Biomedical subjects

R J Kavlock

Publications and source records attributed to R J Kavlock.

At least 109 records · Page 6Linked to original sources

PubMed1986

Effects of neonatal methylmercury exposure on adrenergic receptor binding sites in peripheral tissues of the developing rat.

Neonatal exposure to methylmercury produces changes in patterns of tissue growth and function, in part, due to alterations in adrenergic neuronal input. To explore the mechanisms by which these changes come about, newborn rats were exposed to methylmercury (1 or 2.5 mg/kg per day) throughout the preweaning stage and the ontogeny of adrenergic receptor binding sites evaluated in liver, kidney, heart and lung, using [3H]prazosin (alpha 1-receptors), [3H]rauwolscine (alpha 2-receptors) and [125I]pindolol (beta-receptors). In the kidney, methylmercury caused decreases in beta- and alpha 1-receptor binding and increases in alpha 2-binding; previous work has shown that beta-receptor-mediated responses are generally enhanced in methylmercury-exposed pups, and the down-regulation of beta-receptor binding thus probably represents a compensatory action secondary to alterations in post-receptor coupling mechanisms. The effects of methylmercury on hepatic adrenergic receptors were different from those seen in the kidney, with substantial elevations in beta- and alpha 1-receptor binding apparent in the preweaning stage; this agrees also with the differences in effects of the mercurial on trophic reactivity and growth in the 2 tissues. Despite the fact that methylmercury causes activation of neonatal cardiac sympathetic nerves, beta-receptor binding sites in the heart were unaffected by methylmercury exposure; the failure to down-regulate cardiac postsynaptic receptors in the face of increased nerve activity again represents an anomaly of synaptic regulatory function. These results indicate that methylmercury alters adrenergic responsiveness, in part, through actions on the development of receptor binding sites, and further, that the organ-specificity and receptor subtype-selectivity are consistent with subsequent effects of the organomercurial on adrenergic participation in target organ growth; however, changes in receptor binding alone do not account for all of the effects of methylmercury on synaptic activity or trophic responses.

Aging↗

PubMed1986

Effects on the fetus of maternal nitrofen exposure in the protein-deprived rat.

The separate and combined effects of protein deprivation and nitrofen exposure were studied in the pregnant rat. Animals were fed diets containing 24, 8, 6 or 4% casein throughout gestation. Within each diet group, subgroups were gavage-fed with 12.5 (lower dose) and 25 (higher dose) mg nitrofen/kg body weight or with oil carrier only on days 7-21 of gestation. Dams were weighed and food intake was measured daily. On day 21 of gestation, cesarean-derived pups were examined for congenital anomalies and dissected for determination of organ weights. Skeletons were alizarin-stained and examined for skeletal anomalies and developmental stage. No effects on the skeleton or gross congenital anomalies were seen. Fetal size and weights of liver, kidney, intestine, heart, lung and brain were reduced with decreasing casein content of the diet and as a result of the higher dose of nitrofen. An effect of interaction between diet and nitrofen exposure was shown in the kidney, intestine and lung weights. Specific toxicity affecting organ size was shown to occur in the intestine and lung. An interaction between diet and nitrofen specifically affected kidney and intestine. Brain size tended to be preserved, a possible protective mechanism negated by nitrofen exposure. The data suggest also that kidney, intestine and lung are particularly affected. Effects, however, occur primarily in young of severely malnourished dams receiving a relatively high dose of nitrofen.

Abnormalities, Drug-Induced↗

PubMed1986

Functional consequences of prenatal methylmercury exposure: effects on renal and hepatic responses to trophic stimuli and on renal excretory mechanisms.

