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1.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802611

RESUMO

The objective of this work has been to characterize the estrogenic activity of bisphenol-A (BPA) and the adverse effects on the endocannabinoid system (ECS) in modulating germ cell progression. Male offspring exposed to BPA during the foetal-perinatal period at doses below the no-observed-adverse-effect-level were used to investigate the exposure effects in adulthood. Results showed that BPA accumulates specifically in epididymal fat rather than in abdominal fat and targets testicular expression of 3ß-hydroxysteroid dehydrogenase and cytochrome P450 aromatase, thus promoting sustained increase of estrogens and a decrease of testosterone. The exposure to BPA affects the expression levels of some ECS components, namely type-1 (CB1) and type-2 cannabinoid (CB2) receptor and monoacylglycerol-lipase (MAGL). Furthermore, it affects the temporal progression of germ cells reported to be responsive to ECS and promotes epithelial germ cell exfoliation. In particular, it increases the germ cell content (i.e., spermatogonia while reducing spermatocytes and spermatids), accelerates progression of spermatocytes and spermatids, promotes epithelial detachment of round and condensed spermatids and interferes with expression of cell-cell junction genes (i.e., zonula occcludens protein-1, vimentin and ß-catenin). Altogether, our study provides evidence that early exposure to BPA produces in adulthood sustained and site-specific BPA accumulation in epididymal fat, becoming a risk factor for the reproductive endocrine pathways associated to ECS.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/metabolismo , Endocanabinoides/metabolismo , Epididimo/efeitos dos fármacos , Estrogênios/metabolismo , Células Germinativas/efeitos dos fármacos , Fenóis/efeitos adversos , Fenóis/metabolismo , Tecido Adiposo/metabolismo , Animais , Sistema Endócrino/efeitos dos fármacos , Sistema Endócrino/metabolismo , Epididimo/metabolismo , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Células Germinativas/metabolismo , Junções Intercelulares/efeitos dos fármacos , Junções Intercelulares/metabolismo , Masculino , Camundongos , Fatores de Risco , Testosterona/metabolismo
2.
J Med Chem ; 64(4): 2291-2309, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33573376

RESUMO

A novel diazaspiro[3.4]octane series was identified from a Plasmodium falciparum whole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with a novel sp3-rich scaffold provided an attractive starting point for a hit-to-lead medicinal chemistry optimization and biological profiling program. Structure-activity-relationship studies led to the identification of compounds that showed low nanomolar asexual blood-stage activity (<50 nM) together with strong gametocyte sterilizing properties that translated to transmission-blocking activity in the standard membrane feeding assay. Mechanistic studies through resistance selection with one of the analogues followed by whole-genome sequencing implicated the P. falciparum cyclic amine resistance locus in the mode of resistance.


Assuntos
Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Compostos de Espiro/farmacologia , Animais , Anopheles/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/metabolismo , Feminino , Células Germinativas/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Ratos , Compostos de Espiro/síntese química , Compostos de Espiro/metabolismo , Relação Estrutura-Atividade
3.
Methods Mol Biol ; 2218: 49-60, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33606222

RESUMO

The regulation of reproduction in zebrafish, the prime model of fish research, is not fully understood. An efficient tool to gain a better understanding of this complicated process is utilization of severely sex-biased families or groups. Here, we describe a method for partial depletion of primordial germ cells (PGCs) that leads to eventual masculinization of zebrafish. The technique is based on injecting early embryos with diluted morpholino oligonucleotides that temporarily interfere with the production of Dead end (Dnd), an RNA-binding protein essential for PGC survival. In addition, we also propose the use of eviscerated trunk, as a suitable alternative for examining gonadal expression in juvenile zebrafish.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Células Germinativas/efeitos dos fármacos , Morfolinos/administração & dosagem , Oligonucleotídeos/administração & dosagem , Animais , Embrião não Mamífero/metabolismo , Feminino , Células Germinativas/metabolismo , Gônadas/efeitos dos fármacos , Gônadas/metabolismo , Injeções , Masculino , Proteínas de Ligação a RNA/metabolismo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
4.
Methods Mol Biol ; 2218: 61-73, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33606223

