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Biomedical subjects

C C Willhite

Publications and source records attributed to C C Willhite.

68 records · Page 4Linked to original sources
PubMed1983

Developmental toxicology of acetonitrile in the Syrian golden hamster.

Pregnant hamsters were exposed to acetonitrile by inhalation, ingestion, or ip injection during the early primitive streak stage of embryogenesis. Inhalation of 1,800 or 3,800 ppm acetonitrile for 60 min failed to induce malformations in the near-term offspring whereas inhalation of 5,000 or 8,000 ppm acetonitrile was associated with production of severe axial skeletal (dysraphic) disorders. One fetus afflicted with extrathoracic ectopia cordis was recovered from a dam exposed to 8,000 ppm acetonitrile. An oral or ip dose of 100-400 mg/kg acetonitrile in hamsters of equivalent gestational age also caused malformations identical to those noted following inhalation exposure. Some dams exposed to the highest concentrations or doses of acetonitrile displayed overt signs of poisoning. Multiple injections of sodium thiosulfate antagonized the mortality and signs of intoxication associated with acetonitrile treatment. Offspring of thiosulfate-treated hamsters exposed to acetonitrile failed to exhibit the marked teratogenic response that was associated with exposure to equivalent concentrations or doses of acetonitrile alone. Elevated concentrations of cyanide and thiocyanate were detected in all tissues studied at 2.5 hr after an oral or ip dose of acetonitrile. Cyanide was liberated when acetonitrile was incubated in vitro with hamster liver slices or NADPH-fortified hepatic microsomal preparations. The results suggested that in vivo liberation of cyanide from acetonitrile was responsible for the production of terata.

Abnormalities, Drug-Induced↗
PubMed1982

Congenital malformations induced by laetrile.

Laetrile administered orally ot pregnant hamsters caused skeletal malformations in the offspring, but intravenous laetrile filed to result in embryopathic effects. Oral laetrile significantly increased in situ cyanide concentrations, while intravenous laetrile did not. Thiosulfate administration protected embryos from the teratogenic effects of oral laetrile. The embryopathic effects of oral laetrile appear to be due to cyanide released by bacterial beta-glucosidase activity.

Abnormalities, Drug-Induced↗
PubMed1982

Teratogenic potential of quercetin in the rat.

A single oral dose of 2, 20, 200, or 2000 mg quercetin/kg was administered to pregnant rats on the morning of day 9 of gestation. Other groups of pregnant rats received similar oral doses of quercetin daily, on days 6-15 of gestation. Some quercetin-treated groups showed a significant decrease in the average weight of day-20 foetuses compared with the corresponding control weight. However, studies of the foetuses recovered on day 20 of gestation failed to reveal any reproducible dose-related syndrome of teratogenic effects attributable to quercetin treatment.

Abnormalities, Drug-Induced↗
PubMed1981

Teratogenic effects of aliphatic nitriles.

Intraperitoneal injection of acrylonitrile at 1.51-2.26 mmole/kg (80-120 mg/kg) or propionitrile at 0.54-1.51 mmole/kg (30-83 mg/kg) on the morning of Day 8 of gestation in the hamster induced exencephaly, encephalocoeles, and rib fusions and bifurcations in the offspring. These doses of the aliphatic nitriles also resulted in obvious toxicity to the dams. Multiple intraperitoneal injections of sodium thiosulfate at 4.03 mmole/kg (1 gm/kg) protected both dams and embryos against toxicity. When the larger doses of either acrylonitrile or propionitrile were given in the presence of sodium thiosulfate, teratogenic effects were observed in the absence of overt signs of maternal poisoning. A survey of the literature describes many studies which demonstrate that acrylonitrile and propionitrile are converted in vivo to toxicologically significant concentrations of cyanide and that sodium thiosulfate, an established cyanide antagonist, can provide protective actions against poisoning by either acrylonitrile or propionitrile. The observations suggest that the teratogenic effects of both acrylonitrile and propionitrile are related to the metabolic release of cyanide.

Abnormalities, Drug-Induced↗
PubMed1981

Morphogenesis of axial skeletal (dysraphic) disorders induced by aliphatic nitriles.

