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1.
Regul Toxicol Pharmacol ; 138: 105337, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36649819

RESUMEN

An expert panel was assembled to evaluate reproductive toxicology study data and their application to health risk assessment to provide input on the data quality, interpretation, and application of data from three multi-generation reproductive toxicity studies of N-methylpyrrolidone (NMP). Panelists were engaged using a double-blinded, modified Delphi format that consisted of three rounds. Key studies were scored using the U.S. Environmental Protection Agency's (EPA) questions and general considerations to guide the evaluation of experimental animal studies for systematic review. The primary conclusions of the panel are that one of the studies (Exxon, 1991) is not a high-quality study due to several design flaws that includes: (1) exceedance of the maximum tolerable dose in the high dose group; (2) failure to adjust feed concentrations of NMP during the lactation period, resulting in NMP doses that were 2- to 3-fold higher than nominal levels; and/or (3) underlying reproductive performance problems in the strain of rats used. For these reasons, the panel recommended that this study should not be considered for quantitative risk assessment of NMP. Exclusion of this study, and its corresponding data for male fertility and female fecundity, from the quantitative risk assessment results in a change in the identification of the most sensitive endpoint. Instead, changes in rat fetal/pup body weight, an endpoint previously selected by EPA, was identified as an appropriate basis for human health risk assessment based on a consideration of the best available science and weight of scientific evidence supported by the NMP toxicity database.


Asunto(s)
Pirrolidinonas , Reproducción , Humanos , Ratas , Masculino , Animales , Femenino , Pirrolidinonas/toxicidad , Peso Fetal , Medición de Riesgo
2.
Science ; 208(4443): 508-10, 1980 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-7367874

RESUMEN

Phenobarbital administration to pregnant rats from day 12 to day 19 of gestation suppressed body weight gain and produced significant effects on reproductive function in their offspring. These effects included delays in the onset of puberty, disorders in the estrous cycle, and infertility. Moreover, the animals exposed to phenobarbital in utero showed altered concentrations of sex steroids, gonadotrophic hormones, and estrogen receptors. These findings suggest that phenobarbital treatment during prenatal development can produce permanent alterations in sexual maturation.


Asunto(s)
Fenobarbital/efectos adversos , Reproducción/efectos de los fármacos , Animales , Estro/efectos de los fármacos , Femenino , Hormona Luteinizante/sangre , Intercambio Materno-Fetal , Embarazo , Ratas , Receptores de Estrógenos/efectos de los fármacos , Maduración Sexual/efectos de los fármacos
3.
Biochim Biophys Acta ; 411(1): 97-105, 1975 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-1182206

RESUMEN

We report a sensitive and rapid radioassay method for p-aminobenzoic acid N-acetyltransferase. The principle of this assay involves acetylation of p-aminobenzoic acid with [1-14C] labeled acetyl coenzyme A and direct extraction of enzymically formed radioactive p-acetamidobenzoic acid into nonaqueous scintillation fluid. Using this radiometric assay, hepatic and extrahepatic tissue distributions from rat and rabbit were studied. Rabbit blastocyst and endometrial N-acetyltransferase specific activities were equivalent to hepatic activities. Perinatal development studies in rats and rabbits revealed that fetal and neonatal animals are capable of N-acetylation. Rat liver developmental studies exhibited two peaks of activity with the first peak occurring in the late fetus followed by a second peak 3 days after birth. Rabbit fetal and neonatal enzyme activity increased to adult levels by the second week after birth in liver and gut, however, lung showed a different developmental pattern. These studies demonstrate that fetal extrahepatic tissues, like adult tissues, play an important role in N-acetylation.