RESUMO

Primordial germ cells (PGCs) are the precursor cells that form during early embryogenesis and later differentiate into oocytes or spermatozoa. Abnormal development of PGCs is frequently a causative factor of infertility and germ cell tumors. However, our understanding of PGC development remains insufficient, and we have few pharmacological tools for manipulating PGC development for biological study or therapy. The zebrafish (Danio rerio) embryos provide an excellent in vivo animal model to study PGCs, because zebrafish embryos are transparent and develop outside the mother. Importantly, the model is also amenable to facile chemical manipulations, including scalable screening to discover novel compounds that alter PGC development. This chapter describes methodologies for manipulating the germline (i.e., PGCs) with small molecules and for monitoring PGC development. Utilizing the 3'UTR of PGC marker genes such as nanos3 and ddx4/vasa is a key component of these methodologies, which consist of expressing fluorescent or luminescent proteins in PGCs, treatment with small molecules, and quantitative observation of PGC development.


Assuntos
Células Germinativas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Regiões 3' não Traduzidas/genética , Animais , RNA Helicases DEAD-box/genética , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Feminino , Proteínas Luminescentes/genética , Masculino , Proteínas de Ligação a RNA/genética , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
5.
Ecotoxicol Environ Saf ; 208: 111579, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396102

RESUMO

Studies about radiation damage in vivo are very significant for healthy risk assessment as well as cancer radiotherapy. Ceramide as a second messenger has been found to be related to radiation-induced apoptosis. However, the detailed mechanisms in living systems are still not fully understood. In the present study, the effects of ceramide in gamma radiation-induced response were investigated using Caenorhabditis elegans. Our results indicated that ceramide was required for gamma radiation-induced whole-body germ cell apoptosis by the production of radical oxygen species and decrease of mitochondrial transmembrane potential. Using genetic ceramide synthase-related mutated strains and exogenous C16-ceramide, we illustrated that ceramide could regulate DNA damage response (DDR) pathway to mediate radiation-induced germ cell apoptosis. Moreover, ceramide was found to function epistatic to pmk-1 and mpk-1 in MAPK pathway to promote radiation-induced apoptosis in Caenorhabditis elegans. These results demonstrated ceramide could potentially mediated gamma radiation-induced apoptosis through regulating mitochondrial function, DDR pathway and MAPK pathway.


Assuntos
Caenorhabditis elegans/fisiologia , Ceramidas/farmacologia , Protetores contra Radiação/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos da radiação , Proteínas de Caenorhabditis elegans/genética , Ceramidas/metabolismo , Dano ao DNA , Células Germinativas/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Radiação , Espécies Reativas de Oxigênio/metabolismo
6.
Ecotoxicol Environ Saf ; 209: 111783, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33383340

RESUMO

Decabromodiphenyl ether (BDE-209) is widely used as a flame retardant in many products like electronic equipments, plastics, furniture and textiles. BDE-209, a thyroid hormones (THs)-disrupting chemical, affects male reproductive health through altered THs status in mouse model. The present study was designed in continuation to our earlier work to elucidate whether early life exposure to BDE-209 has a long term potential risk to male reproductive health. This study, therefore, aimed to evaluate the effect of maternal BDE-209 exposure during lactation and to elucidate possible mechanism(s) of its action on male reproduction in adult Parkes mice offspring. Lactating female Parkes mice were orally gavaged with 500, and 700 mg/kg body weight of BDE-209 in corn oil from postnatal day (PND) 1 to PND 28 along with 6-propyl-2-thiouracil (PTU)-treated positive controls and vehicle-treated controls. Male pups of lactating dams were euthanized at PND 75. Maternal BDE-209 exposure during lactation markedly affected histoarchitecture of testis and testosterone production with concomitant down-regulation in the expression of various steroidogenic markers in adult offspring. Maternal exposure to BDE-209 during lactation also interfered with germ cell dynamics and oxidative status in testes of adult mice offspring. A decreased expression of connexin 43 and androgen receptor was also evident in testes of these mice offspring; further, number, motility and viability of spermatozoa were also adversely affected in these mice. The results thus provide evidences that maternal exposure to BDE-209 during lactation causes reproductive toxicity in adult mice offspring.


