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1.
Chem Sci ; 15(24): 9369-9375, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38903219

RESUMO

α-Phenylthioaldehydes are readily prepared using a simple multi-step procedure and herein are introduced as a new precursor for the NHC-catalysed generation of acyl azolium and azolium enolate intermediates that are of widespread synthetic interest and utility. Treatment of α-phenylthioaldehydes with an NHC precatalyst and base produces an efficient redox rearrangement via a Breslow intermediate, elimination of thiophenolate, and subsequent rebound addition to the generated acyl azolium to give the corresponding thiol ester. In the presence of an external alcohol, competition between redox rearrangement and redox esterification can be controlled through judicious choice of the N-aryl substituent within the NHC precatalyst and the base used in the reaction. With NEt3 as base, NHCs bearing electron-withdrawing (N-C6F5 or N-C6H2Cl3) substituents favour redox rearrangement, while triazolium precatalysts with electron-rich N-aryl substituents (N-Ph, N-Mes) result in preferential redox esterification. Using DBU, redox esterification is preferred due to transesterification of the initially formed thiol ester product. Additionally, α-phenylthioaldehyde-derived azolium enolates have been used in enantioselective formal [4 + 2]-cycloaddition reactions to access dihydropyridinone heterocycles with high enantioselectivity (up to >95 : 5 dr, 98 : 2 er).

2.
Pharmaceuticals (Basel) ; 17(3)2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38543120

RESUMO

This review article explores the evolving landscape of Molecular Radiotherapy (MRT), emphasizing Peptide Receptor Radionuclide Therapy (PRRT) for neuroendocrine tumours (NETs). The primary focus is on the transition from ß-emitting radiopharmaceuticals to α-emitting agents in PRRT, offering a critical analysis of the radiobiological basis, clinical applications, and ongoing developments in Targeted Alpha Therapy (TAT). Through an extensive literature review, the article delves into the mechanisms and effectiveness of PRRT in targeting somatostatin subtype 2 receptors, highlighting both its successes and limitations. The discussion extends to the emerging paradigm of TAT, underlining its higher potency and specificity with α-particle emissions, which promise enhanced therapeutic efficacy and reduced toxicity. The review critically evaluates preclinical and clinical data, emphasizing the need for standardised dosimetry and a deeper understanding of the dose-response relationship in TAT. The review concludes by underscoring the significant potential of TAT in treating SSTR2-overexpressing cancers, especially in patients refractory to ß-PRRT, while also acknowledging the current challenges and the necessity for further research to optimize treatment protocols.

3.
Thyroid ; 31(12): 1829-1838, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34598656

RESUMO

Background: Patients with Graves' disease are commonly treated with radioiodine. There remains controversy over whether the aim of treatment should be to achieve euthyroidism or hypothyroidism, and whether treatments should be administered with standard levels of radioactivity or personalized according to the radiation absorbed doses delivered to the thyroid. The aim of this review was to investigate whether a relationship exists between radiation absorbed dose and treatment outcome. Methods: A systematic review and meta-analysis of all reports published before February 13, 2020, were performed using PubMed, Web of Science, OVID MEDLINE, and Embase. Proportion of patients achieving nonhyperthyroid status was the primary outcome. Secondary outcomes were proportion of patients who were specifically euthyroid or hypothyroid. A random-effects meta-analysis of proportions was performed for primary and secondary outcomes, and the impact of the radiation absorbed dose on treatment outcome was assessed through meta-regression. The study is registered with PROSPERO (CRD42020175010). Results: A total of 1122 studies were identified of which 15, comprising 2303 Graves' disease patients, were eligible for the meta-analysis. A strong association was found between radiation absorbed dose and nonhyperthyroid and hypothyroid outcomes (odds ratio [OR] = 1.11 [95% confidence interval {CI} 1.08-1.14] and OR = 1.09 [CI 1.06-1.12] per 10 Gy increase). Higher rates of euthyroid outcome were found for radiation absorbed doses within the range 120-180 Gy when compared with outside this range (n = 1172, OR = 2.50 [CI 1.17-5.35], p = 0.018). A maximum euthyroid response of 38% was identified at a radiation absorbed dose of 128 Gy. Conclusions: The presented radiation absorbed dose-response relationships can facilitate personalized treatment planning for radioiodine treatment of patients with Graves' disease. Further studies are required to determine how patient-specific covariates can inform personalized treatments.