The effects of prenatal exposure to methylmercury on the functional development of renal and hepatic response systems was examined in the developing rat. Methylmercury produced an elevation of basal activity of renal ornithine decarboxylase (ODC, an enzyme involved in regulation of cellular maturation) and an eventual relative hypertrophy; liver ODC was reduced and hypertrophy was not evident. In contrast, the reactivity of liver ODC to trophic stimulants (vasopressin, isoproterenol) was markedly enhanced by prenatal methylmercury exposure, whereas renal ODC responses were much less affected (vasopressin) or actually reduced (isoproterenol). Targeted actions of methylmercury on renal excretory function were also prominent, with increased fractional excretions of urea and electrolytes and an eventual reduction in glomerular filtration as assessed by creatinine clearance. In addition, the reactivity of the kidney to challenge with desmopressin was altered coincidentally with the appearance of the effects on basal clearance mechanisms. These studies show that doses of methylmercury ordinarily associated with selective actions on development of neurobehavioral patterns also influence the functional ontogeny of other organ systems; furthermore, the fact that the target tissues are different for prenatal vs. postnatal methylmercury exposure, indicates that the functional teratology of methylmercury exhibits critical periods of sensitivity.

Animals↗

PubMed1986

Effects on the fetus of maternal benomyl exposure in the protein-deprived rat.

The separate and combined effects of protein deprivation and benomyl [(methyl 1-butylcarbomoyl)-2-benzimidazole carbamate] exposure were studied in the pregnant rat fed a diet containing 24% (control) or 8% (deficient) casein throughout gestation. Within each diet group, subgroups were gavaged at 31.2 mg/kg body weight with benomyl or corn-oil carrier only on d 7-16 or 7-21 of gestation. No effects on the skeleton were seen. Benomyl exposure in the last 2 wk in dams fed the 24% casein diet resulted in a high incidence of fetal brain anomalies. This effect did not occur in those with benomyl exposure during the period of organogenesis only and was reduced in groups fed the protein-deficient diet. Exposure to benomyl in the last 2 wk in the protein-deprived rat resulted in a decrease in the weight of the fetal heart in excess of that attributable to diet alone. Lungs were a smaller portion of body weight in fetuses of benomyl-treated dams in both diet groups. The teratogenic effect on the brain in animals exposed to benomyl in wk 2 and 3 of gestation suggests that screening for teratogenic effects during organogenesis only may be insufficient.

Administration, Oral↗

PubMed1986

Kidney morphology and function in the young of rats malnourished and exposed to nitrofen during pregnancy.

The separate and combined effects of prenatal protein deficiency (6% casein) and prenatal nitrofen (2,4-dichlorophenyl-p-nitrophenyl ether) exposure (12.5 mg/kg on gestational d 7-21) on renal morphology in the 21-d fetal and postnatal rat were examined. Body weights and kidney weights were reduced in prenatally protein-deprived (PPD) pups at birth and on postnatal day (PND) 10. Numbers of mature glomeruli, creatinine clearance, water diuresis, and response of antidiuretic hormone (ADH), but not the concentrating ability, were lower in the PPD neonates. These changes suggest that prenatal protein deficiency delays renal development and possibly results in a decrease in glomerular clearance and in tubular response to a water load and to antidiuretic hormone. Prenatal nitrofen exposure reduced body weight and kidney size on PND 0 and 10. An increased incidence of hydronephrosis was indicated in the nitrofen-exposed fetus. Prenatal nitrofen exposure depressed the ability to excrete excess water, the response to ADH, and urine-concentrating ability. The functional deficits indicate tubular dysfunction, but little or no effect on glomerular function, as indicated by the absence of an effect on creatinine clearance. Postnatal survival was reduced to 22% by PND in the PPD plus nitrofen pups. Also, prenatal nitrofen exposure increased the susceptibility of the glomeruli in the gestational day (GD) 21 PPD fetus to the adverse effects of prenatal protein deficiency. By PND 10 the toxic effects were of the same order. Renal dysfunction may contribute to the increased mortality in PPD plus nitrofen pups by reducing the ability to respond to stress, but the effects are not sufficiently marked to be considered the primary cause of death.

Animals↗

PubMed1986

Pharmacologic probing of renal development in the neonatal rat.

