambucil during the period of metanephric differentiation results in morphological and functional alterations of the kidneys after birth. The present study describes the effects of chlorambucil treatment at various gestational ages on neonatal renal function to determine if critical periods other than day 11 exist for inducing functional developmental toxicity of the kidneys. Groups of pregnant Sprague-Dawley rats were exposed to 4.5 mg/kg of chlorambucil on gestation days 9, 11, 13 or 15 and the offspring were evaluated for neonatal growth and viability, gross malformations of the kidneys, and renal physiology. The results demonstrate that the critical period for the induction of specific renal defects and hypoplasia lies on day 11 of gestation, but functional alterations of the kidneys were observed after exposure on day 15 of gestation. In terms of practical application, a combination of the basal clearance test and the renal concentration test together provide an efficient means for detecting prenatally induced functional alterations of the kidneys. When renal malformations or anomalies are observed in standard teratology bioassays, studies using techniques similar to those described here may be extremely useful in determining the biological significance as well as permanence or transience of effects such as renal hypoplasia, dilated renal pelvis, and dilated ureter.

Abnormalities, Drug-Induced↗
PubMed1987

Prenatal exposure to methylmercury alters development of adrenergic receptor binding sites in peripheral sympathetic target tissues.

In order to assess the impact of prenatal exposure to methylmercury on sympathetic neurotransmission, effects on development of adrenergic receptor binding sites in peripheral tissues were evaluated. In the liver, methylmercury produced a dose-dependent increase in alpha 1-, alpha 2- and beta-receptor binding of radioligands throughout the first 5 weeks of postnatal life. Similarly, renal alpha-receptor subtypes showed increased binding capabilities, but binding to beta-receptor sites was reduced. At least some of the changes in receptors appear to be of functional significance, as physiological reactivity to adrenergic stimulation is altered in the same directions in these two tissues. The actions of methylmercury displayed tissue specificity in that the same receptor populations were largely unaffected in other tissues (lung, heart). These results suggest that methylmercury exposure in utero alters adrenergic responses through targeted effects on postsynaptic receptor populations in specific tissues.

Animals↗
PubMed1987

Development of adrenergic receptor binding sites in brain regions of the neonatal rat: effects of prenatal or postnatal exposure to methylmercury.

In order to understand the effects of developmental exposure to methylmercury on the ontogeny of synaptic function, we examined the impact of prenatal or postnatal exposure on acquisition of receptor binding sites for norepinephrine. The actions of the mercurial were both regionally- and receptor subtype-selective and depended upon the maturational profile of each region. alpha 1- alpha 2- and beta-receptor sites in the cerebellum, the region which develops last, were the most vulnerable to methylmercury. In contrast, the same receptor subtypes in the midbrain + brainstem, which develops earliest, were resistant to methylmercury. The cerebral cortex, which matures at a time midway between cerebellum and midbrain + brainstem, also displayed intermediate vulnerability to actions of methylmercury on receptors. Within the cerebellum, prenatal exposure to 1 mg/kg of methylmercury interfered the most with ontogeny of alpha 1-receptor binding, less so for alpha 2-receptors and least for beta-receptors. Lower doses of methylmercury tended to increase receptor binding for all subtypes, a fact which may contribute to promotion of neurological development seen in animals exposed to those levels. These data support the view that methylmercury exerts a dual spectrum of action on developing synapses, with promotional effects predominating at low doses and inhibitory actions at higher doses. The net effect on responsiveness to neurotransmitters is influenced, in part, by the actions on developing receptor sites which are in turn dependent upon the specific regional timetables for cellular maturation and receptor acquisition.

Animals↗
PubMed1987

Pharmacologic probing of mercuric chloride-induced renal dysfunction in the neonatal rat.

Acetazolamide, furosemide, chlorothiazide and amiloride are pharmacologic agents that act primarily in the proximal tubule, loop of Henle, early distal tubule and late distal tubule and collecting duct, respectively. These diuretic agents were used to evaluate the functional integrity of discrete segments of the nephron in the neonatal rat following treatment with a known nephrotoxicant. Six-day old rats were treated s.c. with the proximal tubule toxicant mercuric chloride (1 or 3.2 mg/kg) or saline. Twenty-four hours later, when evidence of mercury nephrotoxicity is detectable, creatinine clearance and the fractional excretion of water and various components of the filtrate were determined using a 2-hr clearance period immediately after injection of a diuretic. The effects of mercury (3.2 mg/kg) were consistent with its ability to cause acute renal failure and proximal tubular necrosis and also indicated an apparent disruption of the cycling of urea in the nephron. A decrease in the fractional excretion of water, combined sodium and potassium and total osmotic solutes indicated that the diuretic response to acetazolamide was markedly attenuated in the mercuric chloride-treated pups whereas the responses to furosemide, chlorothiazide and amiloride were not altered by mercury treatment. Results from this study illustrate the specificity of these diuretics as pharmacologic probes of mercuric chloride induced renal dysfunction and, therefore, support their usefulness as tools in the investigation of renal developmental toxicity.