Assuntos
Doença de Graves/radioterapia , Radioisótopos do Iodo/farmacocinética , Dosagem Radioterapêutica , Glândula Tireoide/efeitos da radiação , Humanos , Radioisótopos do Iodo/uso terapêutico
4.
Toxicol Sci ; 182(2): 195-214, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-33983380

RESUMO

Previously, we demonstrated that exposure to some diortho-phthalate esters during sexual differentiation disrupts male reproductive development by reducing fetal rat testis testosterone production (T Prod) and gene expression in a dose-related manner. The objectives of the current project were to expand the number of test compounds that might reduce fetal T Prod, including phthalates, phthalate alternatives, pesticides, and drugs, and to compare reductions in T Prod with altered testis mRNA expression. We found that PEs that disrupt T Prod also reduced expression of a unique "cluster" of mRNAs for about 35 genes related to sterol transport, testosterone and insulin-like hormone 3 hormone syntheses, and lipoprotein signaling and cholesterol synthesis. However, phthalates had little or no effect on mRNA expression of genes in peroxisome proliferator-activated receptor (PPAR) pathways in the fetal liver, whereas the 3 PPAR agonists induced the expression of mRNA for multiple fetal liver PPAR pathway genes without reducing testis T Prod. In summary, phthalates that disrupt T Prod act via a novel adverse outcome pathway including down regulation of mRNA for genes involved in fetal endocrine function and cholesterol synthesis and metabolism. This profile was not displayed by PEs that did not reduce T Prod, PPAR agonists or the other chemicals. Reductions in fetal testis gene expression and T Prod in utero can be used to establish relative potency factors that can be used quantitatively to predict the doses of individual PEs and mixtures of phthalates that produce adverse reproductive tract effects in male offspring.


Assuntos
Rotas de Resultados Adversos , Ácidos Ftálicos , Animais , Biomarcadores , Relação Dose-Resposta a Droga , Genômica , Masculino , Ácidos Ftálicos/toxicidade , Ratos , Ratos Sprague-Dawley , Testículo , Testosterona
5.
Reprod Toxicol ; 98: 13-28, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32229253

RESUMO

The general population, including children and adolescents, is exposed to 4-methylimidazole (4-MI) in the diet. 4-MI is a by-product of caramel color manufacturing. It has been previously classified as a possible human carcinogen and displays potential reproductive toxicity. A follow up assessment of reproductive toxicity was conducted in rats utilizing the reproductive assessment by continuous breeding paradigm, in which multiple generations were exposed to 4-MI in diet at 750, 2500, and 5000 ppm. 4-MI exposure was associated with delays in preputial separation and vaginal opening, impairment in reproductive performance, and concomitant histopathological findings in the prostate, testis, and epididymis at 2500 and 5000 ppm. The Lowest Observed Adverse Effect Level for reproductive (based on prostate atrophy) and developmental toxicity (based on delays in preputial separation and vaginal opening) was 750 ppm, equivalent to approximately 50-60 mg/kg bw/day.


Assuntos
Imidazóis/toxicidade , Animais , Dieta , Epididimo/efeitos dos fármacos , Epididimo/patologia , Feminino , Masculino , Próstata/efeitos dos fármacos , Próstata/patologia , Ratos Sprague-Dawley , Reprodução/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/patologia , Vagina/anormalidades , Vagina/efeitos dos fármacos
6.
Toxicol Appl Pharmacol ; 365: 112-123, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30639414