Asunto(s)
Acetiltransferasas/metabolismo , Hígado/enzimología , Acetiltransferasas/análisis , Aminobenzoatos , Animales , Cloromercuribenzoatos/farmacología , Estudios de Evaluación como Asunto , Feto , Edad Gestacional , Hígado/efectos de los fármacos , Masculino , Manganeso/farmacología , Métodos , Especificidad de Órganos , Conejos , Ratas , Zinc/farmacología
4.
Environ Health Perspect ; 103 Suppl 6: 197-205, 1995 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-8549474

RESUMEN

This review contains a succinct overview of the nature and extent of the problem of contamination of human milk with environmental and occupational chemicals, excluding drugs. Factors influencing the levels of contaminants in breast milk are discussed. Also, data on major chemicals of concern with potential health risk(s) to the general population and risk-benefit considerations are dealt with briefly. Based on the available data on the subject, research needs have been identified and policy recommendations are suggested.


Asunto(s)
Contaminantes Ambientales/análisis , Leche Humana/química , Femenino , Contaminación de Alimentos , Humanos , Lactante , Recién Nacido , Residuos de Plaguicidas/análisis
5.
Environ Health Perspect ; 12: 97-102, 1975 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-1227867

RESUMEN

Placental transfer rates of cadmium were investigated in rats in relation to dose (0.1, 0.4, and 1.6 mg Cd/kg) and the gestational age (12, 15, and 20 days) when rats were treated. Pregnant rats were injected intravenously with a single dose of 109CdCl2 (approximately 20 muCi/animal), and animals were sacrificed after 24 hr. 109Cd concentrations were measured in the fetus, placenta, maternal liver, and blood. Cadmium crossed the placenta at all doses and at all gestational ages tested. However, higher percentages of administered cadmium accumulated in the fetus with increasing dose and increasing gestational age. For example, after pregnant rats were injected with low, middle, and high doses of Cd on day 12 of gestation, fetuses accumulated 0.0001, 0.0028, and 0.0095 per cent of the injected dose, respectively. Percentages of administered Cd detected in placental tissue did not change consistently with dose but Cd levels did increase with gestational age. Placental to maternal blood Cd concentration ratios increased with gestational age but not with dose. Maternal liver to fetal liver concentration ratios were 295, 137, and 27 for low, middle and high doses, respectively, 24 hr after pregnant rats were treated on day 20 of gestation. These results are discussed in relation to placental damage, metallothionein inducibility, and fetotoxicity.


Asunto(s)
Cadmio/metabolismo , Edad Gestacional , Intercambio Materno-Fetal , Placenta/metabolismo , Animales , Cadmio/administración & dosificación , Cadmio/sangre , Femenino , Feto/metabolismo , Hígado/metabolismo , Embarazo , Radioisótopos , Ratas , Factores de Tiempo
6.
Environ Health Perspect ; 108 Suppl 3: 569-71, 2000 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10852856

RESUMEN

The work group on cardiovascular and endocrine effects was asked to review the current state of knowledge about children's windows of vulnerability to developmental toxicants and to recommend how that information may be used to improve risk assessment and public health. We considered differences between structural defects, where periods of vulnerability are rather well defined, and functional defects, where periods of vulnerability are quite elusive.


Asunto(s)
Sistema Cardiovascular/efectos de los fármacos , Sistema Cardiovascular/crecimiento & desarrollo , Protección a la Infancia , Sistema Endocrino/efectos de los fármacos , Sistema Endocrino/crecimiento & desarrollo , Xenobióticos/efectos adversos , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Medición de Riesgo , Teratógenos/toxicidad , Factores de Tiempo
7.
Chem Biol Interact ; 11(1): 15-26, 1975 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-806369

RESUMEN

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) administered to pregnant rats at 3 mu-g/kg as a single oral dose during early, middle, or late gestation caused marked elevations of some maternal hepatic microsomal enzymes for at least 10 weeks after treatment. This dose was not teratogenic and fetal rates of glucuronidation of testosterone and p-nitrophenol (PNP) were unaffected. Increases in fetal liver benzpyrene hydroxylase (BPH) activities were evident during late gestation although cytochrome P-450 and cytochrome b-5 contents were unchanged. The offspring of pregnant rats administered TCDD had markedly elevated hepatic PNP UDP-glucuronyltransferase (UDPGT) BPH, and microsomal cytochrome contents whereas the perinatal development of testosterone UDPGT was unchanged. PNP glucuronidation attained a maximal 8-fold increase above controls by 3 weeks after birth and activities were twice that of controls 8 weeks after birth (adults). Maximal increases in benzpyrene hydroxylation rates occurred one day after birth when in the prenatally exposed group activities were approximately 20 times higher than controls. Foster mother experiments demonstrated that the postnatal inductive effect resulted both from exposure of newborns to TCDD via maternal milk and the activation of an inducing mechanism occurring after birth. Tese data demonstrate that multiple factors are responsible for the induction of hepatic microsomal enzymes in the newborn following administration of TCDD to pregnant rats.