Acetazolamide↗
PubMed1986

Prenatal exposure to the fungicide dinocap causes behavioral torticollis, ballooning and cleft palate in mice, but not rats or hamsters.

The present study is an evaluation of the developmental toxicity of dinocap in three rodent species using an in vivo teratology screen. Our protocol uses postnatal viability, weight gain, and morphological and behavioral development through weaning to assess the developmental toxicity of compounds. Dinocap administered orally on days 7 to 16 of gestation to the CD-1 mouse resulted in increased postnatal mortality at 25 mg/kg/d (80% in block 1 and 40% in block 2). Many of the treated pups that died during the neonatal period were "ballooned" and had cleft palates. Although there was no treatment related mortality in the 12 mg/kg/d dosage group, 6% (14/226) of these mice and 24% (23/96) of the survivors from the 25 mg/kg/d dosage group displayed torticollis (a twisting of the neck resulting in an abnormal tilting of the head). These tilted-head mice held the head and forepart of the body tilted constantly to one side, both when resting and walking. The tilt was in either direction but was always constant for a given animal; in different mice, the angle varied considerably from almost 0 to 30 degrees. Some mice circled repeatedly in one direction in the home cage, others bobbed their heads and did back-flips, while others rolled over, always rolling in the same direction. In the hamster, developmental toxicity was seen at (100 and 200 mg/kg/d) or near (50 mg/kg/d) maternally toxic doses but no behavioral alterations were noted and none of the pups were ballooned.

Animals↗
PubMed1986

Effects on the fetal rat intestine of maternal malnutrition and exposure to nitrofen (2,4-dichlorophenyl-p-nitrophenyl ether).

The effects of maternal protein-energy malnutrition and exposure to nitrofen on selected aspects of intestinal morphology and function were studied in the fetal rat. Pregnant rats were fed, throughout gestation, diets containing 24% or 6% casein as the sole source of protein. Reduced total food intake produced protein-energy malnutrition (PEM). Each diet group was divided in half and gavaged with either 12.5 mg nitrofen in corn oil/kg/day or corn oil carrier only from days 7 to 21 of gestation. Body weight, intestinal weight, length, and diameter were measured as were villus length (VL), villus width (VW), and number of villi per length of intestine (VMM). Protein (horseradish peroxidase) and lipid absorption were studied histochemically. Lactase and dipeptidase activities were determined in proximal, medial, and distal thirds of the intestine. Results showed that the restricted maternal diet resulted in reduced fetal body weight (BW), intestinal weight (IW) and length (IL), reduced IW/BW and IW/IL ratios, VH, and VMM. The VW was reduced only in the distal third. Protein and lipid absorption were unaffected. Lactase and dipeptidase activities were reduced. Maternal nitrofen exposure resulted in reduced body weight, intestinal size, and lipid absorption, with some evidence of interaction with the diet effects on enzyme activities. It is concluded that effects of maternal malnutrition were extensive, but that nitrofen exposure, at this dosage level, is not likely to contribute to the postnatal fetal mortality rate in either adequately nourished or malnourished rats.

Animals↗
PubMed1986

Co-culture of rat embryos and hepatocytes: in vitro detection of a proteratogen.

The technique of whole embryo culture developed by New [Environ Health Perspect 18:105-110, 1976] provides a sensitive assay to evaluate the effects of a test chemical on embryo development independent of maternal influences. To detect proteratogens, this assay must be coupled with an exogenous metabolic activation system. We have developed methods for the co-cultivation of rat embryos with primary hepatocytes, which offers several advantages over subcellular fractions when providing metabolic activation for in vitro assays. In the present study, rat embryos removed from the dam on day 10 of pregnancy were co-cultivated in vitro with primary cultures of rat, rabbit, or hamster hepatocytes. Embryos co-cultivated with hepatocytes developed normally, as did embryos exposed to a test chemical, cyclophosphamide (CP) in the absence of hepatocytes. When embryos were co-cultivated with hepatocytes and exposed to CP, a dose-related embryotoxicity was observed, indicating metabolic activation of the proteratogen. Using hepatocytes isolated from rats pretreated in vivo with phenobarbital, we observed an increase in CP-induced malformations and embryotoxicity compared to those of embryos exposed to CP in the presence of uninduced hepatocytes. The teratogenic bioactivation of CP was inhibited in vitro by the addition of metyrapone. When similar numbers of hepatocytes were used for metabolic activation of CP the induced embryotoxicity was greater in the presence of rabbit and hamster hepatocytes than with rat hepatocytes. Development of procedures for the culture of rat embryos with hepatocytes from other species suggests the utility of this in vitro system for the investigation of species differences in sensitivity to chemical teratogens.