RESUMO

We showed previously that in utero exposure to the cholesterol-lowering drug simvastatin (SMV) during sex differentiation lowers fetal lipids and testicular testosterone production (T Prod) in Hsd:SD rats. Here, the effects of SMV on fetal lipids and T Prod in Crl:CD(SD) rats were correlated with postnatal alterations in F1 males. The current study was conducted in two parts: 1) a prenatal assessment to confirm and further characterize the dose response relationship among previously reported alterations of SMV on fetal T Prod and the fetal lipid profile and 2) a postnatal assessment to determine the effects of SMV exposure during the periods of major organogenesis and/or sexual differentiation on F1 offspring growth and development. We hypothesized that SMV would have adverse effects on postnatal development and sexual differentiation as a consequence of the disruptions of fetal lipid levels and testicular T Prod since fetal cholesterol is essential for normal intrauterine growth and development and steroid synthesis. In the prenatal assessment, SMV was administered orally at 0, 15.6, 31.25, 62.5, 80, 90, 100, and 110 mg SMV/kg/d from GD 14-18, the period that cover the critical window of sex differentiation in the male rat fetus. T Prod was maximally reduced by ~40% at 62.5 mg/kg/d, and higher doses induced overt maternal and toxicity. In the postnatal assessment, SMV was administered at 0, 15.6, 31.25, and 62.5 mg/kg/d from GD 8-18 to determine if it altered postnatal development. We found that exposure during this time frame to 62.5 mg SMV/kg/d reduced pup viability by 92%, decreased neonatal anogenital distance, and altered testis histology and morphology in 17% of the F1 males. In another group, SMV was administered only during the masculinizing window (GD14-18) at 62.5 mg/kg/d to determine if male rat sexual differentiation and postnatal reproductive development were altered. SMV-exposed F1 males displayed female-like areolae/nipples, delayed puberty, and reduced seminal vesicle and levator ani-bulbocavernosus weights. Together, these results demonstrate that in utero exposure to SMV reduces offspring viability and permanently disrupts reproductive tract development in the male offspring. While the effects of high dose, short term in utero exposure to SMV in the adult male are likely androgen-dependent and consistent with the 40% reduction in T Prod in the fetal testes, long-term, lower dose administration induced some effects that were likely not mediated by decreased T Prod.


Assuntos
Feto/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Sinvastatina/toxicidade , Testículo/efeitos dos fármacos , Testosterona/metabolismo , Animais , Relação Dose-Resposta a Droga , Feminino , Feto/metabolismo , Idade Gestacional , Masculino , Técnicas de Cultura de Órgãos , Organogênese/efeitos dos fármacos , Gravidez , Ratos Sprague-Dawley , Medição de Risco , Diferenciação Sexual/efeitos dos fármacos , Desenvolvimento Sexual/efeitos dos fármacos , Testículo/crescimento & desenvolvimento , Testículo/metabolismo
7.
Toxicol Sci ; 167(1): 6-14, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30496580

RESUMO

The National Toxicology Program (NTP) receives requests to evaluate chemicals with potential to cause adverse health effects, including developmental neurotoxicity (DNT). Some recent requests have included classes of chemicals such as flame retardants, polycyclic aromatic compounds, perfluoroalkyl substances, and bisphenol A analogs with approximately 20-50 compounds per class, many of which include commercial mixtures. However, all the compounds within a class cannot be tested using traditional DNT animal testing guideline studies due to resource and time limitations. Hence, a rapid and biologically relevant screening approach is required to prioritize compounds for further in vivo testing. Because neurodevelopment is a complex process involving multiple distinct cellular processes, one assay will unlikely address the complexity. Hence, the NTP sought to characterize a battery of in vitro and alternative animal assays to quantify chemical effects on a variety of neurodevelopmental processes. A culmination of this effort resulted in a NTP-hosted collaborative project with approximately 40 participants spanning across domains of academia, industry, government, and regulatory agencies; collaborators presented data on cell-based assays and alternative animal models that was generated using a targeted set of compounds provided by the NTP. The NTP analyzed the assay results using benchmark concentration (BMC) modeling to be able to compare results across the divergent assays. The results were shared with the contributing researchers on a private web application during the workshop, and are now publicly available. This article highlights the overview and goals of the project, and describes the NTP's approach in creating the chemical library, development of NTPs data analysis strategy, and the structure of the web application. Finally, we discuss key issues with emphasis on the utility of this approach, and knowledge gaps that need to be addressed for its use in regulatory decision making.