Asunto(s)
Dioxinas/farmacología , Microsomas Hepáticos/enzimología , Dibenzodioxinas Policloradas/farmacología , Embarazo , Animales , Animales Recién Nacidos , Benzopirenos , Sistema Enzimático del Citocromo P-450/metabolismo , Citocromos/metabolismo , Inducción Enzimática/efectos de los fármacos , Femenino , Edad Gestacional , Glucuronidasa/metabolismo , Glucuronosiltransferasa/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Oxigenasas de Función Mixta/metabolismo , Nitrofenoles , Ratas , Testosterona , Factores de Tiempo
10.
Pediatr Pharmacol (New York) ; 2(3): 223-9, 1982.
Artículo en Inglés | MEDLINE | ID: mdl-6984504

RESUMEN

Hepatic and extrahepatic distribution and the perinatal developmental pattern of p-aminobenzoic acid (PABA)-N-acetyltransferase (E.C.2.3.1.5) in guinea pig liver, lung, and placenta were studied. In adult guinea pigs, kidney and small intestine enzyme specific activities were equivalent to hepatic activity. Lung enzyme activity was about 15% of that in adult liver. No sex differences in hepatic or extrahepatic distribution of enzyme levels were evident. The perinatal development study revealed that fetal as well as neonatal animals are capable of N-acetylation. The peak in liver and lung activity occur between 3 and 8 days after birth. Placenta has about 50% of adult liver activity for PABA-N-acetylation and it declines near term. These data indicate that extrahepatic organs of guinea pigs significantly contribute to PABA-N-acetylation.


Asunto(s)
Acetiltransferasas/análisis , Animales Recién Nacidos/metabolismo , Feto/enzimología , Hígado/enzimología , Ácido 4-Aminobenzoico/metabolismo , Animales , Femenino , Cobayas , Pulmón/enzimología , Masculino , Placenta/enzimología , Embarazo , Factores Sexuales
11.
Pediatr Res ; 14(8): 939-42, 1980 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-6999441

RESUMEN

The frequency of gram-negative infections and endotoxemia in the perinatal period prompted an investigation of the effects of endotoxin (Escherichia coli 026B6) on hepatic drug metabolism. Gravid female rats given injections IP with different dosages of lipopolysaccharide during late pregnancy resulted in significant depression of the liver microsomal cytochrome P-450 dependent monooxygenase activities. The acute administration of endotoxin to mothers (1.4 mg/kg on seventh day after parturition) significantly decreased the hepatic activity of aminopyrine demethylase and contents of cytochrome P-450 of suckling neonates and mothers. However, chronic administration of endotoxin (0.2 mg/kg/day for 7 days) to lactating mothers did not alter neonatal enzyme activities. When neonates themselves were given injections of endotoxin (1.0 mg/kg) at 7, 16, and 27 days of age, a significant reduction in levels of mixed function oxidase enzymes was observed. These observations suggest that the ability of mothers and neonates to metabolize drugs is significantly decreased upon exposure to endotoxin, and this demands careful evaluation of drug disposition studies in gram-negative sepsis.


Asunto(s)
Endotoxinas/farmacología , Microsomas Hepáticos/metabolismo , Oxigenasas de Función Mixta/metabolismo , Oxidorreductasas/metabolismo , Factores de Edad , Animales , Animales Recién Nacidos , Escherichia coli , Femenino , Lactancia , Embarazo , Ratas
12.
Biol Res Pregnancy Perinatol ; 4(2): 48-55, 1983.
Artículo en Inglés | MEDLINE | ID: mdl-6411137

RESUMEN

This article reviews the delayed effects of anticonvulsants (phenobarbital, phenytoin, and valproate) administered in utero upon the reproductive function in the offspring. Experimental data from the authors' laboratories are discussed in light of this context. Furthermore, comments are made emphasizing the gaps in our knowledge concerning the problem of drug exposure during pregnancy and the complex nature of drug effects upon the reproductive system.