Assuntos
Retardadores de Chama/toxicidade , Éteres Difenil Halogenados/toxicidade , Espermatogênese/efeitos dos fármacos , Animais , Conexina 43/metabolismo , Feminino , Células Germinativas/efeitos dos fármacos , Lactação/efeitos dos fármacos , Masculino , Exposição Materna , Camundongos , Receptores Androgênicos/metabolismo , Espermatozoides/efeitos dos fármacos , Esteroides/metabolismo , Testículo/efeitos dos fármacos , Testosterona/metabolismo , Hormônios Tireóideos/metabolismo
7.
Int. j. morphol ; 38(6): 1525-1527, Dec. 2020. graf
Artigo em Inglês | LILACS | ID: biblio-1134471

RESUMO

SUMMARY: The study reported the influence of the high and acute dose of Letrozole on the testis morphology in paca (Cuniculus paca), an aromatase inhibitor that reduces the endogenous estrogen, the essential hormone for spermatogenesis. Morphological changes were observed in seminiferous epithelium with germ cells with apoptotic characteristics and presence of vacuoles and nuclei in pycnose.


RESUMEN: El objetivo de este estudio fue analizar la influencia de una dosis alta de Letrozol en la morfología de los testículos de la paca (Cuniculus paca), un inhibidor de la aromatasa que reduce el estrógeno endógeno, la hormona esencial para la espermatogénesis. Se observaron cambios morfológicos en el epitelio seminífero con células germinales con características apoptóticas y la presencia de vacuolas y núcleos en picnosis.


Assuntos
Animais , Masculino , Testículo/efeitos dos fármacos , Inibidores da Aromatase/administração & dosagem , Cuniculidae , Letrozol/administração & dosagem , Epitélio Seminífero/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Imuno-Histoquímica , Orquiectomia , Microscopia Eletrônica de Transmissão , Células Germinativas/efeitos dos fármacos
8.
Toxicol Lett ; 334: 102-109, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33002525

RESUMO

Beauvericin is an ubiquitous mycotoxin with relevant occurrence in food and feed. It causes a high toxicity in several cell lines, but its general mechanism of action is not fully understood and only limited in vivo studies have been performed. We used Caenorhabditis elegans as a model organism to investigate effects of beauvericin. The mycotoxin displays a moderate acute toxicity at 100 µM; at this concentration also reproductive toxicity occurred (reduction of total progeny to 32.1 %), developmental toxicity was detectable at 250 µM. However, even lower concentrations were capable to reduce stress resistance and life span of the nematode: A significant reduction was detected at 10 µM beauvericin (decrease in mean survival time of 4.3 % and reduction in life span of 12.9 %). An increase in lipofuscin fluorescence was demonstrated starting at 10 µM suggesting oxidative stress as a mechanism of beauvericin toxicity. Beauvericin (100 µM) increases the number of apoptotic germ cells comparable to the positive control UV-C (400 J/m2). Conclusion: Low concentrations of beauvericin are capable to cause adverse effects in C. elegans, which may be relevant for hazard identification of this compound.


Assuntos
Apoptose/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Depsipeptídeos/toxicidade , Células Germinativas/efeitos dos fármacos , Lipofuscina/metabolismo , Longevidade/efeitos dos fármacos , Micotoxinas/toxicidade , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Relação Dose-Resposta a Droga , Fertilidade/efeitos dos fármacos , Contaminação de Alimentos , Células Germinativas/patologia , Atividade Motora/efeitos dos fármacos , Testes de Toxicidade Aguda
9.
PLoS One ; 15(9): e0238637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903270