Assuntos
Alternativas aos Testes com Animais/métodos , Poluentes Ambientais/classificação , Poluentes Ambientais/toxicidade , Programas Governamentais , Síndromes Neurotóxicas/etiologia , Toxicologia , Alternativas aos Testes com Animais/tendências , Animais , Guias como Assunto , Desenvolvimento de Programas , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/toxicidade , Testes de Toxicidade , Toxicologia/métodos , Toxicologia/tendências , Estados Unidos
8.
Toxicol Pathol ; 45(1): 107-113, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27708197

RESUMO

Regulatory studies of developmental and reproductive toxicity (DART) studies have remained largely unchanged for decades, with exposures occurring at various phases of the reproductive cycle and toxicity evaluations at different ages/times depending on the study purpose. The National Toxicology Program has conducted studies examining the power to detect adverse effects where there is a prenatal exposure, but evaluations occur postnatally. In these studies, examination is required of only 1 male and female pup from each litter beyond weaning. This provides poor resolving power to detect rare events (e.g., reproductive tract malformations). If an adverse effect is detected, there is little confidence in the shape of the dose-response curve (and the Benchmark Dose or No Observed Adverse Effect Level [NOAEL]). We have developed a new protocol to evaluate DART, the modified one generation study, with exposure commencing with pregnant animals and retention of 4 males and females from each litter beyond weaning to improve statistical power. These animals can be allocated to specific cohorts that examine subchronic toxicity, teratology, littering, and neurobehavioral toxicity in the same study. This approach also results in a reduction in animal numbers used, compared with individual stand-alone studies, and offers increased numbers of end points evaluated compared with recent Organization for Economic Cooperation and Development proposals.


Assuntos
Reprodução/efeitos dos fármacos , Projetos de Pesquisa/normas , Teratogênicos/toxicidade , Testes de Toxicidade/métodos , Animais , Feminino , Guias como Assunto , Masculino , Gravidez
9.
Toxicol Sci ; 149(1): 178-91, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26454885

RESUMO

Phthalate esters (PEs) constitute a large class of compounds that are used for many consumer product applications. Many of the C2-C7 di-ortho PEs reduce fetal testicular hormone and gene expression levels in rats resulting in adverse effects seen later in life but it appears that relatively large reductions in fetal testosterone (T) levels and testis gene expression may be required to adversely affect reproductive development (Hannas, B. R., Lambright, C. S., Furr, J., Evans, N., Foster, P. M., Gray, E. L., and Wilson, V. S. (2012). Genomic biomarkers of phthalate-induced male reproductive developmental toxicity: a targeted RT-PCR array approach for defining relative potency. Toxicol. Sci. 125, 544-557). The objectives of this study were (1) to model the relationships between changes in fetal male rat plasma testosterone (PT), T levels in the testis (TT), T production (PROD), and testis gene expression with the reproductive malformation rates, and (2) to quantify the "biologically relevant reductions" (BRRs) in fetal T necessary to induce adverse effects in the offspring. In the fetal experiment, Harlan Sprague-Dawley rats were dosed with dipentyl phthalate (DPeP) at 0, 11, 33, 100, and 300 mg/kg/day from gestational days (GD) 14-18 and fetal testicular T, PT levels, and T Prod and gene expression were assessed on GD 18. In the postnatal experiment, rats were dosed with DPeP from GD 8-18 and reproductive development was monitored through adulthood. The dose-response curves for TT levels (ED(50) = 53 mg/kg) and T PROD (ED(50) = 45 mg/kg) were similar, whereas PT was reduced at ED50 = 19 mg/kg. When the reductions in TPROD and Insl3 mRNA were compared with the postnatal effects of in utero DPeP, dose-related reproductive alterations were noted when T PROD and Insl3 mRNA were reduced by >45% and 42%, respectively. The determination of BRR levels may enable risk assessors to utilize fetal endocrine data to help establish points of departure for quantitative risk assessments.


Assuntos
Feto/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Testículo/efeitos dos fármacos , Testosterona/biossíntese , Animais , Relação Dose-Resposta a Droga , Ésteres/toxicidade , Feminino , Feto/metabolismo , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Sprague-Dawley , Reprodução/efeitos dos fármacos , Testículo/química , Testículo/metabolismo , Testosterona/análise , Testosterona/sangue
10.
Birth Defects Res B Dev Reprod Toxicol ; 104(1): 35-51, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25707689

