Domoic acid: a teratology and homeostatic study in rats.
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Abnormalities, Drug-Induced↗
Biomedical subjects
K S Khera
Publications and source records attributed to K S Khera.
Mouse placenta: hemodynamics in the main maternal vessel and histopathologic changes induced by 2-methoxyethanol and 2-methoxyacetic acid following maternal dosing.
The two main maternal vessels that are a major, if not the entire, source of maternal blood for the mouse placenta are unique in possessing intraluminal valvular projections. The morphologic configuration of these projections suggests their potential to converge, diverge, and rotate blood currents flowing under systolic pressure. The intravascular occurrence of circular fibrin bodies composed of concentric fibrin strands coagulated from the plasma and almost no blood cellular elements in these strands lends credence to this concept. Histopathologic changes in the extraembryonic and embryonic tissues induced by an intraperitoneal injection of 250 or 500 mg/kg of 2-methoxyethanol, or its metabolite, 2-methoxyacetic acid, via oral gavage were determined 48 hr after dosing CD-1 mice on day 11 of pregnancy. Both compounds caused 1) marked congestion and dilatation, associated with or without fibrinous occlusions, of the main maternal vessel of the placenta, 2) serosanguinous exudation and maternal hemorrhages from the placental periphery, 3) necrosis and desquamation involving the mesometrial surface or peripheral edge of the placenta, 4) translabyrinthine embryonic hemorrhage into the maternal circulation, and 5) embryonic hemorrhages into the exocoelomic, amniotic, and pericardial cavities. These lesions signify a disordered maternal circulation in the placenta suggestive of potentially serious pathologic effects. These lesions may play a role in the resorption, reduction in fetal body weight, and syndactyly or oligodactyly attributed to 2-methoxyethanol and 2-methoxyacetic acid.
Acetates↗
A morphologic basis postulated for valproic acid's embryotoxic action in rats.
A tentative 3 phase sequence of pathogenesis is proposed for the embryotoxic action of valproic acid (800 mg/kg) administered orally to rats on day 13 of pregnancy. This is based on histopathological changes in the extraembryonic and embryonic tissues which occurred in the absence of any biologically significant effect on maternal homeostasis. Major events in the first, decidual (or maternal) phase are cells lining the maternal sinusoids in the decidua basalis are necrosed, desquamated, and washed away by the arterial circulation through the afferent channels. The necrosed cells, with their walls still intact, occlude the lumen of these arterial channels at the point of their entry into the giant cell-trophospongial zone. The channel occlusions cause ischemia and homeostasis of the maternal circulation in the labyrinth by reducing the rate of inflow of maternal blood. The embolic occlusion of maternal arterial channels apparently results in a long-term reduction in the number and size of maternal channels that supply arterial blood to the labyrinth. In the second or placental phase, the parenchyma of the labyrinth and connective tissue in the chorionic plate and umbilical cord, which have been deprived of nutrition and oxygen by the ischemia and stasis of maternal blood in the labyrinth, undergo degenerative changes. In the third or embryonic phase, a pleiotropic karyorrhexis in the embryo, initiated as early as 4 h postdosing, appeared aggravated, presumably by the preceding labyrinthine degeneration of the placental phase. The valproic acid-induced embryotoxicity thus seemed to result from a combination of maternal, placental, and embryonic changes.
Animals↗
The "maternal arterial space" in the center of rats' placenta may be venous, not arterial.
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Animals↗
Valproic acid-induced placental and teratogenic effects in rats.
Studies on teratogenicity and pathology of the cenceptus were conducted in Sprague-Dawley rats treated with 600, 800, and 1,000 mg/kg valproic acid po on day 13 of pregnancy. Each of the three doses was maternotoxic and caused (1) resorptions and/or abortions, reduction in the number of live fetuses per litter and mean fetal weight, and defects of the tail, rib and phalanx; and (2) degenerative changes in the labyrinth (thrombosis, angiectasis in the maternal lacunar network, necrosis of cytotrophoblasts and suppressed proliferation of fetal capillaries), reduced diameter nearing obliteration of umbilical vessels, with or without karyorrhexis of embryonic tissues. The lesions in the placental labyrinth were specific but, in the embryonic tissues, they were generalized. It was postulated that the vascular lesions in the labyrinth and umbilicus may have influenced embryonic development by reducing maternoembryonic gaseous and nutritional exchange.
