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1.
Clin Pharmacol Ther ; 113(2): 226-245, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-35388453

RESUMEN

This review presents a European Federation of Pharmaceutical Industries and Association/PreClinical Development Expert Group (EFPIA-PDEG) topic group consensus on a data-driven approach to harmonized contraception recommendations for clinical trial protocols and product labeling. There is no international agreement in pharmaceutical clinical trial protocols or product labeling on when/if female and/or male contraception is warranted and for how long after the last dose. This absence of consensus has resulted in different recommendations among regions. For most pharmaceuticals, contraception recommendations are generally based exclusively on nonclinical data and/or mechanism. For clinical trials, contraception is the default position and is maintained for women throughout clinical development, whereas appropriate information can justify removing male contraception. Conversely, contraception is only recommended in product labeling when warranted. A base case rationale is proposed for whether or not female and/or male contraception is/are warranted, using available genotoxicity and developmental toxicity data. Contraception is generally warranted for both male and female subjects treated with mutagenic pharmaceuticals. We propose as a starting point that contraception is not typically warranted when the margin is 10-fold or greater between clinical exposure at the maximum recommended human dose and exposure at the no observed adverse effect level (NOAEL) for purely aneugenic pharmaceuticals and for pharmaceuticals that induce fetal malformations or embryo-fetal lethality. Other factors are discussed, including contraception methods, pregnancy testing, drug clearance, options for managing the absence of a developmental toxicity NOAEL, drug-drug interactions, radiopharmaceuticals, and other drug modalities. Overall, we present a data-driven rationale that can serve as a basis for consistent contraception recommendations in clinical trials and in product labeling across regions.


Asunto(s)
Anticoncepción , Industria Farmacéutica , Embarazo , Humanos , Masculino , Femenino , Anticoncepción/efectos adversos , Nivel sin Efectos Adversos Observados , Consenso , Preparaciones Farmacéuticas
2.
Toxicol Appl Pharmacol ; 428: 115673, 2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-34364948

RESUMEN

Pegbelfermin (PGBF) is a PEGylated fibroblast growth factor 21 (FGF21) analogue in development for treatment of nonalcoholic steatohepatitis (NASH). Mouse models highlight potential utility of FGF21 in NASH, but also suggest negative effects on bone, though these findings are confounded by profound FGF21-related decreases in body mass/growth. This study aimed to profile PGBF-related bone effects in adult nonhuman primates after long-term, clinically-relevant exposures. Adult male cynomolgus monkeys received weekly subcutaneous PGBF (0.3, 0.75 mg/kg) or control injections for 1 year (n = 5/group). Assessments included body weight, clinical chemistry, adiponectin levels, bone turnover biomarkers, skeletal radiography, pharmacokinetics, immunogenicity, and histopathology. Bone densitometry and body composition were evaluated in vivo and/or ex vivo with dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, and biomechanical strength testing. After 1 year of PGBF administration, there was clear evidence of sustained PGBF pharmacology in monkeys (peak increase in serum adiponectin of 1.7× and 2.35× pretest at 0.3 and 0.75 mg/kg PGBF, respectively) and decreased body weight compared with control at exposures comparable to those tested in humans. At 0.75 mg/kg PGBF, pharmacologically-mediated reductions in lean mass, lean area, and fat area were observed relative to controls. There were no PGBF-related effects on bone biomarkers, radiography, densitometry, or strength. Together, these data demonstrate that PGBF did not adversely alter bone metabolism, density, or strength following 1 year of dosing at clinically relevant (0.7-2.2× human AUC[0-168 h] at 20 mg once weekly), pharmacologically-active exposures in adult monkeys, suggesting a low potential for negative effects on bone quality in adult humans.


