RESUMEN

Cylindrospermopsin (CYN) is a tricyclic alkaloid toxin produced by fresh water cyanobacterial species worldwide. CYN has been responsible for both livestock and human poisoning after oral exposure. This study investigated the toxicity of CYN to pregnant mice exposed during different segments of gestation. The course of recovery and individual responses to the toxin were evaluated. Adverse effects of CYN were monitored up to 7 weeks post-dosing by clinical examination, histopathology, biochemistry and gene expression. Exposure on gestational days (GD) 8-12 induced significantly more lethality than GD13-17 exposure. Periorbital, gastrointestinal and distal tail hemorrhages were seen in both groups. Serum markers indicative of hepatic injury (alanine amino transferase, aspartate amino transferase and sorbitol dehydrogenase) were increased in both groups; markers of renal dysfunction (blood urea nitrogen and creatinine) were elevated in the GD8-12 animals. Histopathology was observed in the liver (centrilobular necrosis) and kidney (interstitial inflammation) in groups exhibiting abnormal serum markers. The expression profiles of genes involved in ribosomal biogenesis, xenobiotic and lipid metabolism, inflammatory response and oxidative stress were altered 24 h after the final dose. One week after dosing, gross, histological and serum parameters had returned to normal, although increased liver/body weight ratio and one instance of gastrointestinal bleeding was found in the GD13-17 group. Gene expression changes persisted up to 2 weeks post-dosing and returned to normal by 4 weeks. Responses of individual animals to CYN exposure indicated highly significant inter-animal variability within the treated groups.

Asunto(s)

Alcaloides/toxicidad , Cianobacterias , Embrión de Mamíferos/efectos de los fármacos , Exposición Materna/efectos adversos , Uracilo/análogos & derivados , Contaminantes Químicos del Agua/toxicidad , Animales , Toxinas Bacterianas , Biomarcadores/sangre , Toxinas de Cianobacterias , Pérdida del Embrión/inducido químicamente , Femenino , Muerte Fetal/inducido químicamente , Expresión Génica/efectos de los fármacos , Hemorragia/inducido químicamente , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Necrosis/inducido químicamente , Necrosis/patología , Nefritis Intersticial/inducido químicamente , Nefritis Intersticial/patología , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/patología , Recuperación de la Función , Uracilo/toxicidad

RESUMEN

The impacts of adverse environments during the prenatal and/or early postnatal periods may be manifested as functional deficits that occur later in life. Epidemiological studies have shown an association of sub-optimal pregnancy outcomes in one generation with similar events in the following one, a phenomenon termed the "intergenerational effect". Data indicate that the incidence of adverse pregnancy outcomes and/or low birth weight infants is more closely correlated with the mother's perinatal environment than with that during her pregnancy. However, epidemiological studies are inherently limited given the variability of lifestyles, ethnicity, nutritional status, and exposures to environmental factors. An appropriate animal model would permit control of parameters that may be impossible to evaluate in human populations. The current studies investigated the mouse as a possible animal model. Pregnant CD-1 mice were placed on an ad libitum or food-restricted diet (50% normal) throughout gestation to generate control (CON) and intrauterine growth retarded (IUGR) litters. At birth (postnatal day (PD) 1) pups (F1) were cross-fostered to control dams in litters of either 8 (CON) or 16 (postnatal food restriction (FR)). The experimental groups thus generated represented adequate nutrition (CON-CON) and undernutrition during the prenatal (IUGR-CON), or postnatal periods (CON-FR), or both (IUGR-FR). Pups of dams on a restricted diet during gestation had significant IUGR (P<0.001) as compared to controls (birth weights of 1.32 g versus 1.63 g). At weaning, the average weight of the pups was dependent on postnatal litter size and the difference in birth weights between IUGR and CON animals was not a significant factor. CON-CON pup weight was 24.1g and IUGR-CON was 22.2 g as compared to the CON-FR (17.0 g) and IUGR-FR (17.3 g) groups. The difference in weaning pup weights between the FR and CON groups was significant (P<0.01). The F1 FR females did not reach CON female weights at any time point through 11 months after weaning. At PD60, a single breeding period for all groups of females with CON males began and continued for 75 days with 17 opportunities for breeding. Animals that became pregnant during this time were removed and allowed to litter. No significant differences were noted in average F2 litter size or average pup weight at birth: (CON-CON 12.2/1.62 g; IUGR-CON 11.9/1.6 2 g; CON-FR 10.9/1.70 g; IUGR-FR 11.3/1.61 g). We conclude that body weight at birth in the CD-1 mouse is not correlated with growth through the period of weaning (PD28). We did not find any evidence for an intergenerational reproductive effect after developmental undernutrition.