Animals↗
Extraembryonic tissue changes induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,4,7,8-pentachlorodibenzofuran with a note on direction of maternal blood flow in the labyrinth of C57BL/6N mice.
Histologic changes in extraembryonic and embryonic tissues induced by 3 or 6 micrograms 2,3,7,8-tetrachlorodibenzo-p-dioxin/kg (TCDD) or 80 micrograms 2,3,4,7,8-pentachlorodibenzofuran/kg/day (4-PeCDF) were studied 24 h after the last of four daily doses administered orally to C57BL/6N mice on days 10-13 of pregnancy. Both test compounds ruptured (1) the embryo-maternal vascular barrier in the labyrinth, which resulted in hemorrhage of embryonic blood into the maternal circulation, (2) the visceral yolk sac membrane with the embryonic blood from the vitelline vessels escaping into the uterine, exocelomic and amniotic cavities, and (3) the maternal vascular spaces of the placental periphery resulting in hemorrhages into the interconceptal space. The role of the hemorrhagic lesions in the induction of cleft palate and hydronephrosis by the two compounds remains to be investigated. The presence of embryonic nucleated erythroblasts that hemorrhaged into the maternal lacunar network allowed the identification of maternal venous channels in the placenta. It revealed that (1) the labyrinth could be tentatively divided into two caudocranially oriented zones, an arterial and a venous zone; (2) the maternal blood in the labyrinthine lacunae circulated from the arterial to the venous zone, somewhat parallel to the uterine axis; and (3) the largest maternal vessels in the center of the placenta hitherto named the "central maternal artery," was in fact, venous.
Animals↗
Chemically induced alterations in maternal homeostasis and histology of conceptus: their etiologic significance in rat fetal anomalies.
Possible relationships between maternal acid-base-electrolyte imbalance, histological changes in the maternal/extraembryonic tissues (decidua, placenta, membranes enclosing cavities), and fetal anomalies induced by maternotoxic doses of ethylene glycol, sodium salicylate, and cadmium chloride in rats were investigated. Acid-base-electrolyte, histologic and, teratologic studies were conducted concurrently with, as far as feasible, a similar protocol. Ethylene glycol caused 1) maternal homeostatic changes including metabolic acidosis and hyperosmolality, 2) extraembryonic lesions with degeneration of allantois and reduced villigenesis being more prevalent, and 3) materno-fetal effects such as decreases in fetal and maternal body weights, decreased maternal food intake, and fetal abnormalities (vertebral, rib, and sternebral defects). Few of these changes occurred when NaHCO3, an endogenous agent known to correct metabolic acidosis, was coadministered with ethylene glycol. Ethylene glycol-induced maternal metabolic acidosis, concurrent with hyperosmolality, was suspected to contribute toward reduction in villigenesis and fetal anomalies, including body weight reductions. Sodium salicylate induced the following: 1) mild maternal acidosis, hypokalemia, and hypophosphatemia with no significant change in pH; 2) maternal hemorrhage in extraembryonic cavities, papillary proliferation of the visceral yolk sac endoderm, and failure to form the chorioallantoic labyrinth; and 3) resorptions, hydrocephaly, rib defects, and fetal body weight reduction. Upon simultaneous treatment with sodium salicylate, NaHCO3 significantly reduced, and NH4Cl enhanced the incidence of the above histologic and teratologic effects, without significantly altering acid-base values. An etiologic association between the above salicylate-induced maternal and extraembryonic lesions and teratogenicity was likely. Cadmium chloride, whether administered by the intraperitoneal (ip) or intravenous (iv) route, caused 1) hydrocephaly, anophthalmia, vertebral and rib defects, reduction in fetal body weight, resorptions and maternal toxicity (acute peritonitis by the ip route only), and 2) extensive necrosis and hemorrhage in the decidua basalis, hemorrhage in the ectoplacental cone and around Reichert's membrane, and absence of chorioallantoic labyrinth. An etiologic relationship between these teratologic and histologic effects seemed probable, since both were dose-related. From the above studies, it was hypothesized that maternal factors--metabolic acidosis, hyperosmolality, hemorrhages in the ectoplacental cone, extraembryonic cavities, and around Reichert's membrane, and necrosis of decidua basalis--may have, directly or indirectly, reduced fetal nutrition and materno-embryonic gaseous exchange, which ultimately altered fetal development.