RESUMO

Neonicotinoids, a class of insecticides structurally similar to nicotine that target biting and sucking insects, are the most widely used insecticides today, in part due to their supposed low toxicity in other organisms. However, a growing body of research has found that even low doses of neonicotinoids can induce unexpected negative effects on the physiology and survival of a wide range of non-target organisms. Importantly, no work has been done on the commercial formulations of pesticides that include imidacloprid as the active ingredient, but that also contain many other components. The present study examines the sublethal effects of "Tree and Shrub"™ ("T+S"), a commercial insecticide containing the neonicotinoid imidacloprid as its active ingredient, on Caenorhabditis elegans. We discovered that "T+S" significantly stunted the overall growth in wildtype nematodes, an effect that was exacerbated by concurrent exposure to heat stress. "T+S" also negatively impacted fecundity as measured by increased germline apoptosis, a decrease in egg-laying, and fewer viable offspring. Lastly, exposure to "T+S" resulted in degenerative changes in nicotinic cholinergic neurons in wildtype nematodes. As a whole, these findings demonstrate widespread toxic effects of neonicotinoids to critical functions in nematodes.


Assuntos
Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/fisiologia , Inseticidas/toxicidade , Locomoção/efeitos dos fármacos , Neonicotinoides/toxicidade , Animais , Apoptose/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Aberrações Cromossômicas , Fertilidade/efeitos dos fármacos , Células Germinativas/citologia , Células Germinativas/efeitos dos fármacos , Resposta ao Choque Térmico , Degeneração Neural/patologia , Oviposição/efeitos dos fármacos , Reprodução/efeitos dos fármacos
10.
Chemosphere ; 261: 127613, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32738708

RESUMO

Triclosan (TCS), an antibacterial and antifungal agent present in some consumer products, has been detected in the environment at varying concentrations. TCS exposure has been found to cause developmental abnormalities and endocrine disruption in various species of fish. It is not clearly understood whether TCS exposure causes epigenetic alterations in developing embryos and their germ cells. In the present study, we examined the effects of TCS exposure (0, 50, 100 and, 200 µg/L) on embryonic development and primordial germ cells (PGCs), which are precursors of sperm and eggs, in medaka (Oyzias latipes). Developmental TCS exposure from 8 h post-fertilization through 15 days post-fertilization (dpf) resulted in several developmental abnormalities, including enlarged yolk sac, decreased head trunk angle (HTA), and severe edema in the pericardial region. The male ratio increased in the 100 µg/L TCS exposure group, which was negatively correlated with the expression of cyp19ala (a gene encoding aromatase) and arα (androgen receptor alpha). Developmental 50 µg/L TCS exposure resulted in global hypomethylation in the whole body but not in the isolated PGCs. Expression of the gene encoding DNA methyltransferases (dnmt1 and dnmt3aa) was decreased by 50 µg/L TCS exposure both in the whole body and PGCs. TCS altered the expression of genes encoding enzymes involved in DNA methylation and demethylation in PGCs, suggesting epigenetic effects on germ cells. The present results demonstrate that the embryos exposed to the tested concentrations of TCS develop deformities during the early life stages and that the TCS within this range possesses endocrine disrupting properties potential enough to alter sex ratios of developing embryos.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Oryzias/embriologia , Triclosan/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Metilação de DNA/efeitos dos fármacos , Disruptores Endócrinos/farmacologia , Epigênese Genética/efeitos dos fármacos , Epigenômica , Células Germinativas/efeitos dos fármacos , Masculino , Triclosan/farmacologia
11.
Mutat Res ; 853: 503171, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32522346