The previous study (Willhite et al., '81) linked the administration of acrylonitrile or propionitrile in the pregnant hamster to the production of severe axial skeletal (dysraphic) malformations in the hamster fetus. The present investigation dealt with histological study of both early embryos and term fetuses challenged with a teratogenic dose of either of these nitriles. Inspection of hamster embryos 10 hours after the teratogenic stimulus revealed mesodermal changes including a reduced number of cells, shrinkage of the cell cytoplasm, and enlarged extracellular spaces. In addition, a reduced number of mitotic figures and focal necrobiosis were noted. The affected embryos were smaller and were delayed in their development as compared to controls. Analysis of the fourteen-day-old hamster fetuses revealed the basichondrocranium in both cranioschisis occulta with encephalocoele and cranioschisis aperta with exencephyaly to be shorter than control and lordotic to the vertebral axis. These alterations were more accentuated in cranioschisis aperta than in cranioschisis occulta. The ultimate skeletal malformations may be the reflection of a primary paraxial mesodermal insufficiency.

Abnormalities, Drug-Induced↗
PubMed1981

Inhalation toxicology of acute exposure to aliphatic nitriles.

Male CD-1 mice were exposed for 60 min to toxic concentrations of acetonitrile, propionitrile, or n-butyronitrile and were maintained for the following 14 d. The LC50 values for acetonitrile, propionitrile, and n-butyronitrile were 2,693, 163, and 249 ppm, respectively. Pretreatment with Na2S2O3 or NaNO2, two common inorganic cyanide antagonists, can provide significant (p < 0.05) protection against the mortality associated with exposure to lethal concentrations of these nitriles. Administration of Na2S2O3 consistently provided a greater measure of protection than did NaNO2 against nitrile poisoning. Pretreatment with a heptatotoxic dose of CCl4 can protect mice against death from inhalation of lethal concentrations of these nitriles. The present results are compared with those of previous studies, and the conclusions support the rationale for administration of inorganic cyanide antagonists to individuals poisoned by inhalation of acetonitrile, propionitrile, or n-butyronitrile.

Acetonitriles↗
PubMed1978

Teratogenic potential of blighted potato concentrate in rabbits, hamsters, and miniature swine.

Freeze-dried preparations of potatoes infected with phytophthora infestans or Alternaria solani were fed to pregnant hamsters, rabbits, and miniature swine. No evidence was observed that these diets or the extracts of respective blights were capable of producing teratologic effects in hamsters. Lesions of neurulation and anencephaly were noticed in rabbits and swine, respectively. The need for further pharmacological and toxicological evaluation in sensitive species is emphasized.

Alternaria↗
PubMedDate not supplied

Pharmacokinetics, tissue distribution and placental permeability of tetrahydro-tetramethyl-naphthalenyl-propenyl benzoic acid (a retinoidal benzoic acid derivative) in hamsters.

Tritiated tetrahydro-tetramethyl-naphthalenyl-propenyl benzoic acid (TTNPB; Ro 13-7410) was administered as a single oral bolus to pregnant hamsters (day 8) to determine the maternal plasma pharmacokinetic profile and peripheral tissue distribution patterns. Blood and tissue, including embryo or fetus, were collected at specific time intervals to 96 h and assayed for total radioactive compounds and/or parent retinoid. No lag time was required to describe retinoid absorption (t 1/2 pi = 1.2 h) with peak plasma levels at 2.4 h; the concentrations then declined with exponential elimination from the central compartment (t 1/2 e = 3 h). The maximum concentrations of circulating radioactive compound or metabolites after 100 micrograms/kg [3H]2-TTNPB occurred in liver greater than fetus greater than adrenal greater than lung approximately equal to kidney greater than plasma; after 1000 micrograms/kg, maternal liver accumulated the highest concentration followed by plasma greater than fetus = placenta = uterus. An unidentified, polar metabolite was detected in plasma at 0.5 h and by 12 h constituted greater than 90% of the total circulating radioactivity. TTNPB was absorbed and cleared more slowly, concentrated in the conceptus to a higher degree and possessed greater intrinsic activity than the naturally-occurring tetraene retinoids. These properties contribute to the marked teratogenic activity of TTNPB as compared to the tetraene retinoids.

Animals↗
PubMedDate not supplied

Receptor-selective retinoid agonists and teratogenic activity.

