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1.
Environ Pollut ; 266(Pt 1): 115201, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32693302

RESUMO

Triazoles are used as antifungal agents, they mostly inhibit two enzymes: 14α-demethylase and aromatase. These enzymes are utilised also in other species and therefore the affection in non-target species in the environment is expected as well. Besides, triazoles are often being applied in a mixture and they can also interact with other substances present. This study clarifies how three selected representative triazoles (tebuconazole, penconazole and cyproconazole) interact with each other (group effect) and in mixtures (cocktail effect) with copper, essential/toxic for all organisms. Within the experiments on electrospray and collision-induced dissociations (both ESI-MS), it has been found that the fragments correspond to typical triazole metabolites. For their formation, the presence of copper ions is crucial. The inhibitory effect of Cu cocktails on aromatase enzymatic activity has been studied. The presence of Cu ions together with triazole(s) significantly increases the inhibitory effect on aromatase activity. The highest inhibitory effect (more than 60%) on aromatase activity is produced by cocktails containing penconazole and Cu ions, namely by penconazole/Cu and penconazole/tebuconazole/Cu. The reactivity of triazoles in groups is not significantly affected by the interactions among them. Additionally, the role of triazoles in copper Fenton reaction regulation has been observed and described. These changes may be attributed to the formation and stabilization of the complexes with the central Cu ion, with usually one, two or three triazolic ligands, depending on the mixture. The study demonstrates that the interaction of triazoles and Cu ions is a complex process; their impact on metabolism seems to be rather extensive and must be evaluated in the context of biochemical reactions.


Assuntos
Aromatase , Cobre , Antifúngicos , Oxirredução , Triazóis
6.
Toxicology ; 437: 152440, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32197950

RESUMO

Arsenic is an endocrine disruptor that promotes breast cancer (BCa) development. Estrogen synthesis, through aromatase activation, is essential for BCa promotion and progression through activating the G-coupled estrogen receptor 1 (GPER1), regulating rapid nongenomic effects involved in cell proliferation and migration of BCa cells. Herein, was studied the role of aromatase activation and the GPER1 pathway on sodium arsenite-induced promotion and progression of MDA-MB-231 and MDA-MB-453 BCa cell lines. Our results demonstrated that 0.1 µM of sodium arsenite induces cell proliferation, migration, invasion, and stimulates aromatase activity of BCa cell lines MDA-MB-231, MDA-MB-453, MCF-7, but not in a nontumorigenic breast epithelial cell line (MCF-12A). Using letrozole (an aromatase inhibitor) and G-15 (a GPER1-selective antagonist), we demonstrated that sodium arsenite-induced proliferation and migration is mediated by induction of aromatase enzyme and, at least in part, by GPER1 activation in MDA-MB-231 and MDA-MB-453 cells. Sodium arsenite induced phosphorylation of Src that participated in sodium arsenite-induced aromatase activity, and -cell proliferation of MDA-MB-231 cell line. Overall, data suggests that sodium arsenite induces a positive-feedback loop, resulting in the promotion and progression of BCa cells, through induction of aromatase activity, E2 production, GPER1 stimulation, and Src activation.


Assuntos
Aromatase/metabolismo , Arsenitos/toxicidade , Neoplasias da Mama/enzimologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ativadores de Enzimas/toxicidade , Compostos de Sódio/toxicidade , Neoplasias da Mama/patologia , Ativação Enzimática , Estradiol/metabolismo , Feminino , Humanos , Células MCF-7 , Invasividade Neoplásica , Fosforilação , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais , Quinases da Família src/metabolismo
7.
Toxicol Lett ; 326: 70-77, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32113805