Asunto(s)
Anticonvulsivantes/efectos adversos , Efectos Tardíos de la Exposición Prenatal , Reproducción/efectos de los fármacos , Animales , Estro/efectos de los fármacos , Femenino , Fertilidad/efectos de los fármacos , Hormona Luteinizante/sangre , Masculino , Fenobarbital/efectos adversos , Fenitoína/efectos adversos , Embarazo , Ratas , Maduración Sexual/efectos de los fármacos , Testosterona/metabolismo , Ácido Valproico/efectos adversos
13.
Pharmacology ; 26(2): 100-9, 1983.
Artículo en Inglés | MEDLINE | ID: mdl-6844387

RESUMEN

The effects of the combination of low protein diet feeding and endotoxin (E. coli, serotype 026 B6) upon rat hepatic microsomal mixed function oxidase (MFO) enzymes were investigated. Short-term (7 days) feeding of low protein (8%) diet and acute (single dose) exposure to endotoxin resulted in an additive decrease in MFO enzymes. However, chronic (7 days) endotoxin exposure did not depress liver microsomal MFO enzyme activities except for aniline hydroxylase. Long-term (105 days) feeding of the low protein diet and acute endotoxin exposure further decreased aminopyrine N-demethylase and benzo(a)pyrene hydroxylase activities compared to individual treatments. These results suggest that, under these experimental conditions, the two host-related environmental factors interact and potentiate a decrease in rat hepatic microsomal drug metabolizing enzymes. These observations may be of clinical relevance to explain altered drug reactions in patients with gram-negative infections and endotoxemia under the conditions of malnutrition.


Asunto(s)
Endotoxinas/farmacología , Hígado/metabolismo , Oxigenasas de Función Mixta/metabolismo , Oxidorreductasas/metabolismo , Preparaciones Farmacéuticas/metabolismo , Deficiencia de Proteína/metabolismo , Animales , Dieta , Femenino , Microsomas Hepáticos/enzimología , Ratas , Ratas Endogámicas , Factores de Tiempo
14.
Res Commun Chem Pathol Pharmacol ; 38(3): 513-6, 1982 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-7163643

RESUMEN

The effect of thyroxine administration on the activities of hepatic microsomal monooxygenases were studied in neonatal rats. While there were no sexual differences in the activities of hepatic hexobarbital hydroxylase, cytochrome P-450 and cytochrome b5 in 8 day old rats, thyroxine administration significantly reduced the activities of these monooxygenases in both male and female neonates. The results suggest that the liver of the neonatal rat has not developed the ability to respond to the enzyme-stimulating effects of thyroxine as reported for adults.


Asunto(s)
Animales Recién Nacidos/metabolismo , Hígado/enzimología , Oxigenasas/antagonistas & inhibidores , Tiroxina/farmacología , Animales , Femenino , Embarazo , Ratas
15.
Proc Soc Exp Biol Med ; 168(2): 175-9, 1981 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-6183668

RESUMEN

Phenytoin administered to pregnant mice during the critical embryonic period of palatal differentiation produced 50% cleft palates in the Ajax (A/J) strain compared to 1.6% clefts in the C57BL/6 (B6) strain of mice. Furthermore, a single maternal injection of phenytoin produced a significantly greater and more persistent decrease in fetal palatal RNA and protein synthesis in the sensitive A/J strain compared to that in the insensitive B6 strain of mice. Thus, these differential effects of phenytoin on RNA and protein synthesis are associated with the differential susceptibility to the teratogenic action of phenytoin in the two strains.