Asunto(s)
Densidad Ósea/efectos de los fármacos , Remodelación Ósea/efectos de los fármacos , Factores de Crecimiento de Fibroblastos/análogos & derivados , Polietilenglicoles/administración & dosificación , Animales , Densidad Ósea/fisiología , Remodelación Ósea/fisiología , Esquema de Medicación , Factores de Crecimiento de Fibroblastos/administración & dosificación , Factores de Crecimiento de Fibroblastos/química , Haplorrinos , Macaca fascicularis , Masculino , Polietilenglicoles/química , Factores de Tiempo
3.
Birth Defects Res ; 111(16): 1178-1191, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31228335

RESUMEN

Literature suggests that murine allogeneic pregnancy models are an alternative approach for evaluating the developmental toxicity of immune-stimulating agents. In this study, multiple syngeneic and allogeneic murine pregnancy models were used to assess the potential embryo-fetal effects of four different murine antibodies (IgG1 or IgG2 ) that activate the immune system by binding to T-cell receptors (PD-L1, LAG-3, and GITR). The pregnancy models were generated by within and between matings of five different inbred strains of mice (CBA/CaJ, DBA/2J, BALB/c, C57BL/6, and CBA/J). The antibodies were administered every 2-3 days by intraperitoneal injection (n = 12-29/group) during gestation days 6 to 14. There were no differences in embryo-fetal endpoints between the allogeneic and syngeneic pregnancies. Additionally, treatment with the antibodies had no effect on mean postimplantation loss in either the syngeneic or allogeneic pregnancies despite confirmation of pharmacologically-relevant systemic exposures. These results suggest that allogeneic murine pregnancy models need further validation and testing before they can be reliably used as an alternative approach for assessing the developmental effects of agents that stimulate the immune system.


Asunto(s)
Inmunoglobulina G/inmunología , Linfocinas/inmunología , Ratones Endogámicos/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Antígenos CD/inmunología , Antígeno B7-H1/inmunología , Femenino , Proteína Relacionada con TNFR Inducida por Glucocorticoide/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Modelos Animales , Embarazo , Reproducibilidad de los Resultados , Proteína del Gen 3 de Activación de Linfocitos
4.
Birth Defects Res ; 110(10): 840-850, 2018 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-29436169

RESUMEN

BACKGROUND: Current developmental toxicity testing adheres largely to protocols suggested in 1966 involving the administration of test compound to pregnant laboratory animals. After more than 50 years of embryo-fetal development testing, are we ready to consider a different approach to human developmental toxicity testing? METHODS: A workshop was held under the auspices of the Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute to consider how we might design developmental toxicity testing if we started over with 21st century knowledge and techniques (revolution). We first consider what changes to the current protocols might be recommended to make them more predictive for human risk (evolution). RESULTS: The evolutionary approach includes modifications of existing protocols and can include humanized models, disease models, more accurate assessment and testing of metabolites, and informed approaches to dose selection. The revolution could start with hypothesis-driven testing where we take what we know about a compound or close analog and answer specific questions using targeted experimental techniques rather than a one-protocol-fits-all approach. Central to the idea of hypothesis-driven testing is the concept that testing can be done at the level of mode of action. It might be feasible to identify a small number of key events at a molecular or cellular level that predict an adverse outcome and for which testing could be performed in vitro or in silico or, rarely, using limited in vivo models. Techniques for evaluating these key events exist today or are in development. DISCUSSION: Opportunities exist for refining and then replacing current developmental toxicity testing protocols using techniques that have already been developed or are within reach.


Asunto(s)
Desarrollo Embrionario/fisiología , Desarrollo Fetal/fisiología , Pruebas de Toxicidad/métodos , Animales , Femenino , Humanos , Embarazo , Medición de Riesgo
5.
Crit Rev Toxicol ; 47(5): 402-414, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-27766926

RESUMEN

A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects between rat and rabbit study outcomes for individual compounds, EFDT studies in two species have added value over single studies.


Asunto(s)
Embrión de Mamíferos/fisiología , Desarrollo Embrionario/efectos de los fármacos , Preparaciones Farmacéuticas , Animales , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Embrión de Mamíferos/efectos de los fármacos , Conejos , Ratas
6.
Crit Rev Toxicol ; 46(10): 900-910, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27848393