Asunto(s)

Fenómenos Fisiológicos Nutricionales de los Animales , Privación de Alimentos , Reproducción , Animales , Peso al Nacer , Femenino , Retardo del Crecimiento Fetal/complicaciones , Tamaño de la Camada , Ratones , Ratones Endogámicos , Trastornos Nutricionales/complicaciones , Embarazo , Resultado del Embarazo , Factores de Tiempo , Destete

RESUMEN

Microcystin-LR (MC-LR) is a cyanobacterial toxin generated by the organism Microcystis aeruginosa. Although the hepatotoxicity of this chemical has been characterized, the potential developmental toxicity in vertebrates has not been well studied. The purpose of this study was to elucidate the effects of this toxin on the in vivo and in vitro development of mammals and the development of an Anuran (toad). Initial acute toxicity experiments with female CD-1 mice were accomplished with MC-LR administered i.p. in saline. Lethality occurred at 128 and 160 microg kg (-1) and histopathology revealed massive hepatic necrosis with diffuse hemorrhage. Developmental toxicity studies were done with MC-LR administered i.p. for 2-day periods: gestation days 7-8, 9-10 or 11-12. Doses used ranged from 2 to 128 microg kg(-1). On gestation day 17, fetuses were weighed and analyzed for gross morphological and skeletal defects. No treatment-related differences were seen in litter size, viability, weight or the incidence of anomalies. Groups of dams dosed with 32-128 microg kg(-1) on gestation days 7-8, 9-10 or 11-12 were allowed to give birth and the growth and development of their pups were followed postnatally. There were no significant effects noted in the offspring of the treated dams. Neurulation-staged CD-1 mouse conceptuses were exposed to 50-1000 nM MC-LR in whole embryo culture for 24 h. No significant increase in abnormalities or developmental delays was observed. Finally, exposure of the developing toad. Bufo arenarum was done from stage 17 (tail bud) for 10 days at concentrations of 1-20 mg l(-1). No effect on morphological development or survival was noted in any exposed groups. These data indicate that microcystin does not appear to affect development adversely in the mouse (in vivo or in vitro) or the toad at the doses and exposure parameters used.

Asunto(s)

Bufo arenarum/anomalías , Embrión de Mamíferos/efectos de los fármacos , Embrión no Mamífero/efectos de los fármacos , Inhibidores Enzimáticos/toxicidad , Péptidos Cíclicos/toxicidad , Animales , Cianobacterias/patogenicidad , Embrión de Mamíferos/anomalías , Embrión no Mamífero/anomalías , Inhibidores Enzimáticos/administración & dosificación , Femenino , Técnicas In Vitro , Dosificación Letal Mediana , Toxinas Marinas , Exposición Materna/efectos adversos , Ratones , Microcistinas , Péptidos Cíclicos/administración & dosificación , Tasa de Supervivencia , Pruebas de Toxicidad Aguda

RESUMEN

5-Aza-2'-deoxycytidine (d-AZA) inhibits methylation of DNA, a process that serves as an epigenetic regulator of gene expression. We have shown that d-AZA causes temporally related defects in mice. Gestational day (GD) 10 treatment induced severe long-bone defects of the hindlimb but not the forelimb. Exposure of younger embryos (GD 8 or 9) does not induce similar defects in forelimbs. This limb-dependent response suggests that methylation alterations in genes specific for fore- or hindlimbs may contribute to the observed pattern of defects. Subtraction hybridization (SH) studies were conducted to identify differential expression of DNA subsequent to the administration of d-AZA to mice on GD 10. Hindlimb buds collected from both treated and untreated embryos at 4, 12, and 24 hours post-treatment were used. A clone isolated from the untreated sample (down-regulation in treated tissue) was identified as a member of the murine B1 family of repetitive sequences. The two other clones isolated from the treated tissue (up-regulation) were homologous to avian myogenic regulatory protein mRNA and activin receptor type II gene. Both species are active during embryogenesis. These findings suggest that the isolated clones may have roles in abnormal embryonic development when inappropriately expressed.