RESUMO

BACKGROUND: 2-Hydroxy-4-methoxybenzophenone (HMB) is an ultraviolet (UV) absorbing compound used in many cosmetic products as a UV-protecting agent and in plastics for preventing UV-induced photodecomposition. HMB has been detected in over 95% of randomly collected human urine samples from adults and from premature infants, and it may have estrogenic potential. METHODS: To determine the effects of maternal and lactational exposure to HMB on development and reproductive organs of offspring, time-mated female Harlan Sprague-Dawley rats were dosed with 0, 1000, 3000, 10,000, 25,000, or 50,000 ppm HMB (seven to eight per group) added to chow from gestation day 6 until weaning on postnatal day (PND) 23. RESULTS AND CONCLUSION: Exposure to HMB was associated with reduced body and organ weights in female and male offspring. No significant differences were observed in the number of implantation sites/litter, mean resorptions/litter, % litters with resorptions, number and weights of live fetuses, or sex ratios between the control and HMB dose groups. Normalized anogenital distance in male pups at PND 23 was decreased in the highest dose group. Spermatocyte development was impaired in testes of male offspring in the highest dose group. In females, follicular development was delayed in the highest dose group. However, by evaluating levels of the compound in rat serum, the doses at which adverse events occurred are much higher than usual human exposure levels. Thus, exposure to less than 10,000 ppm HMB does not appear to be associated with adverse effects on the reproductive system in rats.


Assuntos
Benzofenonas/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Lactação/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/patologia , Reprodução/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Contagem de Células , Feminino , Masculino , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Ratos Sprague-Dawley , Túbulos Seminíferos/efeitos dos fármacos , Túbulos Seminíferos/patologia , Espermatócitos/efeitos dos fármacos , Espermatócitos/patologia , Testosterona/sangue
11.
Toxicol Sci ; 141(2): 524-37, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25055962

RESUMO

Sex differentiation of the male reproductive tract in mammals is driven, in part, by fetal androgen production. In utero, some phthalate esters (PEs) alter fetal Leydig cell differentiation, reducing the expression of several genes associated with steroid synthesis/transport, and consequently, lowering fetal androgen and Insl3 hormone levels. Simvastatin (SMV) is a cholesterol-lowering drug that directly inhibits HMG-CoA reductase. SMV may also disrupt steroid biosynthesis, but through a different mode of action (MOA) than the PEs. As cholesterol is a precursor of steroid hormone biosynthesis, we hypothesized that in utero exposure to SMV during the critical period of sex differentiation would lower fetal testicular testosterone (T) production without affecting genes involved in cholesterol and androgen synthesis and transport. Secondly, we hypothesized that a mixture of SMV and a PE, which may have different MOAs, would reduce testosterone levels in an additive manner. Pregnant Sprague Dawley rats were dosed orally with SMV, dipentyl phthalate (DPeP), or SMV plus DPeP from gestational days 14-18, and fetuses were evaluated on GD18. On GD18, SMV lowered fetal T production and serum triglycerides, low density lipoprotein, high density lipoprotein, and total cholesterol levels, and downregulated two genes in the fetal testis that were different from those altered by PEs. When SMV and DPeP were administered as a mixture, fetal T production was significantly reduced in an additive manner, thus demonstrating that a mixture of chemicals can induce additive effects on fetal T production even though they display different MOAs.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Ácidos Ftálicos/toxicidade , Sinvastatina/toxicidade , Testículo/efeitos dos fármacos , Testosterona/biossíntese , Animais , Relação Dose-Resposta a Droga , Regulação para Baixo , Feminino , Sangue Fetal/metabolismo , Idade Gestacional , Lipídeos/sangue , Masculino , Exposição Materna , Gravidez , Ratos Sprague-Dawley , Diferenciação Sexual , Testículo/crescimento & desenvolvimento , Testículo/metabolismo , Técnicas de Cultura de Tecidos
12.
Toxicol Pathol ; 42(8): 1165-7, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24862797

RESUMO

The National Toxicology Program (NTP) has developed a new flexible study design, termed the modified one generation (MOG) reproduction study. The MOG study will encompass measurements of developmental and reproductive toxicity parameters as well as enable the setting of appropriate dose levels for a cancer bioassay through evaluation of target organ toxicity that is based on test article exposure that starts during gestation. This study design is compared and contrasted with the new Organization for Economic Co-operation and Development (OECD) 443 test guideline, the extended one generation reproduction study. The MOG study has a number of advantages, with a focus on F 1 animals, the generation of adequately powered, robust data sets that include both pre and postnatal developmental toxicity information, and the measurement of effects on reproductive structure and function in the same animals. This new study design does not employ the use of internal triggers in the design structure for the use of animals already on test and is also consistent with the principles of the 3R's.