RESUMEN

Regulatory non-clinical safety testing of human pharmaceuticals typically requires embryo-fetal developmental toxicity (EFDT) testing in two species (one rodent and one non-rodent). The question has been raised whether under some conditions EFDT testing could be limited to one species, or whether the testing in a second species could be decided on a case-by-case basis. As part of a consortium initiative, we built and queried a database of 379 compounds with EFDT studies (in both rat and rabbit animal models) conducted for marketed and non-marketed pharmaceuticals for their potential for adverse developmental and maternal outcomes, including EFDT incidence and the nature and severity of adverse findings. Manifestation of EFDT in either one or both species was demonstrated for 282 compounds (74%). EFDT was detected in only one species (rat or rabbit) in almost a third (31%, 118 compounds), with 58% (68 compounds) of rat studies and 42% (50 compounds) of rabbit studies identifying an EFDT signal. For 24 compounds (6%), fetal malformations were observed in one species (rat or rabbit) in the absence of any EFDT in the second species. In general, growth retardation, fetal variations, and malformations were more prominent in the rat, whereas embryo-fetal death was observed more often in the rabbit. Discordance across species may be attributed to factors such as maternal toxicity, study design differences, pharmacokinetic differences, and pharmacologic relevance of species. The current analysis suggests that in general both species are equally sensitive on the basis of an overall EFDT LOAEL comparison, but selective EFDT toxicity in one species is not uncommon. Also, there appear to be species differences in the prevalence of various EFDT manifestations (i.e. embryo-fetal death, growth retardation, and dysmorphogenesis) between rat and rabbit, suggesting that the use of both species has a higher probability of detecting developmental toxicants than either one alone.


Asunto(s)
Desarrollo Fetal/efectos de los fármacos , Sustancias Peligrosas/toxicidad , Modelos Animales , Pruebas de Mutagenicidad/métodos , Teratógenos/toxicidad , Anomalías Inducidas por Medicamentos , Animales , Conejos , Ratas
7.
Toxicol Pathol ; 44(6): 789-809, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27235322

RESUMEN

Standard components of nonclinical toxicity testing for novel pharmaceuticals include clinical and anatomic pathology, as well as separate evaluation of effects on reproduction and development to inform clinical development and labeling. General study designs in regulatory guidances do not specifically mandate use of pathology or reproductive end points across all study types; thus, inclusion and use of these end points are variable. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology (STP) formed a Working Group to assess the current guidelines and practices on the use of reproductive, anatomic pathology, and clinical pathology end points in general, reproductive, and developmental toxicology studies. The Working Group constructed a survey sent to pathologists and reproductive toxicologists, and responses from participating organizations were collected through the STP for evaluation by the Working Group. The regulatory context, relevant survey results, and collective experience of the Working Group are discussed and provide the basis of each assessment by study type. Overall, the current practice of including specific end points on a case-by-case basis is considered appropriate. Points to consider are summarized for inclusion of reproductive end points in general toxicity studies and for the informed use of pathology end points in reproductive and developmental toxicity studies.


Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/normas , Toxicología/métodos , Toxicología/normas , Animales , Adhesión a Directriz , Humanos , Patología Clínica/métodos , Patología Clínica/normas , Pruebas de Toxicidad/métodos , Pruebas de Toxicidad/normas
8.
Reprod Toxicol ; 59: 22-30, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26854737

RESUMEN

Small molecule pharmaceutical products are assumed to reach concentrations in semen similar to those in blood plasma. Exposure modeling for these small-molecule products in humans assumes a daily dose of 5mL of semen and 100% absorption from the vagina with distribution to the conceptus through the maternal systemic circulation. Monoclonal antibody drugs are present in semen at concentrations about 2% or less of those in blood, and the modeling used for small molecules will over-estimate the possibility of conceptus exposure to immunoglobulins. It is not known whether peptide products reach semen, but in general peptide medications are destroyed by vaginal peptidases, and conceptus exposure is predicted to be minimal. Theoretical exposure routes to pharmaceuticals that might result in exposure of the conceptus greater than that of maternal systemic exposures include direct access through the cervical canal, adsorption to sperm for carriage into the oocyte, and direct delivery from the vaginal veins or lymphatics to the uterine artery. There is some evidence for direct access to the uterus for progesterone, terbutaline, and danazol, but the evidence does not involve exposures during pregnancy in most instances. Studies in mice, rats, rabbits, and monkeys do not suggest that exposure to small molecule pharmaceuticals in semen imposes risks to the conceptus beyond those that can be predicted using modeling of systemic maternal exposure. Monoclonal antibody and peptide exposure in semen does not pose a significant risk to the conceptus.