RESUMO

The tests used and the general principles behind test strategies are now often over 30 years old. It may be time by now, given that our knowledge of genetic toxicology has improved and that we also technically are better able to investigate DNA damage making use of modern molecular biological techniques, to start thinking on a new test strategy. In the present paper, it is discussed that the time is there to consider a new approach for genotoxicity assessment of substances. A fit for all test strategy was discussed making use of the most recent technological methods and techniques. It was also indicated that in silico tools should be more accepted by regulatory institutes/bodies as supporting information to better conclude which tests should be required for each separate substance to demonstrate its genotoxic potency. Next to that there should be a good rationale for performing in vivo studies. Finally, the need for germ cell genotoxicity testing, essential when classification and labeling of substances is mandatory, was discussed. It was suggested to change the GHS for genotoxicity classification and labelling from in vivo tests in germ cells into in vivo tests in somatic cells. Quantitative genotoxicology was also discussed. It appeared that we are currently at a transition, where the science developing to justify carrying out human health risk assessments based on genetic toxicology data sets supported by mechanistic data and exposure data. However, implementation will take time, and acceptance will be supported through the development of numerous case studies. Major remaining questions are: is genetic damage a relevant endpoint in itself, or should the risk assessment be carried out on the apical endpoint of cancer and which genotoxic endpoint should be used to derive the point of departure (PoD) for the human exposure limit?


Assuntos
Testes de Mutagenicidade/métodos , Testes de Mutagenicidade/normas , Animais , Dano ao DNA/efeitos dos fármacos , Células Germinativas/efeitos dos fármacos , Humanos , Indústrias/métodos , Indústrias/normas , Mutagênicos/toxicidade , Neoplasias/induzido quimicamente , Medição de Risco/métodos , Medição de Risco/normas
12.
J Toxicol Environ Health B Crit Rev ; 23(3): 91-106, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32046612

RESUMO

Male germ stem cells are responsible for transmission of genetic information to the next generation. Some chemicals exert a negative impact on male germ cells, either directly, or indirectly affecting them through their action on somatic cells. Ultimately, these effects might inhibit fertility, and may exhibit negative consequences on future offspring. Genotoxic anticancer agents may interact with DNA in germ cells potentially leading to a heritable germline mutation. Experimental information in support of this theory has not always been reproducible and suitable in vivo studies remain limited. Thus, alternative male germ cell tests, which are now able to detect phase specificity of such agents, might be used by regulatory agencies to help evaluate the potential risk of mutation. However, there is an urgent need for such approaches for identification of male reproductive genotoxins since this area has until recently been dependent on in vivo studies. Many factors drive alternative approaches, including the (1) commitment to the principles of the 3R's (Replacement, Reduction, and Refinement), (2) time-consuming nature and high cost of animal experiments, and (3) new opportunities presented by new molecular analytical assays. There is as yet currently no apparent appropriate model of full mammalian spermatogenesis in vitro, under the REACH initiative, where new tests introduced to assess genotoxicity and mutagenicity need to avoid unnecessary testing on animals. Accordingly, a battery of tests used in conjunction with the high throughput STAPUT gravity sedimentation was recently developed for purification of male germ cells to investigate genotoxicity for phase specificity in germ cells. This system might be valuable for the examination of phases previously only available in mammals with large-scale studies of germ cell genotoxicity in vivo. The aim of this review was to focus on this alternative approach and its applications as well as on chemicals of known in vivo phase specificities used during this test system development.


Assuntos
Células Germinativas/efeitos dos fármacos , Testes de Mutagenicidade/métodos , Mutagênicos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Mutação em Linhagem Germinativa/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Mutagênese/efeitos dos fármacos , Medição de Risco , Sensibilidade e Especificidade
13.
BMC Genomics ; 21(1): 73, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31973692