Animals↗
PubMed1986

The effects of maternal murine cytomegalovirus infection on the mouse conceptus at different gestational stages.

The effects of murine cytomegalovirus (MCMV) on the prenatal development of the CD-1 mouse were investigated. Two sets of experiments were performed. In the first, mice were inoculated with different doses of MCMV on gestational day 7, and in the second, pregnant animals were inoculated with a subacute injection dose at different gestational stages. The effects of maternal infection on pregnancy in terms of maternal sickness, embryo lethality, date of parturition, litter size, postnatal death, and pups' body weight on d 1 and d 3 postpartum were investigated. High-dose MCMV infection on d 7 of pregnancy resulted in a significant increase in early embryo resorption and also in a reduction of the neonatal body weight of surviving pups. Two gestational stages were identified as being especially susceptible to MCMV infection. Most embryonic death as indicated by resorption rates was found after treatment on d 9, whereas perinatal death was most frequent when treatment was done on d 13 of gestation. Still births and neonatal death within 24 h of birth were found commonly in this latter group, which also showed the most pronounced growth retardation. The phenomenon of delay in time of parturition was noted and found to be most significant in groups of animals that were inoculated on d 3 or d 13. This investigation suggests that the effects of MCMV on the CD-1 mouse vary greatly with the age of the embryo and the course of the infection.

Animals↗
PubMed1986

Cell number and size in selected organs of fetuses of rats malnourished and exposed to nitrofen.

The effects of maternal exposure to nitrofen or protein-energy malnutrition on the number and sizes of cells in selected organs of the fetal rat have been studied. Pregnant rats were fed either an adequate (CON) or protein-energy deficient diet (PEM) throughout gestation. Each diet group was divided into two subgroups. One subgroup was gavaged with 25 mg nitrofen/kg body weight on gestational days 7-21 and the other, with corn oil carrier only. Fetal liver, kidneys, intestine, heart, lung, and brain were weighed and assayed for DNA, RNA, and protein. Maternal protein deficiency resulted in a reduction in organ weight and total DNA, RNA, and protein in all six organs. Maternal nitrofen exposure resulted in reduced weight and reduced protein in all organs except the brain. Total DNA and RNA were reduced in intestine, heart, and lung, and total RNA was also reduced in the liver following maternal nitrofen exposure. An interaction between diet and toxin affected lung weight, DNA, RNA, and protein, intestinal total protein, and heart DNA. Protein/DNA ratios were reduced in liver, intestine, and brain in the group fed the inadequate diet and in intestine only following nitrofen exposure. The deficient diet resulted in increased RNA/DNA ratio in the fetal liver and heart and a decreased ratio in the kidney and brain. Nitrofen exposure resulted in a lower RNA/DNA ratio in the liver. The data indicate that maternal protein-energy malnutrition results in smaller organs in the fetuses with fewer cells and containing less protein and RNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Teratogenic effects of the fungicide dinocap in the mouse.

The teratogenic potential of the fungicide dinocap was evaluated in CD-1 mice. Pregnant mice were dosed by intubation with dinocap in corn oil on gestation days 7-16. Doses used were 0, 5, 10, 20, 40, 80, and 120 mg/kg/day, based on day 6 weight. Dams were killed on day 18, at which time fetuses were counted, weighed, and preserved for necropsy or skeletal examination. The highest dose killed 80% of the dams dosed, while 29% of the dams in the 80 mg/kg group died during dosing. There was no dose-related maternal mortality at lower doses. Net maternal weight gain was affected only at 80 mg/kg/day. There were no live fetuses at 120 mg/kg/day. The number of live fetuses per litter was decreased and resorptions increased at 80 mg/kg. Dose-related decreases in gravid uterus weight and fetal weight were significant at all doses of dinocap. Cleft palate was found in fetuses at 5(1/234; 0.4%), 20(46/195; 23.6%), 40(140/185; 75.5%), and 80(63/85; 74.1%) mg/kg/day. There was a dose-related increase in supernumerary ribs and a low frequency of exencephaly and umbilical hernia at high doses. This study shows that dinocap is teratogenic in the CD-1 mouse at doses well below those causing maternal toxicity.