This study was designed to examine the ontogeny of renal functions in the neonatal rat using various pharmacologic agents as probes. The renal responses of 2-, 6-, and 10-day-old rats to diuretic agents known to act on proximal tubules, loops of Henle and distal tubules were assessed. These included acetazolamide, furosemide, mercaptomerin, chlorothiazide and amiloride. Following administration of a diuretic agent, urine was collected at 90-min intervals for 6 h and urine volume, osmolality, chloride and pH were measured. Acetazolamide, furosemide, chlorothiazide and amiloride induced diuresis at each age indicating that the respective reabsorptive mechanisms were present and functional by 2 days of age. At all ages furosemide evoked a maximal response in eliminating the interstitial fluid gradient as indicated by the formation of an isosmotic urine in treated pups. However, the volume of the diuresis at 2 days of age was half those at 6 and 10 days, reflecting enhanced activity of the countercurrent multiplication apparatus in the maturing pups. Administration of mercaptomerin did not produce pharmacologic diuresis, but rather resulted in acute renal failure; although the nephrotoxicity was to a lesser extent in 2-day-old pups. The ability of the neonatal rat to respond to these pharmacologic probes demonstrates that the integrity of these renal functions is established in this species early in postnatal life.

Acetazolamide↗

PubMed1985

The postnatal effects of prenatal exposure to low doses of nitrofen (2,4-dichlorophenyl-p-nitrophenyl ether) in Sprague-Dawley rats.

Nitrofen was administered to pregnant Sprague-Dawley rats by gavage on days 8-16 of gestation at 5 different dose levels--0, 0.46, 1.39, 4.17 and 12.5 mg/kg/day. Diaphragmatic hernias were found in pups that died immediately after birth at the 3 highest dose levels. At the 1.39-mg/kg dose level 3 of the 4 pups examined had diaphragmatic hernias, at the 4.17-mg/kg dose level 2 out of 3 pups had diaphragmatic hernias, and at the 12.5-mg/kg dose level all 5 pups found dead had diaphragmatic hernias. Locomotor activity of the offspring was measured on postnatal days 17 and 24, and hyperactivity was evident at the 3 highest dose levels. However, when the rats were later tested at 45, 49 and 90 days of age they had apparently recovered from this earlier hyperactivity. In the female rat, nitrofen did not delay the onset of puberty as measured by the age of vaginal opening or the age at first estrus. At necropsy of the offspring which began on postnatal day 133, Harderian gland weight reduction and hydronephrosis were seen at the 4.17- and 12.5-mg/kg dose levels, while no effects were found in body, liver, testes, seminal vesicle, kidney, or lung weights. Results of the present study and earlier studies demonstrate that rats are more sensitive than mice to the teratogenic effect of nitrofen (Gray et al., Science, 215 (1982) 293 and Gray et al., Toxicol. Appl. Pharmacol., 67 (1983) 1). In general, nitrofen affects the same organ systems in rats as it does in mice, but the rank order of sensitivity of these effects differs from those described earlier in the mouse by Gray et al. (Toxicol. Appl. Pharmacol., 67 (1983) 1).

Animals↗

PubMed1985

The effect of acute maternal toxicity on fetal development in the mouse.

The effects of acute alterations in maternal health status upon fetal development were assessed following exposure of pregnant CD-1 mice on day 8 of gestation to one of ten chemicals at doses calculated to exert either a low or a moderate degree of maternal lethality. The dams were killed on day 18 of gestation, and the fetuses were examined by routine teratological techniques. The chemicals were cacodylic acid, caffeine, deltamethrin, dinoseb, ethylene bisisothiocyanate sulfide (EBIS), endrin, guthion, kepone, sodium salicylate, and toxaphene. Three (cacodylic acid, EBIS, and kepone) produced dose-related increases in the incidence of dams with completely resorbed litters. Prenatal mortality in litters that contained live fetuses at term was elevated only for one chemical (cacodylic acid). Fetal weight was reduced in three instances (cacodylic acid, endrin, and guthion), while the incidence of terata was markedly elevated for two (cacodylic acid and kepone). For two other chemicals (endrin and sodium salicylate), a low incidence was found of defects that were similar to defects induced by those chemicals in other species. These effects appear to be chemospecific in nature and not the result of some indirect maternal action. Thus, maternal health status, as measured by the incidence of lethality in the treated groups and by the magnitude of maternal weight gain in surviving females, presents no simple explanation for many manifestations of fetal toxicity. However, for seven chemicals (excluding deltamethrin, EBIS, and kepone) an increased incidence of supernumerary ribs was observed. For three of these seven chemicals (caffeine, dinoseb, and toxaphene), supernumerary ribs was the only observed fetal effect. There was a significant linear inverse relationship between maternal weight gain during gestation and the incidence of extra ribs in the treated groups compared to their respective controls. Under the experimental conditions of this study, it appears that the incidence of supernumerary ribs increased in response to a nonspecific maternal toxicity.