Asunto(s)

Azacitidina/análogos & derivados , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Miembro Posterior/anomalías , Teratógenos/farmacología , Animales , Azacitidina/farmacología , Clonación Molecular , Decitabina , Femenino , Regulación del Desarrollo de la Expresión Génica/genética , Ratones , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Embarazo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética

RESUMEN

America's population "stew" creates specific challenges to health plans attempting to reach ethnically differentiated enrollee groups. In this article, the author provides snapshots of four ethnic groups, suggests some marketing considerations when preparing communications to these groups, and helps draw some conclusions about marketing managed care products to a culturally diverse population.

Asunto(s)

Etnicidad , Programas Controlados de Atención en Salud/organización & administración , Comercialización de los Servicios de Salud/métodos , Relaciones Comunidad-Institución , Características Culturales , Humanos , Comunicación Persuasiva , Estados Unidos

RESUMEN

DNA methylation is a probable mechanism for regulating gene expression, and alterations in methylation may significantly affect embryonic development. We administered the cytidine analogue 5-aza-2'-deoxycytidine (dAZA), a specific and potent demethylator of DNA, to pregnant mice to determine its teratogenicity and effects on embryonic cell death and cell cycle. Groups of females were dosed intraperitoneally on gestation day 10 with doses of 0.05-3 mg/kg dAZA and killed at 4, 8, or 28 hr later. Two embryos per litter were immediately stained with Nile blue sulfate (NBS) to identify areas of cell death; the remaining embryos were frozen and stored for subsequent flow cytometric (FCM) analysis of the cellular DNA synthetic cycle in limb buds. A dose-related accumulation of cells in the S and G2/M phases was observed at 4 and 8 hr after maternal dosing. S-phase accumulation was the most sensitive indicator of effect; a dose-related increase in the percentage of hindlimb bud cells in S-phase was evident at all dosages 4 hr after maternal dosing. By 28 hr postdosing, a normal cell cycle phase distribution was observed at doses of < 0.3 mg/kg. However, cell cycle perturbations persisted at higher dosages. NBS staining demonstrated increased cell death in areas of rapid cell division, indicative of replication-associated cytotoxicity, at doses of > or = 0.1 mg/kg. Observation of litters from additional dams killed at term revealed that at dosages of > or = 0.3 mg/kg, cleft palate and hindlimb defects were significantly elevated. In addition, above 0.3 mg/kg, fetal weight was significantly decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

Azacitidina/análogos & derivados , Teratógenos/toxicidad , Animales , Azacitidina/toxicidad , Ciclo Celular/efectos de los fármacos , Muerte Celular , ADN/efectos de los fármacos , Decitabina , Relación Dosis-Respuesta a Droga , Femenino , Citometría de Flujo , Deformidades Congénitas de las Extremidades , Ratones , Embarazo

RESUMEN

The hypothesis that chemically induced overt maternal toxicity induces a characteristic syndrome of adverse developmental effects in the rat was investigated. Pregnant animals (Sprague-Dawley strain) were dosed by oral gavage with one of a series of compounds on days 6-15 of gestation. These chemicals were diquat (DIQ), ethylene-bis-isothiocyanate (EBIS), toxaphene (TOX), styrene (STY), 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenol (2,4,5-Tr), triphenyl tin hydroxide (TPTH), and cacodylic acid (CAC). The compounds were chosen because they exhibited little or no developmental toxicity in previous studies. Dosage levels producing maternal weight loss and/or lethality were determined from preliminary toxicity studies. Significant maternal weight reductions were noted during the course of treatment with all compounds except CAC and 2,4,5-Tr. Maternal lethality was produced by EBIS, TOX, 2,4,-D, and 2,4,5-Tr. The main treatment-related developmental toxicity noted in litters at term consisted of increased lethality (EBIS, TPTH) and decreased fetal weight (EBIS and CAC). Treatment-related anomalies were seen in litters treated with 2,4-D and TOX (supernumerary ribs) and with EBIS and STY (enlarged renal pelvis). No significant developmental effects were produced with DIQ, or 2,4,5-Tr. This study indicates that overt maternal toxicity as defined by weight loss or mortality is not always associated with the same defined syndrome of adverse developmental effects in the rat.