Asunto(s)
Fisura del Paladar/inducido químicamente , Hueso Paladar/embriología , Fenitoína/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Animales , Femenino , Feto/metabolismo , Ratones , Ratones Endogámicos , Hueso Paladar/efectos de los fármacos , Embarazo , ARN/biosíntesis
16.
Res Commun Chem Pathol Pharmacol ; 30(2): 369-72, 1980 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-7444165

RESUMEN

The effects of altered thyroid function upon serum cholin-esterase levels and dichlorvos toxicity were studied in adult male and female rats. No sexual dimorphism was observed in the base level of serum cholinesterase, however, oral administration of dichlorvos (52.5 mg/kg) resulted in 30% mortality to intact female rats. Hypothyroidism significantly elevated while hyperthyroidism decreased serum cholinesterase enzyme activity in both sexes of rats. Hyperthyroid females were more susceptible than males to dichlorvos challenge even with similar decrease in serum cholinesterase activity.


Asunto(s)
Diclorvos/toxicidad , Hormonas Tiroideas/fisiología , Animales , Colinesterasas/sangre , Femenino , Masculino , Glándulas Paratiroides/fisiología , Ratas , Tiroidectomía , Tiroxina/sangre
17.
Drug Metab Dispos ; 5(3): 279-87, 1977.
Artículo en Inglés | MEDLINE | ID: mdl-17527

RESUMEN

The relative activities of uridine diphosphoglucuronyltransferase (UDPGT) and beta-glucuronidase (betaG) were measured during perinatal development of hepatic and extrahepatic tissues to determine the balance between glucuronidation and deglucuronidation reactions at different developmental stages. Liver, lung, kidney, intestine, and placenta were studied in guinea pigs and rabbits. In general, betaG activities exceeded those of UDPGT in fetal tissues, whereas the converse was evident in adults. There were significant species and age differences in the onset of betaG and UDPGT activities and the occurrence of developmental peaks. A dramatic betaG developmental peak was observed in fetal guinea pig intestine and newborn rabbit intestine. Both microsomal and lysosomal betaG exhibited similar developmental patterns in all tissues tested. Hepatic nonsteroid UDPGT activities were higher at parturition than in adult animals, whereas no such developmental peak occurred for steroid UDPGT. Triton X-100 activated fetal UDPGT in vitro by approximately the same factor as it did for adult UDPGT.


Asunto(s)
Animales Recién Nacidos/metabolismo , Feto/metabolismo , Glucuronatos/metabolismo , Hígado/metabolismo , Envejecimiento , Animales , Femenino , Edad Gestacional , Glucuronidasa/metabolismo , Glucuronosiltransferasa/metabolismo , Cobayas , Técnicas In Vitro , Intestino Delgado/enzimología , Intestino Delgado/ultraestructura , Riñón/enzimología , Riñón/ultraestructura , Pulmón/enzimología , Pulmón/ultraestructura , Masculino , Microsomas/enzimología , Microsomas Hepáticos/enzimología , Nitrofenoles/metabolismo , Placenta/enzimología , Placenta/ultraestructura , Polietilenglicoles/farmacología , Embarazo , Conejos , Fracciones Subcelulares/enzimología , Testosterona/metabolismo
18.
Res Commun Chem Pathol Pharmacol ; 15(2): 319-30, 1976 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-10606

RESUMEN

Benzo(a)pyrene hydroxylase activity was found in the bone marrow of control and 3MC-induced New Zealand white rabbits. This activity was localized in the microsomal fraction, was NADPH dependent and CO sensitive. The reaction was inhibited by 7,8-benzoflavone indicating that it was mediated by the 3MC-inducible form of cytochrome P-450. BP hydroxylase activity in rabbit bone marrow was located primarily in white cells, and was considerably higher than that previously reported for cultured human lymphocytes and monocytes. A possible role for the bone marrow mixed-function oxygenase in the production of hemopoietic toxicity is considered.