RESUMO

BACKGROUND: Spermatogenesis is an intricate process regulated by a finely organized network. The orange-spotted grouper (Epinephelus coioides) is a protogynous hermaphroditic fish, but the regulatory mechanism of its spermatogenesis is not well-understood. In the present study, transcriptome sequencing of the male germ cells isolated from orange-spotted grouper was performed to explore the molecular mechanism underlying spermatogenesis. RESULTS: In this study, the orange-spotted grouper was induced to change sex from female to male by 17alpha-methyltestosterone (MT) implantation. During the spermatogenesis, male germ cells (spermatogonia, spermatocytes, spermatids, and spermatozoa) were isolated by laser capture microdissection. Transcriptomic analysis for the isolated cells was performed. A total of 244,984,338 clean reads were generated from four cDNA libraries. Real-time PCR results of 13 genes related to sex differentiation and hormone metabolism indicated that transcriptome data are reliable. RNA-seq data showed that the female-related genes and genes involved in hormone metabolism were highly expressed in spermatogonia and spermatozoa, suggesting that these genes participate in the spermatogenesis. Interestingly, the expression of zbtb family genes showed significantly changes in the RNA-seq data, and their expression patterns were further examined during spermatogenesis. The analysis of cellular localization of Eczbtb40 and the co-localization of Eczbtb40 and Eccyp17a1 in different gonadal stages suggested that Eczbtb40 might interact with Eccyp17a1 during spermatogenesis. CONCLUSIONS: Our study, for the first time, investigated the transcriptome of the male germ cells from orange-spotted grouper, and identified functional genes, GO terms, and KEGG pathways involved in spermatogenesis. Furthermore, Eczbtb40 was first characterized and its role during spermatogenesis was predicted. These data will contribute to future studies on the molecular mechanism of spermatogenesis in teleosts.


Assuntos
Peixes/genética , Perfilação da Expressão Gênica , Células Germinativas/metabolismo , Metiltestosterona/farmacologia , Espermatogênese/genética , Transcriptoma , Animais , Peixes/metabolismo , Células Germinativas/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos
14.
Reprod Domest Anim ; 55(3): 405-417, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31985843

RESUMO

Male germline stem cells (mGSCs) can transmit genetic materials to the next generation and dedifferentiate into pluripotent stem cells. However, in livestock, mGSC lines are difficult to establish, because of the factors that affect their isolation and culture. The extracellular matrix serves as a substrate for attachment and affects the fate of these stem cells. Poly-L-lysine (PL), an extracellular matrix of choice, inhibits and/or kills cancer cells, and promotes the attachment of stem cells in culture. However, how it affects the characteristics and potentials of these stem cells in culture needs to be elucidated. Here, we isolated, enriched and cultured dairy goat mGSCs on five types of extracellular matrices. To explore the best extracellular matrix to use for culturing them, the characteristics and proliferation ability of the cells were determined. Results showed that the cells shared several characteristics with previously reported mGSCs, including the poor effect of PL on their proliferative and colony-forming abilities. Further examination showed upregulation of p53 expression in these cells, which could be inhibiting their proliferation. When a p53 inhibitor was included in the culture medium, it was confirmed to be responsible for the inhibition of proliferation in mGSCs. Optimal concentration of the inhibitor in the culture of these cells was 5 µM. Furthermore, addition of the p53 inhibitor increased the expression of the markers of self-renewal and cell cycle in goat mGSCs. In summary, suppressing p53 is beneficial for the proliferation of dairy goat mGSCs, cultured on PL.


Assuntos
Técnicas de Cultura de Células/veterinária , Células Germinativas/citologia , Cabras/fisiologia , Polilisina/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Técnicas de Cultura de Células/métodos , Proliferação de Células/efeitos dos fármacos , Meios de Cultura , Matriz Extracelular/fisiologia , Células Germinativas/efeitos dos fármacos , Masculino , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
15.
Chemosphere ; 242: 125285, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31896209

RESUMO

The aim of this study was to assess the long-term effects of synthetic progestin norethindrone (NET) on the growth, reproductive histology, and transcriptional expression profiles of genes associated with the hypothalamic-pituitary-gonadal (HPG) axis and germ cells in adult zebrafish. Adult zebrafish were exposed to 7, 84 and 810 ng/L NET for 90 days. The results showed that exposure to 810 ng/L NET caused a significant decrease in growth of females and males. The ovary weight and GSI was significantly reduced by NET at concentrations of 84 or 810 ng/L, which came along with the delay of ovary maturation in females. However, NET at all treatments resulted in acceleration of sperm maturation in males. In the ovaries of females, a strong inhibition of cyp19a1a gene was observed following exposure to NET at 810 ng/L. Similarly, NET at the highest treatment led to a significant down-regulation of cyp17, cyp19a1a, vasa, nanos1, dazl and dmc1 genes in the testes of males. Taken together, the overall results demonstrated that NET could impact growth and gonadal maturation, with significant alterations of transcriptional expression genes along HPG axis and germ cells.