Asunto(s)
Anticuerpos Monoclonales/metabolismo , Embrión de Mamíferos/metabolismo , Feto/metabolismo , Péptidos/metabolismo , Preparaciones Farmacéuticas/metabolismo , Semen/metabolismo , Vagina/metabolismo , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/toxicidad , Transporte Biológico , Embrión de Mamíferos/efectos de los fármacos , Femenino , Feto/efectos de los fármacos , Haplorrinos , Humanos , Masculino , Exposición Materna , Ratones , Modelos Animales , Modelos Biológicos , Exposición Paterna , Péptidos/química , Péptidos/toxicidad , Permeabilidad , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/química , Conejos , Medición de Riesgo , Absorción Vaginal
9.
Reprod Toxicol ; 59: 1-7, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26546978

RESUMEN

Risk assessment for indirect exposure to small molecule pharmaceuticals in semen to the conceptus has traditionally been handled by calculations based on assumptions that any embryo-fetal exposure would be secondary to maternal absorption and redistribution. This study was designed to assess the potential for transcervical passage of drugs from semen. Reproductive tracts of rodents were examined following vaginal dosing with vital dyes during the estrous cycle, mating, and pregnancy. Toluidine Blue was not observed beyond the cervix after vaginal administration in pregnant rats; additionally, it did not pass the cervix in rats during any phase of estrous. In order to address the effects of semen, rats were dosed at receptivity and mated. Vital dyes were not visually evident in the uterus despite vaginal and sperm plug staining. This study provides evidence that direct transcervical passage is not a substantial route of direct embryo-fetal exposure for small molecule drugs in semen.


Asunto(s)
Cuello del Útero/metabolismo , Colorantes/metabolismo , Semen/metabolismo , Conducta Sexual Animal , Cloruro de Tolonio/metabolismo , Administración Intravaginal , Animales , Colorantes/administración & dosificación , Femenino , Edad Gestacional , Masculino , Exposición Materna , Ratones Endogámicos ICR , Exposición Paterna , Permeabilidad , Embarazo , Ratas Sprague-Dawley , Factores de Tiempo , Cloruro de Tolonio/administración & dosificación , Vagina/metabolismo
10.
Reprod Toxicol ; 59: 17-21, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26524246

RESUMEN

Given concern about potential embryo-fetal harm following seminal exposure to drugs with teratogenic potential, pharmaceutical companies use theoretical calculations to estimate seminal concentrations, maternal exposure, and distribution across the placenta to the embryo-fetal compartment for risk assessment. However, it is plausible that there are additional mechanisms whereby the conceptus is exposed. In order to determine if theoretical calculations are sufficiently conservative to predict embryo-fetal exposure from drugs in semen, pregnant cynomolgus monkeys were given a vaginal dose of metronidazole during the early fetal period and cesarean-sectioned. Maternal, fetal, and amniotic fluid samples were analyzed for metronidazole and 2-hydroxymetronidazole. Exposure to metronidazole and its metabolite were comparable in all matrices. These data demonstrated no preferential transfer mechanism to conceptus following intravaginal administration of a small molecule drug; and therefore, suggest that traditional modeling for embryo-fetal exposure to drugs in semen in support of risk assessment for pharmaceutical agents is sufficiently conservative.


Asunto(s)
Líquido Amniótico/metabolismo , Antiinfecciosos/administración & dosificación , Feto/metabolismo , Exposición Materna , Metronidazol/administración & dosificación , Vagina/metabolismo , Administración Intravaginal , Animales , Antiinfecciosos/sangre , Antiinfecciosos/toxicidad , Biotransformación , Femenino , Feto/efectos de los fármacos , Macaca fascicularis , Exposición Materna/efectos adversos , Metronidazol/análogos & derivados , Metronidazol/sangre , Metronidazol/metabolismo , Metronidazol/toxicidad , Permeabilidad , Embarazo , Medición de Riesgo
11.
Reprod Toxicol ; 58: 213-21, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26545974