Abnormalities, Drug-Induced↗
Ethylenethiourea-induced hydrocephalus in vivo and in vitro with a note on the use of a constant gaseous atmosphere for rat embryo cultures.
Embryos were studied either after direct exposure to ethylenethiourea (ETU) during incubation of embryo cultures or after maternal ETU dosing and subsequent embryonic development in utero with a view to assess the similarity of these two systems to produce hydrocephalus. Ten-day-old rat embryos were incubated with nutrient media containing 0-2.0 mM of ETU in a constant gasseous environment following a newly modified method. The cultured embryos showed hydrocephalus in the form of dilated rhombencephalon and other anomalies at the 1.5 and 2.0 mM of ETU after 26 hours of incubation. No anomalies were seen in the control group. In in vivo studies, dilated rhombencephalon or hydrocephalus was not observed when dams, orally dosed with ETU on gestation day 10, were either killed daily for three postdosing days to examine embryos or killed at term to evaluate fetuses. This discrepancy in dilatation that was incidental to the rhombencephalon in the two systems pointed out that the fourth ventricle of the cranial neural tube responded by dilatation in vitro but remained unaffected in vivo following ETU exposure. ETU dosing of dams on the 12th day of pregnancy, when embryos are known to be sensitive to ETU-induced hydrocephalus, followed by serial gross examination of embryos, suggested that edema occurred in a generalized form but only after the appearance of both hydrocephalus (dilatation primarily in mesencephalon) and, the previously reported, neuroblastic necrosis.
Abnormalities, Drug-Induced↗
Maternal toxicity in humans and animals: effects on fetal development and criteria for detection.
Evaluation of published human and animal teratology data revealed associations between maternal toxicity and congenital malformations and embryofetal death. This has been reported elsewhere in detail and is herein summarized. Regarding human data, intrauterine deaths were observed to occur in association with 1) maternal homeostatic changes due to phenylketonuria and diabetes and 2) maternal toxicity resulting from alcohol abuse, use of aminopterin, and, possibly, trimethadione. A pattern of malformations that was similar and thus suggestive of a common cause was noticed among malformations attributed to phenylketonuria, diabetes mellitus, aminopterin, alcohol, warfarin, phenytoin, phenobarbital, trimethadione, and valproic acid. On reviewing 234 studies of agents tested in hamsters, mice, rats and rabbits, a fairly strong association between maternal toxicity and embryo-fetal mortality was observed. Further, a consistent pattern of fetal malformations associated with maternotoxic effects was discovered in a survey of 476 studies of agents tested in these four species. In these reviews, it was postulated that maternal toxicity per se could possibly cause such fetal effects. For evaluating maternotoxic effects in experimental studies, the minimum maternal data required would be frequent measurements of maternal body weight and food consumption, signs of altered behavior, death, and gross lesions at necropsy.
Abnormalities, Drug-Induced↗
Neuronal degeneration caused by ethylenethiourea in neuronal monocell layers in vitro and in fetal rat brain in vivo.
The monocell layers, containing a mixture of neuronal and non-neuronal (primarily glial) cells, were obtained by growing cells dissociated from trypsinized fetal brains of 19-day pregnant rats under optimum conditions. Ethylenethiourea (ETU), at greater than or equal to .5 mM concentrations, caused in monocell layers in vitro a necrosis of neuronal cells and a marked depression in the formation of neurites and fascicles without any noticeable change in the non-neuronal cells. In the in vivo study, ETU orally administered as a single 30 or 45 mg/kg dose to rats on day 19 of pregnancy was found to induce necrosis of neuroblasts in the fetal CNS after 18 and 24 hours of dosing and a high incidence of hydrocephalus in postnatal pups at both doses. In an in vivo/in vitro experiment, rat fetal brains from 19-day pregnant dams which had previously been dosed with 80 or 120 mg ETU/kg were trypsinized and then dissociated into a cell suspension in a nutrient medium. The total number of viable cells in the suspension was significantly reduced compared to the number in the control suspension. The test suspension with cell density adjusted to that in the control suspension grew into monocell layers manifesting a marked decreased population of neuronal cells with a concomitantly increased population of non-neuronal cells. It was concluded that the target of ETU action was most likely the neuronal cells rather than the organization of nervous tissue per se.