RESUMO

In addition to the transfer across the placenta, placenta displays hormonal and xenobiotic metabolism, as well as enzymatic defense against oxidative stress. We analyzed aromatase (CYP19A1), uridine 5'-diphospho-glucuronyltransferase (UGT), glutathione-S-transferase (GST) and catalase (CAT) activities in over 70 placentas from nonsmokers stored at -80 °C from former perfusion studies. A wide interindividual variation in all activities was found. Longterm storage at -80 °C did not affect the activities. Ethoxyresorufin-O-deethylase (EROD, CYP1A1) was not detected in any of the studied placentas perfused with chemicals. Several compounds in placental perfusion changed statistically significantly the enzyme activities in placental tissue. Melamine and nicotine increased CYP19A1, melamine increased UGT and GST, PhIP with ethanol decreased CYP19A1 and increased GST, and PhIP with buprenorphine decreased CAT. Antipyrine in 100 µg/ml also changed the studied enzyme activities, but not statistically significantly. Because antipyrine is a reference compound in placental perfusions, its potential effects must be taken into account in human placental perfusion. Enzyme activities deserve further studies as biomarkers of placental toxicity. Finally, enzyme activities deserve further studies as biomarkers of placental toxicity.


Assuntos
Antipirina/metabolismo , Aromatase/metabolismo , Catalase/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Glucuronosiltransferase/metabolismo , Glutationa Transferase/metabolismo , Placenta/metabolismo , Adulto , Feminino , Humanos , Gravidez
8.
Environ Sci Technol ; 54(7): 4465-4474, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32150676

RESUMO

Despite the ubiquity of organophosphate flame retardants (OPFRs) metabolites in the biota, the endocrine disrupting potency has not been well examined. Herein, we chose three primary metabolites of OPFRs (BCIPP, BDCIPP, and DPHP) to investigate their potential endocrine disrupting effects by in vitro, in vivo, and in silico assays. Three metabolites were agonistic to rat estrogenic receptor alpha (ERα) and antagonists to human mineralocorticoid receptor (MR). BCIPP exerted endocrine disrupting effect contrasting to the negative response of its parental compound. It also poses the strongest binding capacity to ERα among the tested compounds. Both BCIPP and BDCIPP upregulated the genes encoded for estrogenic synthesis enzymes in H295R cells, including 17ßHSD and CYP19. All three compounds stimulated the transcription of CYP11B1, whereas BCIPP and DPHP also triggered CYP11B2, encoding for corticoid production. BDCIPP inhibits genes for progesterone synthesis including CYP11A1, STAR, and 3-ßHSD. The induction of mortality and low hatchability of zebrafish embryo were ranked as BCIPP ≥ BDCIPP > DPHP. All compounds lead to malformation of zebrafish larvae. Both of the hypothalamic-pituitary-adrenocortical and hypothalamic-pituitary-gonadal axes were disrupted, with the highest impact by BCIPP. Altogether, the data clarified OPFRs metabolites may produce comparable or even higher endocrine disrupting effects than OPFRs.


Assuntos
Retardadores de Chama , Animais , Aromatase , Humanos , Organofosfatos , Ratos , Peixe-Zebra
9.
Ecotoxicol Environ Saf ; 193: 110324, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32088548

RESUMO

This study assessed the transcription levels of estrogen-responsive genes, such as vitellogenins (Vtg1 and Vtg2), choriogenins (ChgL, ChgH, and ChgHm), cytochrome P450 aromatase (CYP19a1b), and ER subtypes (ERα, ERß1, and ERß2), in 7 days-post-fertilization (dpf) embryos and 9 and 12 dpf larvae of medaka (Oryzias latipes) exposed to estrogenic endocrine-disrupting chemicals (EDCs). The <5 h-post-fertilization embryos were exposed to EDCs such as 17ß-estradiol (E2), p-n-nonylphenol (NP), and bisphenol A (BPA). In E2 (0.10-222 nM)-treated 7 dpf embryos and 9 or 12 dpf larvae, ChgL, ChgH, and ChgHm expression was up-regulated in a concentration-dependent manner. By contrast, interestingly, Vtg1 and Vtg2 expression was not induced in E2-treated 7 dpf embryos but was significantly induced in 9 and 12 dpf larvae, suggesting a developmental-stage-specific regulatory mechanism underlying Vtg expression. The maximum concentrations of NP (0.09-1.5 µM) and BPA (1.8-30 µM) up-regulated Chg expression in 9 or 12 dpf larvae, and the relative estrogenic potencies (REPs) of E2, NP, and BPA were 1, 2.1 × 10-4, and 1.0 × 10-5, respectively. Chg messenger RNA (mRNA) in medaka embryos and larvae can be used as a sensitive biomarker for screening potential estrogenic EDCs. Our assay system using embryos and larvae can be used as an in vivo alternative model because independent feeding stages (e.g., embryonic and early larval stages) are suitable alternatives.