RESUMEN

Small molecule pharmaceutical products are assumed to reach concentrations in semen similar to those in blood plasma. Exposure modeling for these small-molecule products in humans assumes a daily dose of 5mL of semen and 100% absorption from the vagina with distribution to the conceptus through the maternal systemic circulation. Monoclonal antibody drugs are present in semen at concentrations about 2% or less of those in blood, and the modeling used for small molecules will over-estimate the possibility of conceptus exposure to immunoglobulins. It is not known whether peptide products reach semen, but in general peptide medications are destroyed by vaginal peptidases, and conceptus exposure is predicted to be minimal. Theoretical exposure routes to pharmaceuticals that might result in exposure of the conceptus greater than that of maternal systemic exposures include direct access through the cervical canal, adsorption to sperm for carriage into the oocyte, and direct delivery from the vaginal veins or lymphatics to the uterine artery. There is some evidence for direct access to the uterus for progesterone, terbutaline, and danazol, but the evidence does not involve exposures during pregnancy in most instances. Studies in mice, rats, rabbits, and monkeys do not suggest that exposure to small molecule pharmaceuticals in semen imposes risks to the conceptus beyond those that can be predicted using modeling of systemic maternal exposure. Monoclonal antibody and peptide exposure in semen does not pose a significant risk to the conceptus.


Asunto(s)
Anticuerpos Monoclonales/metabolismo , Cuello del Útero/metabolismo , Embrión de Mamíferos/metabolismo , Preparaciones Farmacéuticas/metabolismo , Proteínas/metabolismo , Semen/metabolismo , Vagina/metabolismo , Animales , Anticuerpos Monoclonales/efectos adversos , Transporte Biológico , Cuello del Útero/efectos de los fármacos , Embrión de Mamíferos/efectos de los fármacos , Femenino , Humanos , Masculino , Modelos Biológicos , Embarazo , Proteínas/efectos adversos , Medición de Riesgo , Factores de Riesgo , Especificidad de la Especie , Vagina/efectos de los fármacos
13.
Clin Chem ; 53(6): 1038-45, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17434907

RESUMEN

BACKGROUND: Gene expression profiling of whole blood may be useful for monitoring toxicological exposure and for diagnosis and monitoring of various diseases. Several methods are available that can be used to transport, store, and extract RNA from whole blood, but it is not clear which procedures alter results. In addition, characterization of interindividual and sex-based variation in gene expression is needed to understand sources and extent of variability. METHODS: Whole blood was obtained from adult male and female volunteers (n = 42) and stored at various temperatures for various lengths of time. RNA was isolated and RNA quality analyzed. Affymetrix GeneChips (n = 23) were used to characterize gene expression profiles (GEPs) and to determine the effects on GEP of storage conditions, extraction techniques, types of GeneChip, or donor sex. Hierarchical clustering and principal component analysis were used to assess interindividual differences. Regression analysis was used to assess the relative impact of the studied variables. RESULTS: Storage of blood samples for >1 week at 4 degrees C diminished subsequent RNA quality. Interindividual GEP differences were seen, but larger effects were observed related to RNA extraction technique, GeneChip, and donor sex. The relative importance of the variables was as follows: storage < genechip < extraction technique < donor sex. CONCLUSION: Sample storage and extraction methods and interindividual differences, particularly donor sex, affect GEP of human whole blood.


Asunto(s)
Perfilación de la Expresión Génica , ARN/aislamiento & purificación , Adulto , Análisis por Conglomerados , Femenino , Perfilación de la Expresión Génica/instrumentación , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos/instrumentación , Análisis de Componente Principal , ARN/sangre , Factores Sexuales
14.
Hum Mol Genet ; 16(7): 763-73, 2007 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-17327269

RESUMEN

We are coming to appreciate that at fertilization human spermatozoa deliver the paternal genome alongside a suite of structures, proteins and RNAs. Although the role of some of the structures and proteins as requisite elements for early human development has been established, the function of the sperm-delivered RNAs remains a point for discussion. The presence of RNAs in transcriptionally quiescent spermatozoa can only be derived from transcription that precedes late spermiogenesis. A cross-platform microarray strategy was used to assess the profile of human spermatozoal transcripts from fertile males who had fathered at least one child compared to teratozoospermic individuals. Unsupervised clustering of the data followed by pathway and ontological analysis revealed the transcriptional perturbation common to the affected individuals. Transcripts encoding components of various cellular remodeling pathways, such as the ubiquitin-proteosome pathway, were severely disrupted. The origin of the perturbation could be traced as far back as the pachytene stage of spermatogenesis. It is anticipated that this diagnostic strategy will prove valuable for understanding male factor infertility.