Abnormalities, Drug-Induced↗

PubMed1985

Early biochemical detection of adverse effects of a neurobehavioral teratogen: influence of prenatal methylmercury exposure on ornithine decarboxylase in brain and other tissues of fetal and neonatal rat.

Ornithine decarboxylase (ODC), an enzymatic regulator of macromolecule synthesis, has proven useful as a biochemical marker for teratologic events. Daily administration of methylmercury (0.5 or 1 mg/kg s.c.) to pregnant rats during the second and third trimesters had a profound effect on ODC in whole fetus that was detectable as early as 13 days of gestation. Levels of enzyme activity in fetal brain also showed a marked increase centered about gestational day 17 as well as a significant elevation during early postnatal life; in the latter case, the cerebellum appeared to be a major target for methylmercury-induced aberrations. These effects were accompanied by little or no alteration in general growth rate, brain weights, or weights of other tissues (liver, heart, lung). Furthermore, no other tissue displayed such dramatic effects on ODC activity. Lowering the dose of methylmercury by an order of magnitude (0.05 to 0.1 mg/kg), levels which are associated with almost purely neurobehavioral effects of the teratogen, still resulted in clear-cut elevations of both whole fetus ODC and fetal and neonatal brain ODC. These results indicate that a sensitive biochemical detection procedure used in the fetus/neonate can successfully predict the subsequent tissue-specific damage to neurotransmitter systems and behavior resulting from methylmercury.

Aging↗

PubMed1985

Toxicity of sodium fluoride to the postnatally developing rat kidney.

The adult rat kidney is an important target organ for sodium fluoride; however, the toxicity of fluoride to the developing kidney is unknown. This study examined renal function following NaF exposure during the first 4 weeks after birth. Sprague-Dawley rats received a single ip injection of 0, 30, or 48 mg/kg NaF on postnatal Day 1, 8, 15, or 29. Alterations in renal function, histology, and morphology were determined 24, 48, and 120 hr after exposure. Measurements of renal function included urine volume, osmolality, the ability to concentrate urine during water deprivation, urinary pH, and chloride content. Rats were then sacrificed and their kidneys processed for observation by light microscopy. Some minor alterations in renal function were observed in the three youngest age groups after NaF exposure. These changes included decreased body weight after treatment with 30 or 48 mg/kg NaF but increased kidney-body weight ratio in the 48 mg/kg group on Day 1; decreased urinary pH in both dose groups after treatment on Day 1 or 8; increased urinary volume 120 hr after treatment on Day 8; and decreased chloride excretion in the 48 mg/kg group 24 hr after injection on Day 1. None of these effects was severe. In contrast to these results, marked renal toxicity was observed in postweaning rats treated on Day 29. The NaF exposure resulted in increased kidney weight and kidney/body weight ratio, profound diuresis, decreased urinary osmolality, and decreased ability to concentrate urine during water deprivation. Urinary chloride excretion was decreased for the first 2 days after NaF exposure, then increased in water-deprived rats 120 hr after treatment. Glucosuria and hematuria were present for 2 days after treatment with 48 mg/kg. Histological lesions were apparent in the proximal tubules of the treated Day 29 rats. Thus, the kidney of the suckling rat is largely unresponsive to NaF toxicity. Renal sensitivity increases abruptly after weaning in the Day 29 rat.

Aging↗

PubMed1985

Amphotericin B- and folic acid-induced nephropathies in developing rats.