Assuntos
Proteínas do Ovo/biossíntese , Disruptores Endócrinos/toxicidade , Estrogênios/toxicidade , Oryzias/embriologia , Oryzias/crescimento & desenvolvimento , Animais , Aromatase/biossíntese , Aromatase/genética , Compostos Benzidrílicos/toxicidade , Proteínas do Ovo/genética , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Estradiol/toxicidade , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/biossíntese , Receptor beta de Estrogênio/genética , Larva/efeitos dos fármacos , Larva/genética , Larva/metabolismo , Masculino , Modelos Animais , Oryzias/genética , Fenóis/toxicidade , RNA Mensageiro/metabolismo , Transcrição Genética/efeitos dos fármacos , Vitelogeninas/biossíntese , Vitelogeninas/genética
10.
Artigo em Inglês | MEDLINE | ID: mdl-32033145

RESUMO

Benzo[a]pyrene (BaP) is a common environmental disrupting chemical that can cause endocrine disorders in organisms. However, the continued interference effects of BaP on multi-generation fish needs further research. In this study, we performed different periods (G1F1-3, G2F2-3, G3F3) of BaP exposure on marine medaka. We determined the embryo toxicity, and analyzed relative reproductive genes (ERα, cyp19a and vtg1) to predict the sexual differentiation of marine medaka. The results showed that high concentrations of BaP (200 µg·L-1) significantly delayed the hatching time of embryos. Moreover, medium/high concentrations of BaP (20 and 200 µg·L-1) prolonged the sexual maturity time of marine medaka. The relative gene expression of ERα, cyp19a and vtg1 were measured at 5 dpf of embryos. We found that BaP had significantly inhibited the expression of the genes related to female fish development. Consequently, there were more males in the offspring sex ratio at BaP exposure. Overall, BaP can cause embryonic toxicity and abnormal sexual differentiation, while the expression of related reproductive genes can effectively indicate the sex ratio.


Assuntos
Benzo(a)pireno/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Diferenciação Sexual/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Aromatase/genética , Receptor alfa de Estrogênio/genética , Feminino , Proteínas de Peixes/genética , Expressão Gênica/efeitos dos fármacos , Masculino , Oryzias/genética , Oryzias/crescimento & desenvolvimento , Reprodução/efeitos dos fármacos , Reprodução/genética , Razão de Masculinidade , Vitelogeninas/genética
12.
Chemistry ; 26(28): 6214-6223, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32049373

RESUMO

The hydroxylation of nonreactive C-H bonds can be easily catalyzed by a variety of metalloenzymes, especially cytochrome P450s (P450s). The mechanism of P450 mediated hydroxylation has been intensively studied, both experimentally and theoretically. However, understanding the regio- and stereoselectivities of substrates hydroxylated by P450s remains a great challenge. Herein, we use a multi-scale modeling approach to investigate the selectivity of testosterone (TES) and dihydrotestosterone (DHT) hydroxylation catalyzed by two important P450s, CYP3A4 and CYP19A1. For CYP3A4, two distinct binding modes for TES/DHT were predicted by dockings and molecular dynamics simulations, in which the experimentally identified sites of metabolism of TES/DHT can access to the catalytic center. The regio- and stereoselectivities of TES/DHT hydroxylation were further evaluated by quantum mechanical and ONIOM calculations. For CYP19A1, we found that sites 1ß, 2ß and 19 can access the catalytic center, with the intrinsic reactivity 2ß>1ß>19. However, our ONIOM calculations indicate that the hydroxylation is favored at site 19 for both TES and DHT, which is consistent with the experiments and reflects the importance of the catalytic environment in determining the selectivity. Our study unravels the mechanism underlying the selectivity of TES/DHT hydroxylation mediated by CYP3A4 and CYP19A1 and is helpful for understanding the selectivity of other substrates that are hydroxylated by P450s.