Asunto(s)

Desarrollo Embrionario y Fetal/efectos de los fármacos , Enfermedades Fetales/inducido químicamente , Isotiocianatos , Ácido 2,4,5-Triclorofenoxiacético/toxicidad , Ácido 2,4-Diclorofenoxiacético/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Ácido Cacodílico/toxicidad , Diquat/toxicidad , Femenino , Muerte Fetal/inducido químicamente , Intercambio Materno-Fetal , Compuestos Orgánicos de Estaño/toxicidad , Embarazo , Complicaciones del Embarazo/inducido químicamente , Ratas , Ratas Endogámicas , Estrés Fisiológico/fisiopatología , Tiocianatos/toxicidad , Toxafeno/toxicidad

RESUMEN

Cyclophosphamide (CP) administered ip to pregnant mice on day 10 of gestation (day of plug = day 0) is teratogenic (exencephaly, cleft palate, and limb malformations) at 20 mg/kg and embryolethal at higher doses. In the present study, CP was administered at 1, 5, 10, or 20 mg/kg on day 10 of gestation. Embryos were removed at 8 and 28 hr postdosing, and two embryos from each litter were immediately stained with Nile blue sulfate (NBS) to identify areas of cell death. The remaining embryos were frozen and forelimb buds subsequently removed for flow cytometric (FCM) analysis of the cellular DNA synthetic cycle. Additional litters were examined near term (day 17) for morphological abnormalities; these data were correlated with embryonic toxicity as detected by NBS staining and FCM analysis. Only the highest dose produced malformations. In marked contrast, a dose-related increase in the percentage of limb bud cells in the S (DNA synthetic) phase of the cell cycle was detectable at all doses. Inhibition of DNA synthesis was detected at all doses 8 hr post exposure and persisted through 28 hr for doses greater than or equal to 10 mg/kg. NBS staining indicated increased cell death in the alar plate of the neural tube 28 hr after exposure to 10 mg/kg CP and generally increased cell death in areas of rapid cell proliferation throughout the embryo at 20 mg/kg. The absence of an overt teratogenic response at dose levels that produced significant perturbation of the cell cycle indicates that a measure of embryonic damage can be compensated for or repaired. The implications of these findings for the existence of thresholds in developmental toxicity are discussed.

Asunto(s)

Ciclofosfamida/toxicidad , Teratógenos , Animales , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Supervivencia Celular , ADN/biosíntesis , Relación Dosis-Respuesta a Droga , Femenino , Citometría de Flujo , Incidencia , Intercambio Materno-Fetal , Ratones , Ratones Endogámicos , Oxazinas , Embarazo , Fase S

RESUMEN

Interactions between exposure to xenobiotics and disease can occur during pregnancy. Few data are available on the consequences of such interactions on developmental parameters. In this study, we investigated potential interactions between murine cytomegalovirus (MCMV), which induces embryolethality, and sodium salicylate, a known teratogen. MCMV administered on Day 12 was embryotoxic over a broad range of doses from 2 x 10(3) to 2 x 10(6) plaque-forming units, and also decreased postnatal weight gain. MCMV administration on Day 8 of gestation caused significant prenatal mortality regardless of salicylate exposure. Salicylate did not cause fetal mortality or malformations at either 500 or 750 mg kg-1 day-1 on Days 9 and 10 of gestation. No evidence of synergistic effects of MCMV and salicylate on embryo/fetal development was seen.

Asunto(s)

Infecciones por Citomegalovirus/fisiopatología , Desarrollo Embrionario y Fetal , Complicaciones Infecciosas del Embarazo/fisiopatología , Salicilato de Sodio/toxicidad , Animales , Desarrollo Embrionario y Fetal/efectos de los fármacos , Femenino , Intercambio Materno-Fetal , Ratones , Embarazo , Resultado del Embarazo

RESUMEN

5-Azacytidine (5-aza), a chemical that is incorporated into DNA and RNA with consequent alterations in the expression of mammalian genes, was administered to pregnant Sprague-Dawley rats on single days during gestation. Doses of 0.5, 1, and 2 mg/kg were given by intraperitoneal injection on d 9, 10, 11, or 12. Dams were killed on d 20 of gestation and fetuses were examined for both external and skeletal defects. 5-Azacytidine affected development on all days tested. The compound was embryolethal, caused reductions in fetal weight, and had profound effects on morphological development. Digit and limb anomalies, exencephaly, micrognathia, gastroschisis, and various rib defects were observed and related to the day of exposure.