The kidneys of newborn rats, which are both morphologically and physiologically immature, have been shown to be relatively insensitive to the nephrotoxic effects of several chemicals. To examine the specificity of these age-related differences, pups received sc injections of either 20 mg/kg of amphotericin B or 250 mg/kg folic acid, two known nephrotoxins in adult animals, on postnatal Day 1, 8, or 15. Renal function was examined by a basal clearance test and a hydropenia challenge at 1, 2, or 5 (6 in the case of amphotericin B) days after treatment. We observed no difference in degree of renal toxicity with age, but repair of renal damage tended to proceed slower at the youngest age. Amphotericin treatment produced uremia, increased fractional excretion of water and sodium, a decreased fractional excretion of urea, and a diminished hydropenia response but no change in creatinine clearance and no renal pathology. The observed pattern of renal toxicity may be attributed to an inability to maintain urea gradients in the distal segment of the nephron. Folic acid treatment resulted in greatly increased kidney weights with marked pathology, uremia with decreased creatinine clearance, increased fractional excretion of water, and a decreased hydropenia response. Unlike the renal toxicity observed following amphotericin treatment, renal toxicity from folic acid appears to be a nonspecific response to cell injury within the renal tubules. The data indicate that, in general, neonates do not possess a relative insensitivity to nephrotoxins and that renal physiological measurements which can be performed in neonatal rats are useful in evaluating and interpreting alterations in renal function.

Aging↗

PubMed1985

Biochemical and functional alterations in renal and cardiac development resulting from neonatal methylmercury treatment.

Administration of methylmercury (1 or 2.5 mg/kg daily) to neonatal rats caused alterations in both cardiac and renal growth patterns. Heart weights were elevated in the preweaning period in association with hyperplasia (supranormal DNA content); after weaning, the cardiac overgrowth regressed and there was an eventual hypoplasia as evidenced by low DNA content in young adulthood. Renal overgrowth was more pronounced and persistent, but reflected a pure hypertrophy, with no changes in DNA. Renal function was affected by neonatal methylmercury exposure, as assessed through basal clearance techniques. In the immediate period after beginning treatment, there was an impairment of renal function (elevated serum urea, creatinine and osmolality; increased fractional excretions of water, sodium and osmotic particles), with a return to normal by 10 days postnatally. Thereafter, there was a secondary phase of tubular impairment which peaked at the time of maximum hypertrophy. Thus, biochemical and functional indices of organ development can be adversely affected at doses of methylmercury which are usually associated primarily with nervous system-specific damage; effects of methylmercury on neuronal and/or hormonal factors may contribute to the perturbations.

Animals↗

PubMed1985

Effects of neonatal methylmercury exposure on development of nucleic acids and proteins in rat brain: regional specificity.

Exposure of neonatal rats to methylmercury (1 or 2.5 mg/kg SC daily) during the preweaning period caused regionally-specific alterations in DNA, RNA and protein content in brain. In midbrain + brainstem, where neuronal replication and differentiation conclude early, reduced DNA content was prominent at either dose and was apparent well before evidence of general body growth impairment; small deficits in protein content and brain region weight were seen. In contrast, cerebral cortex showed an elevation of DNA in the high dose group and a tendency toward supranormal RNA values at either dose. In cerebellum, where maturation occurs last, both DNA and RNA were markedly stimulated in pups receiving either 1 or 2.5 mg/kg and little effect was seen on proteins or region weight. These results indicate that the response of the developing central nervous system to cell loss caused by methylmercury is dependent upon the stage of development at which exposure occurs: whereas clear-cut reductions in cell number (DNA content) occur in fairly mature, post-replicative regions, those areas undergoing rapid replication and differentiation are likely to exhibit compensatory stimulation or replacement of cells.

Animals↗

PubMed1984

Toxicity of mercuric chloride to the developing rat kidney. II. Effect of increased dosages on renal function in suckling pups.

It has been demonstrated that the sensitivity to HgCl2 nephrotoxicity increases with maturity in the rat, and that neonates are largely unaffected by a dose of 5 mg/kg. In the present study, immature rat pups were exposed to higher doses of HgCl2 to determine whether this effect was attributable to a quantitative or qualitative difference in the renal sensitivity to HgCl2. Sprague-Dawley rats were injected with a single dose of 5, 7.5, 10, 12.5, 20, or 30 mg/kg on Postnatal Day 1; 5, 7.5, 10, 12.5, 15, or 20 mg/kg on Day 8; or 6.25, 7.5, 10, or 12.5 mg/kg on Day 15. Renal function was evaluated at 24, 48, and 120 hr after treatment by measuring urine volume, osmolality, urinary pH, and chloride content, the ability to concentrate urine during water deprivation, and the presence of protein, glucose, or hemoglobin in urine. Animals were then killed and their kidneys weighed. A dose of 20 mg/kg was needed to induce mortality in pups treated at 1 day of age, and 15 mg/kg was needed in pups treated at 8 days of age. In contrast, the 6.25-mg/kg dose given to 15-day-old pups produced some mortality, and all rats given higher doses at 15 days of age died within 2 days. There was marked oliguria or anuria in the rats that died. Kidney weight was increased in a dose-related fashion at all ages. In those animals not rendered oliguric by the treatment, urine volume increased and the ability to secrete a more concentrated urine during water deprivation decreased. Urinary pH was decreased in a dose-related manner. Urinary chloride excretion was temporarily decreased after HgCl2 treatment on Day 1 , but was increased thereafter. Proteinuria, glucosuria, and hematuria were detected in the treated rats, again increasing in frequency and severity with age and dose.