Asunto(s)
Infertilidad Masculina/genética , ARN/genética , Espermatogénesis/genética , Espermatozoides/metabolismo , Adulto , Fertilización/genética , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Espermatozoides/patología , Transcripción Genética
15.
Reprod Toxicol ; 22(4): 647-58, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16914289

RESUMEN

Three triazole fungicides were evaluated for effects on female rat reproductive development. Rats were exposed via feed to propiconazole (P) (100, 500, or 2500 ppm), myclobutanil (M) (100, 500, or 2000 ppm), or triadimefon (T) (100, 500, or 1800 ppm) from gestation day 6 to postnatal day (PND) 98. Body weight (BW) and anogenital distance (AGD) at PND 0, age and BW at vaginal opening (VO), estrous cyclicity, and body and organ weight at necropsy were measured. BW at PND 0 was unaffected by treatment. AGD was increased by M2000. VO was delayed by M2000 and T1800. Estrous cyclicity was initially disrupted by P500, P2500 and T1800, but later normalized. At PND 99 there was a decrease in BW by T1800, an increase in liver weight by P2500 and T1800, and an increase in ovarian weight by M2000 and T1800. It is concluded that exposure to P, M and T adversely impacted female rodent reproductive development.


Asunto(s)
Fungicidas Industriales/toxicidad , Reproducción/efectos de los fármacos , Triazoles/toxicidad , Administración Oral , Animales , Animales Recién Nacidos , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estradiol/sangre , Estro/efectos de los fármacos , Femenino , Fungicidas Industriales/administración & dosificación , Edad Gestacional , Tamaño de la Camada/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Estructura Molecular , Tamaño de los Órganos/efectos de los fármacos , Ovario/efectos de los fármacos , Ovario/patología , Embarazo , Ratas , Ratas Wistar , Reproducción/fisiología , Razón de Masculinidad , Triazoles/administración & dosificación , Triazoles/química , Vagina/efectos de los fármacos
16.
Ann Clin Lab Sci ; 36(2): 115-26, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16682506

RESUMEN

Characterizing gene expression in hair follicles can help to elucidate the hair growth cycle by delineating the genes and pathways involved in follicular growth and degeneration. The objectives of this study were to determine whether intact RNA could be extracted from a small number of plucked, unstaged hair follicles in sufficient quantity to conduct gene expression profiling, and to conduct global gene expression profiling. To this end, RNA was extracted from 1 to 3 unstaged follicles plucked from the scalp of 36 volunteers. The average quantifiable yield of RNA/follicle was 112.5 ng. Ribosomal ratios were lower than normally expected, but investigation indicated the RNA was intact. Ten of the samples were amplified and hybridized to Affymetrix genechips. On average, 2,567 of the total probe sets (8,500) were expressed in each sample; 1,422 were expressed in all 10 samples; 97 were significantly changed in one gender compared to the other, and 41 had high levels of interindividual variability. This study demonstrates that RNA of sufficient quantity and quality to use in microarray hybridizations can be obtained from as little as a single plucked human hair follicle. Genes expressed in all individuals are probably related to follicular growth and could form a starting set for developing signatures of toxicant exposure. The differentially expressed genes could be involved in producing gender and interindividual differences in hair growth.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Folículo Piloso/crecimiento & desarrollo , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Adulto , Análisis por Conglomerados , Femenino , Humanos , Masculino , ARN/aislamiento & purificación , ARN/normas , Factores Sexuales
17.
Toxicol Appl Pharmacol ; 203(2): 114-23, 2005 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-15710172