Asunto(s)

Anomalías Inducidas por Medicamentos , Azacitidina/toxicidad , Feto/efectos de los fármacos , Animales , ADN/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Pruebas de Mutagenicidad , Embarazo , ARN/metabolismo , Ratas , Ratas Endogámicas , Factores de Tiempo

RESUMEN

The results of a series of screening tests to determine the potential teratogenicity and neurotoxicity of developmental exposure to TBTO in rats are presented in this paper. For prenatal exposure, pregnant Long Evans rats were intubated with 0-16 mg/kg/day bis(tri-n-butyltin)oxide TBTO from Days 6 to 20 of gestation (GD 6-20). For postnatal exposure, rat pups were intubated with 0-60 mg/kg TBTO on Postnatal Day 5 (PND 5). Following prenatal exposure, dams were allowed to litter and pups were evaluated using a postnatal teratology screen. Postnatal evaluation for both exposures included motor activity (PND 13-64), the acoustic startle response (PND 22-78), growth, and brain weight. The maximally tolerated dose (MTD) in pregnant rats was 5 mg/kg/day, which is one-third the MTD in nonpregnant rats. There were decreased numbers of live births, and decreased growth and viability at dosages greater than or equal to 10 mg/kg/day. Cleft palate was found in 3% of the 12 mg/kg/day group. There was mortality following postnatal exposure to 60 mg/kg and all prenatal dosages greater than or equal to 10 mg/kg/day. Preweaning body weight was significantly decreased for all postnatal dosages, and all prenatal dosages greater than 2.5 mg/kg/day. Body weight reductions persisted to the postweaning period only in the high dose groups (10 mg/kg/day and 60 mg/kg). Behavioral evaluation demonstrated transient alterations in motor activity development (prenatal exposure only) and the acoustic startle response (postnatal exposure only). Persistent behavioral effects were observed only at dosages that produced overt maternal toxicity and/or postnatal mortality. The demonstration of the teratogenic and neurotoxic potential of TBTO in rats is confounded by associated maternal toxicity and/or pup mortality.

Asunto(s)

Anomalías Inducidas por Medicamentos/fisiopatología , Conducta Animal/efectos de los fármacos , Intercambio Materno-Fetal , Efectos Tardíos de la Exposición Prenatal , Compuestos de Trialquiltina/toxicidad , Animales , Peso al Nacer/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Tamaño de la Camada/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Ratas , Ratas Endogámicas , Reflejo de Sobresalto/efectos de los fármacos , Maduración Sexual/efectos de los fármacos , Compuestos de Trialquiltina/administración & dosificación

RESUMEN

Maternal stress during gestation can produce significant fetal and/or postnatal effects, and can enhance the teratogenicity of other agents. We have previously shown that restraint stress on gestational day 8 in CD-1 mice produces significant increases in encephaloceles and supernumerary and fused ribs. In the present study we have examined the effects of stress induced by restraint on individual days during the period of major organogenesis (days 6-14). Weight loss and stress-induced analgesia as assessed by the tail-flick method were used to determine the degree of stress induced by a 12-h restraint period. Restrained animals lost significantly more weight and had longer tail-flick latencies than the concurrent food and water deprived controls on all gestational days. Significant increases in embryo/fetal mortality were also observed in the offspring of restrained animals. An increased incidence of supernumerary ribs was found in mice restrained on days 7 and 8. Since maternal toxicity induced by chemical teratogens may be accompanied by a general increase in maternal stress, our data suggest that such stress may be an etiological factor in teratology bioassays in which dose levels are sufficiently high to induce overt maternal toxicity.

Asunto(s)

Anomalías Congénitas/etiología , Estrés Fisiológico/complicaciones , Analgesia , Animales , Peso Corporal , Femenino , Ratones , Embarazo , Restricción Física

RESUMEN

Pregnant Sprague-Dawley rats were exposed to either 3500 or 7000 mg/m3 p-xylene from days 7-16 of gestation. Dams were allowed to give birth, and litters were counted, weighed, and observed for external malformations on postnatal days (PD) 1 and 3. Litters were normalized to 8 pups (4 males and 4 females +/- 1) on PD4. On PD21 animals were weaned and littermates housed by sex. Body weights were recorded weekly until weaning and once every 2 weeks thereafter. Central nervous system (CNS) development was evaluated by acoustic startle response on PD13, 17, 21, and 63 as well as figure-8 maze activity on PD22 and 65. Maternal weight gain during the treatment period was significantly less in the high-dose group. No effects were seen on litter size or weight at birth or on PD3. There were no effects of xylene exposure on growth rate. There were no treatment-related effects on acoustic startle response or figure-8 maze activity. Thus, p-xylene as administered in this study does not appear to be a selective developmental toxicant in the rat.

Asunto(s)

Feto/efectos de los fármacos , Xilenos/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Femenino , Masculino , Embarazo , Ratas , Ratas Endogámicas , Reflejo de Sobresalto/efectos de los fármacos