Retinoid mechanism of action is dependent upon interaction with the retinoid nuclear RAR and RXR subfamilies of receptors. Study of ligands selective for the different receptors or which modify that interaction may provide insight into which receptors play roles in or contribute to retinoid teratogenesis. The retinoids considered here include in the RAR alpha-selective arylcarboxamidobenzoic acid CD 336 (Am580), the RAR beta/gamma-selective naphthalenecarboxylic acid CD 135 and the adamantyl-phenylcarboxamidobenzoic acid CD 394, the RAR-selective tetrahydrotetra-methylanthracenylbenzoic acid (TTAB) SRI 3961, the carboxyphenylretinamide SRI 7167-67, and the RXR-selective diarylisopropylidene SR 11217. CD 135 has a 3-fold higher affinity for RAR beta when compared with RAR gamma, whereas CD 394 has a 3-fold higher affinity for RAR gamma when compared with RAR beta. A separate investigation into potential amelioration of retinoid teratogenesis by concomitant administration of the cyclohexanetrione (Ro 31-0521) was also conducted. When pregnant hamsters were given an oral bolus of CD 336 or CD 135 during the early primitive streak stage of gestation, these retinoids proved 60-100 times more potent teratogens than all-trans-retinoic acid. Intubation of CD 394 resulted in production of terata similar to that seen after an equivalent dose of all-trans-retinoic acid. Administration of SRI 3961 found this compound 8000 times more potent than all-trans-retinoic acid, while SRI 7167-67 failed to show any evidence for developmental toxicity even after exposure to 105 mg/kg. Studies with the RXR-selective SR 11217 found it to be far less potent than all-trans-retinoic acid. These data point to the conclusion that those retinoids which have no affinity for retinoid nuclear receptors also have little potential for induction of developmental toxicity at doses which do not also provoke maternal intoxication. Comparing in vitro transcriptional activation of wild-type human RAR for the supertoxic TTNBP (Ro 13-7410) and TTAB (SRI 3961) with their relative teratogenic potency in hamster found that the more toxic congener also had the lower in vitro EC50 transactivation value (at ratios approximating their differential toxicities measured as administered dose). The RAR beta/gamma-selective CD 135 (TTNN) was not as efficient as TTNBP (Ro 13-7410) or TTAB (SRI 3961) in hRAR transactivation and CD 135 was less toxic than either Ro 13-7410 or SRI 3961. Although the RXR-selective SR 11217 failed to elicit terata after moderate doses, malformations consistent with those induced by high doses of retinoic acid could be produced following a single large bolus of SR 11217. Under the conditions here, simultaneous administration of Ro 31-0521 with all-trans-retinoic acid appeared to reduce the total percentage of abnormal fetuses seen after exposure to retinoic acid alone, but fetal body weights remained depressed and the numbers of dead embryos remained elevated, suggesting only limited influence of the cyclohexanetrione on retinoid developmental toxicity.

Animals↗
PubMedDate not supplied

Embryogenesis in cultured whole rat embryos after combined exposures to 3,3',5-triiodo-L-thyronine (T3) plus all-trans-retinoic acid and to T3 plus 9-cis-retinoic acid.

Retinoid-induced malformations of the jaw, ears, face, skull, eyes, and heart in humans and rodents are well known. Data on nuclear receptors and developmental toxicity bioassays indicate that thyroid hormones can modulate the biologic activity of retinoids. The present investigation concerned the potential for interactions of all-trans-retinoic acid (RA) with 3,3'5-triiodo-L-thyronine (T3) and of 9-cis-retinoic acid (9-cis-RA) with T3 in the morphogenesis of cultured whole rat embryos. Varying concentrations of retinoids or T3 were microinjected into the amniotic fluid or placed in the culture medium alone or in combinations of T3 with each retinoid. At 200 ng/ml, T3 increased the incidence of branchial arch defects produced by either RA or 9-cis-RA but did not elicit branchial arch defects alone except at concentrations significantly compromising survival (2,000 ng/ml; 32% mortality). Similarly high culture medium concentrations of T3 alone were associated with failure of neural tube closure in the rhombencephalon (rhombencephalic schisis). At this concentration, other dysmorphia were minimal and at 670 ng/ml T3, no dysmorphogenic or embryotoxic effects could be detected. Modulation of T3 effects by the yolk sac placenta was suggested by failure of microinjected T3 to elicit dysmorphia at very high amniotic fluid concentrations. RA (300 ng/ml) or 9-cis-RA (600 ng/ml) alone elicited no or minimal rhombencephalic schisis at the highest concentrations studied. RA plus T3 produced a much greater than additive effect on rhombencephalic schisis, whereas 9-cis-RA plus T3 produced a less than additive effect. Conversely, much greater than additive effects on anterior schisis were observed for 9-cis-RA plus T3 whereas combined effects of RA and T3 were approximately additive. For most other dysmorphia, the combined effects of each retinoid with T3 were greater than additive and were particularly striking for cephalic defects.

Abnormalities, Drug-Induced↗