Assuntos
Expressão Gênica/efeitos dos fármacos , Noretindrona/toxicidade , Progestinas/toxicidade , Poluentes Químicos da Água/toxicidade , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Animais , Regulação para Baixo , Feminino , Células Germinativas/efeitos dos fármacos , Gônadas/efeitos dos fármacos , Masculino , Ovário/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Diferenciação Sexual/efeitos dos fármacos , Testículo/efeitos dos fármacos , Peixe-Zebra/genética
16.
Pharmacogenomics ; 21(1): 75-81, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31849283

RESUMO

Our current understanding of prostate cancer pharmacogenomics is growing at a rapid pace. Apart from evaluating relevant biomarkers and genomic alterations in tumor tissues, an increasing focus is being placed on decoding the impact of germline alterations on prostate cancer and its treatment. Herein we summarize various germline variants that have shown to associate with response to systemic therapy in men with advanced prostate cancer. Covered biomarkers include HSD3B1, SLCO2B1, SULT1E1, TRMT11, CYP17A1, CYP1B1, genes involved in homologous recombination and DNA mismatch repair.


Assuntos
Complexos Multienzimáticos/genética , Transportadores de Ânions Orgânicos/genética , Progesterona Redutase/genética , Neoplasias da Próstata/tratamento farmacológico , Esteroide 17-alfa-Hidroxilase/genética , Esteroide Isomerases/genética , Biomarcadores Tumorais/genética , Reparo de Erro de Pareamento de DNA/genética , Reparo do DNA/efeitos dos fármacos , Células Germinativas/efeitos dos fármacos , Mutação em Linhagem Germinativa/efeitos dos fármacos , Recombinação Homóloga/genética , Humanos , Masculino , Poli(ADP-Ribose) Polimerases/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
17.
Environ Mol Mutagen ; 61(1): 34-41, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31600846

RESUMO

Mutations induced in somatic cells and germ cells are responsible for a variety of human diseases, and mutation per se has been considered an adverse health concern since the early part of the 20th Century. Although in vitro and in vivo somatic cell mutation data are most commonly used by regulatory agencies for hazard identification, that is, determining whether or not a substance is a potential mutagen and carcinogen, quantitative mutagenicity dose-response data are being used increasingly for risk assessments. Efforts are currently underway to both improve the measurement of mutations and to refine the computational methods used for evaluating mutation data. We recommend continuing the development of these approaches with the objective of establishing consensus regarding the value of including the quantitative analysis of mutation per se as a required endpoint for comprehensive assessments of toxicological risk. Environ. Mol. Mutagen. 61:34-41, 2020. © 2019 Wiley Periodicals, Inc.


Assuntos
Testes de Mutagenicidade/métodos , Mutagênicos/toxicidade , Animais , Carcinógenos/toxicidade , Células Germinativas/efeitos dos fármacos , Células Germinativas/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação/efeitos dos fármacos , Medição de Risco
18.
Environ Mol Mutagen ; 61(1): 42-54, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31472026

RESUMO

Fifty years ago, the Environmental Mutagen Society (now Environmental Mutagenesis and Genomics Society) was founded with a laser-focus on germ cell mutagenesis and the protection of "our most vital assets"-the sperm and egg genomes. Yet, five decades on, despite the fact that many agents have been demonstrated to induce inherited changes in the offspring of exposed laboratory rodents, there is no consensus on whether human germ cell mutagens exist. We argue that it is time to reevaluate the available data and conclude that we already have evidence for the existence of environmental exposures that impact human germ cells. What is missing are definite data to demonstrate a significant increase in de novo mutations in the offspring of exposed parents. We believe that with over two decades of research advancing knowledge and technologies in genomics, we are at the cusp of generating data to conclusively show that environmental exposures cause heritable de novo changes in the human offspring. We call on the research community to harness our technologies, synergize our efforts, and return to our Founders' original focus. The next 50 years must involve collaborative work between clinicians, epidemiologists, genetic toxicologists, genomics experts and bioinformaticians to precisely define how environmental exposures impact germ cell genomes. It is time for the research and regulatory communities to prepare to interpret the coming outpouring of data and develop a framework for managing, communicating and mitigating the risk of exposure to human germ cell mutagens. Environ. Mol. Mutagen. 61:42-54, 2020. © 2019 Her Majesty the Queen in Right of Canada.