Animals↗
PubMed1986

Renal functional teratogenesis resulting from adriamycin exposure.

Pregnant Sprague-Dawley rats were exposed to adriamycin and offspring were evaluated for renal functional competence. Exposure consisted of 0, 1.0 or 1.5 mg/kg/day by intraperitoneal injection on either gestational days 7-10 or 10-12. The exposed offspring were evaluated for 1) growth and viability; 2) serum concentrations and renal clearances of creatinine, urea, glucose, sodium, potassium, chloride, and total osmotic particles; 3) the ability to excrete an osmotically concentrated urine following fluid deprivation; 4) the ability to excrete an osmotically dilute urine following isotonic volume expansion; and 5) the ability to secrete hydrogen ions following administration of a fixed acid. Exposure during days 7-10 of gestation produced greater evidence of overt developmental toxicity than did exposure during days 10-12 of gestation. The reverse was true, however, for the effects of adriamycin on renal function, as the majority of effects on these measures were found in the high-dose pups exposed during days 10-12 of gestation. The application of the renal function tests did not lower the observed effect level for adriamycin-induced developmental toxicity, but it did provide confirmatory information on the nature of the effect, on the magnitude of the effect in the exposed population, and on the possible morphological site of observed functional lesion. For reasons discussed in the text, a combination of the basal clearance test and the renal concentrating test appears to provide the most efficient means for detecting the presence of prenatally induced functional alterations of the kidneys.

Animals↗
PubMed1986

Toxicity of mercuric chloride to the developing rat kidney. III. Distribution and elimination of mercury during postnatal maturation.

Mercuric chloride is a potent nephrotoxicant in the adult rat, but has little effect on newborns. Nephrotoxicity increases with postnatal maturation. This study assesses the changes in tissue distribution and excretion of Hg during postnatal development. Sprague-Dawley rats were injected sc with 5 mg/kg 203HgCl2 on postnatal Day 1, 8, 15, 22, or 29. Hg concentration was measured in the whole body, renal cortex, medulla and papilla, liver, and subcellular fractions of liver and kidney. Binding to cytosolic metallothionein was assessed. Whole-body elimination of Hg was slow at the three younger age groups, as only 20% of the initial load was eliminated by 5 days after injection. Excretion was much more rapid in the two older groups, which eliminated about half of the initial load within 5 days. Concentration of Hg was highest in renal cortex (the principal site of Hg toxicity), and there was an age-related increase in cortical Hg concentration. This may explain the increased toxicity of Hg with age. There was an age-related decrease in hepatic Hg concentration. The high levels of metallothionein present in perinatal rat liver may protect the renal cortex from receiving a toxic dose of Hg; however, the increased concentration of hepatic Hg in newborns is insufficient to account for all of the cortical decrease. It is probable that Hg was distributed to other tissues. In liver and kidney cells of neonates, Hg concentration was highest in the cytosol, decreasing in an age-related manner. This was accompanied by an age-related increase of Hg in the nuclear/mitochondrial fraction. Hg in the cytosol was largely bound to metallothionein, although there were substantial amounts associated with very low-molecular-weight molecules and high-molecular-weight proteins. There are significant maturational changes in the organ, cellular and subcellular distribution of Hg in the rat during the first 4 weeks after birth. These probably explain the increasing sensitivity with maturity to Hg nephrotoxicity.

Aging↗
PubMed1986

Chlorambucil induced congenital renal hypoplasia: effects on basal renal function in the developing rat.

Administration of chlorambucil to pregnant rats on day 11 of gestation induced dose-related alterations in renal growth and function in the postnatal offspring. These effects occurred above and beyond the reductions in body growth and were evident in animals that displayed no overt malformation of the urogenital tract. Reductions in overall growth amounted to 0, 6 and 15% in the 3,4.5 and 6 mg/kg groups, respectively, while kidney weights were reduced by 7, 15 and 23%. The weights of the kidneys relative to the body were reduced 5, 9 and 10% with increasing dose. Although basal renal function was not affected by the degree of hypoplasia seen in the low dose group, reduced glomerular and tubular function were evident following a basal clearance test in the 2 highest dose groups. The data indicate that chlorambucil induced renal hypoplasia results in reductions in renal function that persist for at least the first 3 weeks after birth in the rat and that physiological assessment of developmental toxicity can provide an extremely useful addendum to the more classical morphological criteria.

Animals↗