Assuntos
Aromatase/metabolismo , Citocromo P-450 CYP3A/metabolismo , Di-Hidrotestosterona/química , Testosterona/metabolismo , Aromatase/química , Catálise , Citocromo P-450 CYP3A/química , Humanos , Hidroxilação , Cinética , Oxirredução , Testosterona/química
13.
Development ; 147(4)2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32001440

RESUMO

Sex determination and differentiation are complex processes controlled by many different factors; however, the relationships among these factors are poorly understood. Zebrafish gonadal differentiation exhibits high plasticity involving multiple factors and pathways, which provides an excellent model for investigating the interactions between them. Ovarian aromatase (cyp19a1a) and dmrt1 are key factors in directing vertebrate ovary and testis differentiation, respectively. Knockout of zebrafish cyp19a1a leads to all-male offspring, whereas the loss of dmrt1 results in a female-biased sex ratio. In the present study, we established dmrt1-/- ;cyp19a1a-/- double mutant zebrafish and discovered that the introduction of the dmrt1 mutation into the cyp19a1a mutant could rescue the all-male phenotype of the latter. Interestingly, despite the lack of aromatase/estrogens, the follicles in the ovary of the rescued cyp19a1a mutant could develop normally up to the previtellogenic stage. Further evidence suggested the ovarian aromatase directed ovarian differentiation by suppressing dmrt1 expression via nuclear estrogen receptors (nERs). Our results provide solid evidence for an interaction between cyp19a1a and dmrt1 in zebrafish gonadal differentiation, and for the dispensability of estrogens in controlling early folliculogenesis.


Assuntos
Aromatase/genética , Aromatase/fisiologia , Folículo Ovariano/embriologia , Testículo/embriologia , Fatores de Transcrição/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/fisiologia , Alelos , Animais , Animais Geneticamente Modificados , Diferenciação Celular , Estrogênios/fisiologia , Feminino , Técnicas de Inativação de Genes , Genótipo , Heterozigoto , Masculino , Mutação , Fenótipo , Receptores Estrogênicos/fisiologia , Processos de Determinação Sexual , Diferenciação Sexual , Peixe-Zebra
14.
PLoS One ; 15(1): e0227830, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31971970

RESUMO

Estrogens are important for maintaining metabolic health in males. However, the key sources of local estrogen production for regulating energy metabolism have not been fully defined. Immune cells exhibit aromatase activity and are resident in metabolic tissues. To determine the relative contribution of immune cell-derived estrogens for metabolic health in males, C57BL6/J mice underwent bone marrow transplant with marrow from either wild-type (WT(WT)) or aromatase-deficient (WT(ArKO)) donors. Body weight, body composition, and glucose and insulin tolerance were assessed over 24 weeks with mice maintained on a regular chow diet. No differences were found in insulin sensitivity between groups, but WT(ArKO) mice were more glucose tolerant than WT(WT) mice 20 weeks after transplant, suggestive of enhanced glucose disposal (AUCglucose 6061±3349 in WT(WT) mice versus 3406±1367 in WT(ArKO) mice, p = 0.01). Consistent with this, skeletal muscle from WT(ArKO) mice showed higher expression of the mitochondrial genes Ppargc1a (p = 0.03) and Nrf1 (p = 0.01), as well as glucose transporter type 4 (GLUT4, Scl2a4; p = 0.02). Skeletal muscle from WT(ArKO) mice had a lower concentration of 17ß-estradiol (5489±2189 pg/gm in WT(WT) mice versus 3836±2160 pg/gm in WT(ArKO) mice, p = 0.08) but higher expression of estrogen receptor-α (ERα, Esr1), raising the possibility that aromatase deficiency in immune cells led to a compensatory increase in ERα signaling. No differences between groups were found with regard to body weight, adiposity, or gene expression within adipose tissue or liver. Immune cells are a key source of local 17ß-estradiol production and contribute to metabolic regulation in males, particularly within skeletal muscle. The respective intracrine and paracrine roles of immune cell-derived estrogens require further delineation, as do the pathways that regulate aromatase activity in immune cells specifically within metabolic tissues.