Assuntos
Crescimento e Desenvolvimento/efeitos dos fármacos , Organização para a Cooperação e Desenvolvimento Econômico , Reprodução/efeitos dos fármacos , Testes de Toxicidade , Animais , Disruptores Endócrinos/toxicidade , Humanos , Camundongos , Testes de Toxicidade/métodos , Testes de Toxicidade/normas
14.
ALTEX ; 30(3): 353-77, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23861079

RESUMO

To address the pressing need for better in vitro testicular toxicity models, a workshop sponsored by the International Life Sciences Institute (ILSI), the Health and Environmental Science Institute (HESI), and the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), was held at the Mt. Washington Conference Center in Baltimore, MD, USA on October 26-27, 2011. At this workshop, experts in testis physiology, toxicology, and tissue engineering discussed approaches for creating improved in vitro environments that would be more conducive to maintaining spermatogenesis and steroidogenesis and could provide more predictive models for testicular toxicity testing. This workshop report is intended to provide scientists with a broad overview of relevant testicular toxicity literature and to suggest opportunities where bioengineering principles and techniques could be used to build improved in vitro testicular models for safety evaluation. Tissue engineering techniques could, conceivably, be immediately implemented to improve existing models. However, it is likely that in vitro testis models that use single or multiple cell types will be needed to address such endpoints as accurate prediction of chemically induced testicular toxicity in humans, elucidation of mechanisms of toxicity, and identification of possible biomarkers of testicular toxicity.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Poluentes Ambientais/toxicidade , Testículo/efeitos dos fármacos , Alternativas aos Testes com Animais , Animais , Biomarcadores , Técnicas de Cultura de Células , Células Cultivadas , Humanos , Masculino , Modelos Biológicos , Valor Preditivo dos Testes , Testículo/citologia , Testes de Toxicidade/métodos
15.
Toxicol Sci ; 125(2): 544-57, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22112501

RESUMO

Male rat fetuses exposed to certain phthalate esters (PEs) during sexual differentiation display reproductive tract malformations due to reductions in testosterone (T) production and the expression of steroidogenesis- and INSL3-related genes. In the current study, we used a 96-well real-time PCR array containing key target genes representing sexual determination and differentiation, steroidogenesis, gubernaculum development, and androgen signaling pathways to rank the relative potency of several PEs. We executed dose-response studies with diisobutyl (DIBP), dipentyl (DPeP), dihexyl (DHP), diheptyl (DHeP), diisononyl (DINP), or diisodecyl phthalate (DIDP) and serial dilutions of a mixture of nine phthalates. All phthalates, with the exception of DIDP, reduced fetal testicular T production. Several genes involved in cholesterol transport, androgen synthesis, and Insl3 also were downregulated in a dose-responsive manner by DIBP, DPeP, DHP, DHeP, DINP, and the 9-PE mixture. Despite speculation of peroxisome proliferator activated receptor (PPAR) involvement in the effects of PEs on the fetal testis, no PPAR-related genes were affected in the fetal testes by exposure to any of the tested PEs. Furthermore, the potent PPARα agonist, Wy-14,643, did not reduce fetal testicular T production following gestational day 14-18 exposure, suggesting that the antiandrogenic activity of PEs is not PPARα mediated. The overall sensitivity of the fetal endpoints (gene expression or T production) for the six phthalates from most to least was Cyp11b1 > Star = Scarb1 > Cyp17a1 = T production > Cyp11a1 = Hsd3b = Insl3 > Cyp11b2. The overall potency of the individual phthalates was DPeP > DHP > DIBP ≥ DHeP > DINP. Finally, the observed mixture interaction was adequately modeled by the dose-addition model for most of the affected genes. Together, these data advance our understanding of the collective reproductive toxicity of the PE compounds.