Age Factors↗

PubMed1984

An extended evaluation of an in vivo teratology screen utilizing postnatal growth and viability in the mouse.

A teratology test system proposed by Chernoff and Kavlock utilizes growth and viability for 3 days after birth to prioritize chemicals for standard teratology testing. The present study is an extended observation of the growth and viability of Chernoff and Kavlock's animals from 41 treatments for 250 days to determine if neonatal weight reductions persisted throughout life, if mortality occurred later in life or, if other serious abnormalities developed that could not be anticipated from the neonatal data. One chemical which was positive in the present study would be a false negative in the standard teratology test and the Chernoff/Kavlock Assay (CKA). Congo red did not cause frank malformations or mortality but it specifically altered reproductive function in the offspring. Two chemicals produced a variety of unusual abnormalities that were not apparent in the neonates, indicating that postnatal testing is necessary to determine the full teratogenic potential of some compounds. Mice exposed prenatally to cytosine arabinoside became hydrocephalic and 30% of them lacked lower incisors. Nitrofen caused hydrocephaly, the age of eye-opening was delayed, a few of the mice had no eyes, and most of the mice lacked Harderian glands. Eighteen of the 41 treatments caused mortality of 15%, or greater, by day 3, and four of these treatments resulted in additional mortality past the neonatal period. No compound caused a decrease in viability after the neonatal period without also reducing days 1 or 3 litter sizes, validating the use of this measurement in the CKA. Cytosine arabinoside was administered later in gestation than the CKA dosing regime and caused a marginally significant increase in mortality near birth but killed over 50% of the pups after weaning. Altering the duration or period of exposure in the CKA may necessitate a longer postnatal evaluation than presently recommended. Neonatal weight, the second parameter used in the CKA to prioritize chemicals for additional testing, appears to be less useful than viability. It was a poor predictor of subsequent growth, some early weight effects persisted, while most of those concurrent with maternal weight reductions were transient. A correlation analysis of the parameters measured in the CKA and in the present study, excluding the compounds that produce frank malformations, indicated that compounds that reduced maternal weight gain during dosing had fewer live pups and growth was transiently retarded.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1983

Electrocardiographic responses of rat fetuses with clamped or intact umbilical cords to acute maternal uterine ischemia.

Uterine ischemia results in severe cardiac disturbances in the fetus. It has been postulated that these effects are due to interaction between the fetus and the ischemic uterus or placenta, and not to hypoxia or buildup of metabolites in the fetus. Rat fetal cardiac responses to uterine clamping and umbilical cord clamping were compared by electrocardiography. On day 21 of gestation, fetuses in a total of 14 pregnant rats were exposed to umbilical clamping, uterine clamping, or no clamping. Electrocardiograms were recorded for each fetus immediately after clamping and at 10, 20, and 30 minutes after clamping. Immediately after clamping, the uterine clamping group alone showed severe sinus bradycardia. At all other observation times, fetuses exposed to uterine or umbilical clamping showed bradycardia and other electrocardiographic changes typically associated with hypoxia. Therefore, umbilical clamping protected the fetuses from the adverse effects of uterine clamping for only a very short time.

Animals↗

PubMed1983

Toxicity of mercuric chloride to the developing rat kidney. I. Postnatal ontogeny of renal sensitivity.