RESUMEN

Repeated dosing with the occupational chemical 4-vinylcyclohexene diepoxide (VCD) selectively depletes small pre-antral follicles in the ovaries of rats and mice via apoptosis. The aryl hydrocarbon receptor (AhR) plays a role in mediating the effects of several xenobiotics. Therefore, this study was designed to investigate a potential role of the AhR in VCD-induced ovotoxicity. Female F344 rats, C57BL/6 mice, or AhR-deficient (-/-, AhRKO) mice were dosed daily (15 days) with vehicle, VCD (80 mg/kg, i.p.) and/or the AhR antagonist, alpha-naphthoflavone (ANF; 80 mg/kg, i.p.). Compared with controls, VCD caused a 60% reduction (P < 0.05) in primordial and primary follicles in mice and rats. Concurrent dosing with ANF protected against the VCD-induced follicle loss in rats, but not in mice. As with AhR-intact mice and rats, VCD induced a 70% loss (P < 0.05) of small pre-antral follicles in AhRKO mice. AhR mRNA expression was increased (P < 0.05) by VCD dosing in small pre-antral follicles isolated from ovaries of rats but not mice. AhR protein in rats was increased by VCD dosing in oocyte nuclei in primordial and primary follicles when measured by immunofluorescence and confocal microscopy. In rat small pre-antral follicles, apoptosis-associated caspase-3-like activity was increased (P < 0.05) by VCD treatment, decreased (P < 0.05) by ANF treatment, and unaffected by VCD plus ANF treatment. VCD had no effect on expression of GST Ya1 or GST Ya2 mRNA or CYP 1A1 protein in rats. Taken together, these findings demonstrate a difference between rats and mice in the potential involvement of AhR as related to VCD-induced ovotoxicity. Whereas, AhR appears to be involved in rats, no evidence for a similar role in mice was obtained. Overall, these findings point out that there can be mechanistic species differences in ovarian responses to xenobiotic chemicals.


Asunto(s)
Carcinógenos/toxicidad , Ciclohexanos/toxicidad , Folículo Ovárico/efectos de los fármacos , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Compuestos de Vinilo/toxicidad , Animales , Apoptosis/efectos de los fármacos , Benzoflavonas/farmacología , Caspasa 3 , Caspasas/metabolismo , Recuento de Células , Ciclohexenos , Femenino , Atresia Folicular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Folículo Ovárico/metabolismo , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas F344 , Receptores de Hidrocarburo de Aril/análisis , Receptores de Hidrocarburo de Aril/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Especificidad de la Especie
18.
Endocrinology ; 143(3): 1058-65, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11861533

RESUMEN

Repeated dosing with 4-vinylcyclohexene diepoxide (VCD) accelerates atresia via apoptosis in primordial and primary follicles in ovaries of rats. The mechanisms that control atresia and VCD-induced toxicity are unknown; however, they could involve 17beta-E2. Atresia slows as animals enter puberty, whereas circulating E2 levels increase with the the onset of cyclicity. This inverse relationship suggests that E2 may be involved in the control of atresia. Therefore, this study was designed to determine whether treatment of immature rats with E2 could protect follicles normally destroyed by VCD-induced apoptosis. Female F344 rats were treated daily with E2, ER analogs, and/or VCD for 15 d. VCD alone caused a 50% reduction in primordial and primary follicles. Coinjection of E2 (0.1 mg/kg) and VCD (80 mg/kg) selectively protected primary follicles from VCD-induced follicle loss. This protection was mimicked by an ER agonist, genistein (0.1 mg/kg), and prevented by an ER antagonist, 4-hydroxytamoxifen (2 mg/kg). VCD treatment increased caspase-3-like activity, whereas concurrent treatment with genistein and VCD restored caspase-3-like activity to control levels. VCD treatment had no effect on circulating E2 levels, uterine weight, or E2 binding to the ER, nor could it directly displace E2 from ERbeta. These observations support the idea that ER-mediated protection against VCD-induced follicle toxicity is obtained by reducing apoptosis in small preantral follicles, although VCD does not appear to directly interact with ER.


Asunto(s)
Ciclohexanos/antagonistas & inhibidores , Ciclohexanos/toxicidad , Estradiol/farmacología , Folículo Ovárico/efectos de los fármacos , Compuestos de Vinilo/antagonistas & inhibidores , Compuestos de Vinilo/toxicidad , Animales , Apoptosis/efectos de los fármacos , Unión Competitiva/efectos de los fármacos , Western Blotting , Caspasa 3 , Caspasas/metabolismo , Ciclohexenos , Estradiol/sangre , Estradiol/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Atresia Folicular/efectos de los fármacos , Indicadores y Reactivos , Microscopía Confocal , Oocitos/efectos de los fármacos , ARN/genética , ARN/aislamiento & purificación , Radioinmunoensayo , Ratas , Ratas Endogámicas F344 , Receptores de Estrógenos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
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