Assuntos
Biologia do Desenvolvimento/métodos , Regulação da Expressão Gênica no Desenvolvimento/genética , Marcadores Genéticos , Ácidos Ftálicos/toxicidade , Reação em Cadeia da Polimerase em Tempo Real , Reprodução/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testes de Toxicidade/métodos , Animais , Relação Dose-Resposta a Droga , Feminino , Idade Gestacional , Masculino , Exposição Materna , Modelos Teóricos , Gravidez , Ratos , Ratos Sprague-Dawley , Reprodução/genética , Medição de Risco , Testículo/embriologia , Testículo/metabolismo , Testosterona/metabolismo , Técnicas de Cultura de Tecidos
16.
Birth Defects Res B Dev Reprod Toxicol ; 92(5): 395-403, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21770028

RESUMO

This review is the second in a series of four papers emanating from a workshop entitled "Developmental Toxicology-New Directions," which was sponsored by the ILSI Health and Environmental Sciences Institute's (HESI) Developmental and Reproductive Toxicology Technical Committee. The present review analyzes the strengths and weaknesses of current developmental safety testing approaches in an effort to identify those strengths that should be retained in the future versus the weaknesses that should be eliminated. Workshop participants considered the following to be key strengths of current testing approaches: the integrated biology of pregnant animal models including pharmacokinetic and pharmacodynamic processes, the ability to detect low incidence malformations as well as maternally mediated toxicity, and the long history of use coupled with extensive historical data. A number of weaknesses were related to the resource-intensive nature of developmental toxicity testing (e.g., large number of animals, high costs, low throughput, the inability to keep pace with the demand for more toxicity data). Other weaknesses included the use of very high dose levels that often far exceed human exposure levels, the confounding influence of maternal toxicity, sparse understanding of basic developmental mechanisms and genetics of standard animal models relative to mouse or lower organisms, difficulties interpreting low incidence findings, and issues surrounding the interpretation of minor skeletal variations. An appreciation of these strengths and weaknesses is critical for the design of new approaches to developmental toxicity testing in the 21st century.


Assuntos
Desenvolvimento Fetal/efeitos dos fármacos , Modelos Animais , Testes de Toxicidade/métodos , Animais , Feminino , Humanos , Camundongos , Gravidez , Coelhos , Ratos , Medição de Risco , Segurança
17.
Food Chem Toxicol ; 49(9): 2116-24, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21651954

RESUMO

Androstenedione was marketed as a dietary supplement to increase muscle mass during training. Due to concern over long-term use, the NTP evaluated the subchronic and chronic toxicity and carcinogenicity of androstenedione in male and female F344/N rats and B6C3F1 mice. In subchronic studies, dose limiting effects were not observed. A chronic (2-year) exposure by gavage at 10, 20, or 50 mg/kg in rats and male mice, and 2, 10, or 50 mg/kg in female mice (50 mg/kg, maximum feasible dose) was conducted. Increased incidences of lung alveolar/bronchiolar adenoma and carcinoma occurred in the 20 mg/kg male rats and increases in mononuclear cell leukemia occurred in the 20 and 50 mg/kg female rats, which may have been related to androstenedione administration. In male and female mice, androstenedione was carcinogenic based upon a significant increase in hepatocellular tumors. A marginal increase in pancreatic islet cell adenomas in male (50 mg/kg) and female (2, 10, 50 mg/kg) mice was considered to be related to androstenedione administration. Interestingly, incidences of male rat Leydig cell adenomas and female rat mammary gland fibroadenomas decreased. In conclusion, androstenedione was determined to be carcinogenic in male and female mice, and may have been carcinogenic in rats.


Assuntos
Androstenodiona/toxicidade , Carcinógenos/toxicidade , Animais , Testes de Carcinogenicidade , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Ratos , Ratos Endogâmicos F344
18.
Toxicol Sci ; 120(1): 184-93, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21177253

RESUMO

Phthalate esters (PEs) constitute a large class of plasticizer compounds that are widely used for many consumer product applications. Ten or more members of the PE class of compounds are known to induce male fetal endocrine toxicity and postnatal reproductive malformations by disrupting androgen production during the sexual differentiation period of development. An early study conducted in the rat pubertal model suggested that dipentyl phthalate (DPeP) may be a more potent testicular toxicant than some more extensively studied phthalates. Regulatory agencies require dose-response and potency data to facilitate risk assessment; however, very little data are currently available for DPeP. The goal of this study was to establish a more comprehensive data set for DPeP, focusing on dose-response and potency information for fetal and postnatal male reproductive endpoints. We dosed pregnant rats on gestational day (GD) 17 or GD 14-18 and subsequently evaluated fetal testicular testosterone (T) production on GD 17.5 and GD 18, respectively. We also dosed pregnant rats on GD 8-18 and evaluated early postnatal endpoints in male offspring. Comparison of these data to data previously obtained under similar conditions for di (2-ethylhexyl) phthalate indicates that DPeP is approximately eightfold more potent in reducing fetal T production and two- to threefold more potent in inducing development of early postnatal male reproductive malformations. Additionally, fetal testicular T production was more sensitive to inhibitory effects of DPeP exposure than was gene expression of target genes involved in male reproductive development, supporting the use of this endpoint as a critical effect in the risk assessment process.