Assuntos
Exposição Ambiental/efeitos adversos , Células Germinativas/efeitos dos fármacos , Mutagênicos/toxicidade , Animais , Feminino , Células Germinativas/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Mutagênese/efeitos dos fármacos , Testes de Mutagenicidade/métodos , Medição de Risco , Roedores , Transgenes
19.
J Med Chem ; 63(5): 2240-2262, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31490680

RESUMO

Malaria is still a leading cause of mortality among children in the developing world, and despite the immense progress made in reducing the global burden, further efforts are needed if eradication is to be achieved. In this context, targeting transmission is widely recognized as a necessary intervention toward that goal. After carrying out a screen to discover new transmission-blocking agents, herein we report our medicinal chemistry efforts to study the potential of the most robust hit, DDD01035881, as a male-gamete targeted compound. We reveal key structural features for the activity of this series and identify analogues with greater potency and improved metabolic stability. We believe this study lays the groundwork for further development of this series as a transmission blocking agent.


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Malária/transmissão , Plasmodium falciparum/efeitos dos fármacos , Animais , Descoberta de Drogas , Feminino , Células Germinativas/efeitos dos fármacos , Células Hep G2 , Humanos , Malária/tratamento farmacológico , Malária/prevenção & controle , Masculino , Camundongos , Plasmodium falciparum/citologia , Relação Estrutura-Atividade
20.
Environ Mol Mutagen ; 61(1): 8-24, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31294870

RESUMO

A mutagenesis moonshot addressing the influence of the environment on our genetic wellbeing was launched just 2 months before astronauts landed on the moon. Its impetus included the discovery that X-rays (Muller HJ. [1927]: Science 64:84-87) and chemicals (Auerbach and Robson. [1946]: Nature 157:302) were germ-cell mutagens, the introduction of a growing number of untested chemicals into the environment after World War II, and an increasing awareness of the role of environmental pollution on human health. Due to mounting concern from influential scientists that germ-cell mutagens might be ubiquitous in the environment, Alexander Hollaender and colleagues founded in 1969 the Environmental Mutagen Society (EMS), now the Environmental Mutagenesis and Genomics Society (EMGS); Frits Sobels founded the European EMS in 1970. As Fred de Serres noted, such societies were necessary because protecting populations from environmental mutagens could not be addressed by existing scientific societies, and new multidisciplinary alliances were required to spearhead this movement. The nascent EMS gathered policy makers and scientists from government, industry, and academia who became advocates for laws requiring genetic toxicity testing of pesticides and drugs and helped implement those laws. They created an electronic database of the mutagenesis literature; established a peer-reviewed journal; promoted basic and applied research in DNA repair and mutagenesis; and established training programs that expanded the science worldwide. Despite these successes, one objective remains unfulfilled: identification of human germ-cell mutagens. After 50 years, the voyage continues, and a vibrant EMGS is needed to bring the mission to its intended target of protecting populations from genetic hazards. Environ. Mol. Mutagen. 61:8-24, 2020. © 2019 Wiley Periodicals, Inc.


Assuntos
Exposição Ambiental/efeitos adversos , Genômica , Mutagênese , Mutagênicos/toxicidade , Animais , Genômica/história , Genômica/métodos , Células Germinativas/efeitos dos fármacos , Células Germinativas/metabolismo , Células Germinativas/efeitos da radiação , História do Século XX , História do Século XXI , Humanos , Mutagênese/efeitos dos fármacos , Mutagênese/efeitos da radiação , Testes de Mutagenicidade/história , Testes de Mutagenicidade/métodos , Sociedades Científicas/história , Raios Ultravioleta/efeitos adversos , Raios X/efeitos adversos
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