Asunto(s)
Hidrocarburo de Aril Hidroxilasas , Benzopireno Hidroxilasa , Médula Ósea/enzimología , Animales , Hidrocarburo de Aril Hidroxilasas/análisis , Benzopireno Hidroxilasa/análisis , Benzopireno Hidroxilasa/metabolismo , Médula Ósea/ultraestructura , Inducción Enzimática/efectos de los fármacos , Femenino , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Hígado/enzimología , Metilcolantreno/farmacología , Conejos , Fracciones Subcelulares/enzimología
19.
Xenobiotica ; 12(5): 303-13, 1982 May.
Artículo en Inglés | MEDLINE | ID: mdl-7135999

RESUMEN

1. Bacterial endotoxin, a soluble lipopolysaccharide, has been studied to ascertain its effects in vivo and in vitro on the hepatic drug-metabolizing enzymes of adult male and female rats. 2. 24 h after a single 1 X 0 or 2 X 0 mg/kg i.p. dose of endotoxin, hexobarbital sleeping time was significantly increased in adult male rats. Significant inhibition of liver microsomal cytochrome P-450 occurred after 6 h and continued only until 24 h after endotoxin administration, while injection of inactivated endotoxin did not result in any significant decrease of hepatic mixed-function oxidase enzymes or cytochrome P-450. In contrast, rho-nitrophenol-UDP-glucuronyltransferase enzyme activity was unaffected by these levels of endotoxin. 3. Electron-microscopic examination of rat liver hepatocytes did not reveal any significant change in ultrastructure 24 h after a single i.p. dose of endotoxin. 4. Endotoxin failed to depress the phenobarbitone- or 3-methylcholanthrene-induced forms of cytochrome P-450 and the dependent mono-oxygenase enzymes. Simultaneous administration of phenobarbital and endotoxin resulted in 100% mortality of rats. Combination of 3-methylcholanthrene and endotoxin did not block the induction of cytochrome P-448 or dependent benzo[a]pyrene hydroxylase activity. 5. Addition of endotoxin in vitro resulted in significant inhibition of hepatic microsomal cytochrome P-450 and aminopyrine N-demethylase activity only on preincubation with an NADPH-generating system supplemented with EDTA.


Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Endotoxinas/farmacología , Microsomas Hepáticos/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Inducción Enzimática/efectos de los fármacos , Femenino , Hexobarbital/farmacología , Técnicas In Vitro , Masculino , Metilcolantreno/farmacología , Oxigenasas de Función Mixta/biosíntesis , Ratas , Sueño/efectos de los fármacos
20.
Dev Pharmacol Ther ; 14(2): 135-40, 1989.
Artículo en Inglés | MEDLINE | ID: mdl-2517107

RESUMEN

The objective of this study was to determine whether feeding high dietary fat, during pregnancy and lactation of Sprague-Dawley rats, can modulate hepatic drug-metabolizing enzymes of the offspring during postnatal development. Time-pregnant rats were pair-fed isocalorically 20% (experimental) or 5% (control) corn oil diets from day 10 of gestation until weaning. After weaning, litters from both groups were fed 5% corn oil diet until sacrificed. Offsprings were sacrificed at weaning (23 days), puberty (45 days) and at adult stage (100 days). Feeding diet containing 20% corn oil to dams, resulted in significant increases in liver microsomal cytochrome P-450, b5 contents and aminopyrine N-demethylase activity of the male offspring at weaning, puberty and adult stage of life. A similar but less marked trend was also observed in the female offspring. Thus, it appears that the high dietary fat exposure during perinatal development may result in significant alterations in hepatic drug-metabolizing enzyme activities of the progeny.


Asunto(s)
Envejecimiento/metabolismo , Grasas de la Dieta/administración & dosificación , Hígado/metabolismo , Microsomas Hepáticos/enzimología , Efectos Tardíos de la Exposición Prenatal , Aminopirina N-Demetilasa/metabolismo , Animales , Sistema Enzimático del Citocromo P-450/análisis , Citocromos b5/análisis , Grasas de la Dieta/farmacología , Femenino , Lactancia , Hígado/efectos de los fármacos , Masculino , Microsomas Hepáticos/efectos de los fármacos , NADPH-Ferrihemoproteína Reductasa/metabolismo , Embarazo , Distribución Aleatoria , Ratas , Ratas Endogámicas , Factores Sexuales
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