Although the sensitivity of the adult rat kidney to mercuric chloride has been widely reported, the degree to which this toxicant affects the developing kidney is unknown. Therefore, this study examined the effects of HgCl2 on renal function during postnatal maturation. Sprague-Dawley rats were treated with a single sc injection of 5 mg/kg HgCl2 on Day 1, 8, 15, 22, or 29 after birth. The effects on renal function, histology, and morphology were assessed 24, 48, and 120 hr after each treatment. Measurements of renal function included urine volume, osmolality, the ability to concentrate urine during water deprivation, urinary pH, chloride and protein content, tests for glucosuria, hematuria, and various serum chemistry parameters. Rats were killed and their kidneys processed and examined by light microscopy. The renal sensitivity to HgCl2 increased throughout maturation for every parameter measured. No pups treated with HgCl2 on Day 1 died, but mortality increased to almost 20% in rats treated 22 and 29 days after birth. Body weight was unaffected in Day 1 animals, but was decreased at 120 hr post-treatment in three of the other four age groups. Kidney weights were unaffected in 1- and 8-day olds, but were increased by 10 to 55% in rats that were 15, 22, and 29 days old. Urine volume was increased 48 to 72 hr following treatment at all ages. The ability to concentrate urine in response to water deprivation was compromised in all animals with the exception of those treated on Day 1, and was decreased to the greatest extent in 29-day-olds. Urinary chloride concentration was decreased in Day-22 animals at 24 and 48 hr, and in Day-29 rats at all times observed after injection. Urinary pH was more acidic in treated suckling pups, and more basic in treated pups after weaning on Day 22. Urinary protein content was increased after exposure in all but the pups treated on Day 1. Serum creatinine was increased at 120 hr after injection in Day-8 rats, and 24 and 48 hr after injection in older rats. Glucosuria and hematuria occurred with increasing frequency as the pups matured. Histological evaluation revealed some cortical tubular dilatation in rats treated on Day 1 or Day 8; there was tubular necrosis in older rats. For all parameters observed, the neonatal kidney was largely insensitive to HgCl2 toxicity; however, a trend toward increased sensitivity with increasing age was demonstrated.

Age Factors↗

PubMed1983

Postnatal developmental alterations following prenatal exposure to the herbicide 2,4-dichlorophenyl-p-nitrophenyl ether: a dose response evaluation in the mouse.

Although nitrofen, 2,4-dichlorophenyl-p-nitrophenyl ether, is a relatively nontoxic herbicide, prenatal exposure to doses considerably less than the LD50 value for adult rats and mice produces numerous developmental defects that become apparent as the animals mature. In the present study postnatal development was observed following prenatal exposure during Days 7 to 17 of gestation at doses of 0, 6.25, 12.5, 25, 50, 100, 150, and 200 mg/kg/day. These doses did not cause maternal toxicity as indicated by the viability of the dams or maternal weight gain during pregnancy. By 3 days of age all pups in the two highest dose groups were dead and 50% had died in the 100 mg/kg/day dose group. Some of the dead and moribund pups from the 200 mg/kg/day exposure group necropsied at three days of age had cleft palate (15%) or diaphragmatic hernia (6%). In addition, about 22% of the pups at 200 mg/kg/day developed a distended abdomen from gasping and swallowing air. These pups did not suckle and eventually died. Body weights of offspring were reduced at birth in the 150 and 200 mg/kg/day groups and at 3 days of age in the 100 mg/kg/day group. Growth rates were subsequently retarded at 12.5, 25, 50, and 100 mg/kg. The Harderian glands were reduced or absent in 97, 65, and 4% of the mice in the 100, 50, and 25 mg/kg dosage groups, respectively, and the gland weights were reduced at all dosages, including the lowest dose of 6.25 mg/kg/day. Weights of other organs including lung and liver (at 6.25 and above), seminal vesicle (at 12.5 and above), and testes (at 100 mg/kg/day) were also reduced by prenatal nitrofen exposure. In addition, prenatal treatment with nitrofen produced functional deficits of the reproductive system; puberty was delayed in females and litter sizes were reduced at 50 and 100 mg/kg/day. A cross-fostering experiment with 100 mg/kg/day of nitrofen demonstrated that the effects noted in the present study were produced solely by prenatal exposure; pups exposed to nitrofen in the milk alone as a consequence of any accumulation of nitrofen in the dam during gestation were unaffected.

Abnormalities, Drug-Induced↗