Animals↗
Maternal toxicity of drugs and metabolic disorders--a possible etiologic factor in the intrauterine death and congenital malformation: a critique on human data.
Human data were searched to determine whether an association of metabolically or drug-induced maternal toxicity with congenital malformations and intrauterine death would be valid for the human species. Intrauterine death was found to occur in association with maternal homeostatic alterations resulting from phenylketonuria and diabetes, and with maternal toxicity from toxemia of pregnancy, leukemia, burns, alcohol, aminopterin, isotretinoin, and possibly trimethadione. A pattern of anomalies found similar (except for minor differences) and thus suggestive of a possible common cause, was observed among anomalies to phenylketonuria, diabetes mellitus, aminopterin, alcohol, warfarin, phenytoin, phenobarbital, trimethadione, valproic acid, and isotretinoin. The pattern usually consisted of deficiencies in pre- and postnatal development, mid-facial hypoplasia, cleft palate, atrial or ventricular septal defects, patent ductus arteriosus, hypospadias, hernias, and other less frequent anomalies. The pattern is tentatively associated with alterations in maternal physiology resulting from phenylketonuria and diabetes; maternal toxicity of aminopterin, alcohol, and diverse factors co-occurring with warfarin use; and therapeutic doses (generally toxic in adults) of phenytoin, phenobarbital, trimethadione, and valproic acid. Whether these fetal malformations and intrauterine deaths would occur at nonmaterno-toxic levels of the above teratogenic agents, and, consequently, the strength of the associations could not be estimated for lack of data. However, human data seem to provide some, though weak, support and not to contradict the previous assumption formulated from animal studies that maternal toxicity may be causally related to fetal malformations and embryo-fetal mortality.
Abnormalities, Drug-Induced↗
Ethylenethiourea: a review of teratogenicity and distribution studies and an assessment of reproduction risk.
Ethylenethiourea (ETU) is a specific neuroteratogen that induces communicating hydrocephalus ex vacuo at oral doses far lower than those that cause any observable toxic sign or 50% death (LD50) in the rat dam. The teratogenic activity appears to be related to ETU itself and not to its metabolites. It is dependent upon the presence of an imidazolidine ring with a specific molecular location of sulfur atom. It is unlikely that ETU-induced alterations in thyroid function or thyroxine levels in the maternal rat are involved in teratogenic activity. The initial target following maternal dosing with ETU is the primitive neuroblast that undergoes necrosis, but the subsequent changes leading to the development of hydrocephalus are not clear. Teratogenicity studies in hamsters, mice, guinea pigs, rabbits, and rats revealed that ETU either required extremely high doses to produce malformations or was ineffective. The results of various distribution studies are summarized. Further, investigations dealing with exposure to ETU in the general population and in exposed workers in the rubber industry as well as those involved in the manufacture and spraying of fungicides are discussed briefly with reference to reducing the exposure levels.
Animals↗
A teratology study on vomitoxin (4-deoxynivalenol) in rabbits.
Diets containing 4-deoxynivalenol (vomitoxin) of greater than 98% purity were fed to rabbits on days 0-30 of gestation. The dietary concentrations of 4-deoxynivalenol were 0, 0.00075, 0.0015, 0.003, 0.006, 0.012 and 0.024% and the daily intakes of deoxynivalenol were 0, 0.3, 0.6, 1.0, 1.6, 2.0 and 1.8 mg/kg body weight/day, respectively. A pair-fed group was given a feed intake equivalent to that in the 1.6-mg/kg group. The only significant effects that were observed in foetuses examined at day 30 of gestation occurred only at doses that caused reductions in both the body weight and feed intake of does. The foetal effects consisted of a 100% incidence of resorption in the 1.8- and 2.0-mg/kg groups and decreased mean foetal weight in the 1.0- and 1.6-mg/kg and pair-fed groups. The doses that did not appear to be maternotoxic (0.6 and 0.3 mg/kg) did not show any adverse effects in foetuses at term. Vomitoxin given in the diet during pregnancy failed to show any evidence of teratogenic potential in rabbits.
Abnormalities, Drug-Induced↗
Maternal toxicity: a possible etiological factor in embryo-fetal deaths and fetal malformations of rodent-rabbit species.