Assuntos
Disruptores Endócrinos/toxicidade , Ácidos Ftálicos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Diferenciação Sexual/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Idade Gestacional , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Ratos , Ratos Sprague-Dawley , Diferenciação Sexual/genética , Testículo/embriologia , Testículo/crescimento & desenvolvimento , Testículo/metabolismo
19.
Toxicol Sci ; 116(2): 640-6, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20484383

RESUMO

Deriving No Observed Adverse Effect Level (NOAEL) or benchmark dose is important for risk assessment and can be influenced by study design considerations. In order to define the di-(2-ethylhexyl) phthalate (DEHP) dose-response curve for reproductive malformations, we retained more offspring to adulthood to improve detection of these malformations in the reproductive assessment by continuous breeding study design. Sprague-Dawley rats were given a dietary administration of 1.5 (control), 10, 30, 100, 300, 1000, 7500, and 10,000 ppm DEHP. Male pups were evaluated for gross reproductive tract malformations (RTMs) associated with the "phthalate syndrome." DEHP treatment had minimal effects on P0 males. There was a statistically significant increase in F1 and F2 total RTMs (testis, epididymides, seminal vesicle, and prostate) in the 7500-ppm dose group and F1 10,000-ppm dose group. The 10,000-ppm exposed F1 males did not produce an F2 generation. The NOAEL for F1 and F2 RTM combined data, because in utero exposures were similar, were 100 ppm (4.8 mg/kg/day), which was close to the 5% response benchmark dose lower confidence limit of 142 ppm. The utility of evaluating more pups per litter was examined by generating power curves from a Monte Carlo simulation. These curves indicate a substantial increase in detection rate when three males are evaluated per litter rather than one. A 10% effect across male pups would be detected 5% of the time if one pup per litter was evaluated, but these effects would be detected 66% of the time if three pups per litter were evaluated. Taken together, this study provides a well-defined dose response of DEHP-induced RTMs and demonstrates that retention of more adult F1 and F2 males per litter, animals that were already produced, increases the ability to detect RTMs and presumably other low-incidence phenomena.


Assuntos
Dietilexilftalato/toxicidade , Genitália/anormalidades , Anormalidades Induzidas por Medicamentos , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Método de Monte Carlo , Nível de Efeito Adverso não Observado , Ratos , Ratos Sprague-Dawley
20.
Food Chem Toxicol ; 48(6): 1439-47, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20388530

RESUMO

There have been several studies on the maternal administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and effects in the reproductive tract of male offspring, subsequent to risk assessments undertaken in 2001. This review compares the methodology and results to examine key methodological features, and consistency in reported outcomes. Maternal dosing at >0.8 microg TCDD/kg causes lethality and weight loss, and it is difficult to distinguish between direct and indirect effects of TCDD at these dose levels. Statistically significant effects of maternal doses of <1 microg TCDD/kg (i.e. the dose levels relevant for risk assessment) on prostate weight or epididymal sperm counts in offspring were reported in the minority of studies. The pharmacokinetics of TCDD differs considerably between acute and chronic dosing, and with dose level of TCDD. On the basis of body burden, TCDD had different potency at inducing adverse effects in the only comparison study between acute and chronic dosing. Understanding of the pharmacokinetics of TCDD and relationship to adverse effects in offspring is required. These analyses identify key features of TCDD developmental toxicity in male offspring, and identify data needs for future risk assessment.


Assuntos
Dibenzodioxinas Policloradas/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Reprodução/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Dibenzodioxinas Policloradas/farmacocinética , Gravidez , Reprodutibilidade dos Testes
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