Data from animal teratology studies were surveyed to determine whether embryo-fetal mortality and fetal malformations result from a primary action of the agent on the conceptus or if they are secondary to maternal toxicity--a consequence of administration with high dose levels of test chemicals. A fairly strong association between embryo-fetal mortality and maternal toxicity was revealed by analysis of data from hamsters, mice, rats, and rabbits in 234 studies of chemical and physical agents, of which 83 were conducted at both maternotoxic and nonmaternotoxic doses, 94 only at maternotoxic doses, and 49 at nonmaternotoxic doses. In the above studies, only nine chemicals (four each in hamsters and rabbits and one in rats) were reported to induce embryo-fetal deaths at apparently nonmaternotoxic doses. These findings tend to suggest a contributory role for maternal toxicity in the induction of embryo-fetal deaths. The previously reported hypothesis that certain fetal defects in mice may perhaps be caused by maternal toxicity was also found to be true in a review of data on hamsters, rats, and rabbits. Salient maternal toxicity-associated fetal malformations were exencephaly, encephalocele, micro- or anophalmia, and fused ribs in hamsters and defective (fused, missing, or extra) ribs, vertebrae, and sternebrae, ex-, an-, or microphthalmia, and cleft palate in rats and rabbits. These malformations occurred at low frequencies, generally with no readily apparent dose-response relationship. Presumptive evidence indicates that embryo-fetal deaths, and the above-mentioned fetal malformations in experimental animals, which in published literature are presently attributed to chemical induction for a large number of chemicals, may be a consequence of maternal toxicity per se.
Abnormalities, Drug-Induced↗
Embryotoxicity study on cyclopiazonic acid in mice.
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Abnormalities, Drug-Induced↗
Phenytoin and trimethadione: pharmacokinetics, embryotoxicity, and maternal toxicity.
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Abnormalities, Drug-Induced↗
Nerve cell degeneration and progeny survival following ethylenethiourea treatment during pregnancy in rats.
Ethylenethiourea (ETU)-induced early histologic changes in fetal CNS and their effect on postnatal survival was studied at 0, 15 or 30 mg/kg administered as single oral dose on day 13 of pregnancy. Fetuses, from 4-6 dams killed at post-treatment intervals of 12, 24, 48 and 72 h were fixed and studied for histopathological changes following routine methods. The remaining dams were allowed to litter and their progeny was studied for postnatal survival until 80 days of age. Histologic study revealed the presence of karyorrhexis in the germinal layer of basal lamina of CNS extending from the thoracic spinal cord to the telencephalon twelve hours after treatment with 30 mg of ETU/kg. At 48 h post-treatment, the spinal cord showed obliteration and duplication of the central canal and disorganization of germinal and mantle layers. In the brain, the ventricular lining was focally denuded, neuroepithelial cells were arranged in the form of rosettes and the nerve cell proliferation was disorganized. In the 15 mg of ETU/kg group, cellular necrosis was less severe and consisted of degeneration in a single or a small group of cells widely dispersed in the germinal layer of neuraxis. The initial degenerative changes were observed in a specific nerve cell type, identified as the undifferentiated migrating neuroblast. In the postnatal study, since survival was reduced to 50% at the 30 mg/kg and unaffected at the 15 mg/kg, it was concluded that necrosis of neuroblasts up to a certain degree was compatible with postnatal life until adulthood.
Animals↗
Maternal toxicity--a possible factor in fetal malformations in mice.
The assumption that major fetal malformations are indicative of a chemical's teratogenic potential was not supported by a literature review of teratology studies conducted in mice. In these studies, dose levels of test agents that manifested maternal toxicity as suggested by reduction in dam's body weight, clinical signs of toxicity, or deaths, also invariably caused reduction in fetal body weight, increased resorptions, and rarely fetal deaths. In several such studies, conducted with maternotoxic doses of structurally unrelated test agents, a consistent pattern of fetal defects was discovered. These defects included exencephaly, open eyes, hemivertebrae, fused arches or centra of lumbar or thoracic vertebrae, fused, missing or supernumerary ribs, and fused or scrambled sternebrae. These defects were absent at drug dosages that were distinctly nontoxic for the mother. In a few studies conducted at two or more maternally toxic doses, the degree and severity of maternal toxicity showed a positive correlation with the incidence and severity of above fetal defects. It is hypothesized that maternal toxicity, on its own, may have an etiologic role in these fetal defects.
Abnormalities, Drug-Induced↗