Assuntos
Aromatase/genética , Glucose/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Músculo Esquelético/metabolismo , Animais , Aromatase/metabolismo , Transplante de Medula Óssea , Células Cultivadas , Estrogênios/metabolismo , Deleção de Genes , Teste de Tolerância a Glucose , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
15.
Aquat Toxicol ; 220: 105403, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31927064

RESUMO

Transgenic fish are powerful models that can provide mechanistic information regarding the endocrine activity of test chemicals. In this study, our objective was to use a newly developed transgenic zebrafish line expressing eGFP under the control of the cyp19a1a promoter in the OECD Fish Short Term Reproduction Assay (TG 229) to provide additional mechanistic information on tested substances. For this purpose, we exposed adult transgenic zebrafish to a reference substance of the TG 229, i.e. prochloraz (PCZ; 1.7, 17.2 and 172.6 µg/L). In addition to "classical" endpoints used in the TG 229 (reproductive outputs, vitellogenin), the fluorescence intensity of the ovaries was monitored at 4 different times of exposure using in vivo imaging. Our data revealed that 172.6 µg/L PCZ significantly decreased the number of eggs laid per female per day and the concentrations of vitellogenin in females, reflecting the decreasing E2 synthesis due to the inhibition of the ovarian aromatase activities. At 7 and 14 days, GFP intensities in ovaries were similar over the treatment groups but significantly increased after 21 days at 17.2 and 172.6 µg/L. A similar profile was observed for the endogenous cyp19a1a expression measured by qPCR thereby confirming the reliability of the GFP measurement for assessing aromatase gene expression. The overexpression of the cyp19a1a gene likely reflects a compensatory response to the inhibitory action of PCZ on aromatase enzymatic activities. Overall, this study illustrates the feasibility of using the cyp19a1a-eGFP transgenic line for assessing the effect of PCZ in an OECD test guideline while providing complementary information on the time- and concentration-dependent effects of the compound, without disturbing reproduction of fish. The acquisition of this additional mechanistic information on a key target gene through in vivo fluorescence imaging of the ovaries was realized without increasing the number of individuals.


Assuntos
Animais Geneticamente Modificados , Aromatase/genética , Disruptores Endócrinos/toxicidade , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados/metabolismo , Feminino , Corantes Fluorescentes , Proteínas de Fluorescência Verde/genética , Guias como Assunto , Organização para a Cooperação e Desenvolvimento Econômico , Ovário/efeitos dos fármacos , Ovário/metabolismo , Regiões Promotoras Genéticas , Reprodutibilidade dos Testes , Vitelogeninas/metabolismo , Peixe-Zebra/metabolismo
16.
Nat Chem Biol ; 16(3): 250-256, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31932723

RESUMO

In plants, lineage-specific metabolites can be created by activities derived from the catalytic promiscuity of ancestral proteins, although examples of recruiting detoxification systems to biosynthetic pathways are scarce. The ubiquitous glyoxalase (GLX) system scavenges the cytotoxic methylglyoxal, in which GLXI isomerizes the α-hydroxy carbonyl in the methylglyoxal-glutathione adduct for subsequent hydrolysis. We show that GLXIs across kingdoms are more promiscuous than recognized previously and can act as aromatases without cofactors. In cotton, a specialized GLXI variant, SPG, has lost its GSH-binding sites and organelle-targeting signal, and evolved to aromatize cyclic sesquiterpenes bearing α-hydroxyketones to synthesize defense compounds in the cytosol. Notably, SPG is able to transform acetylated deoxynivalenol, the prevalent mycotoxin contaminating cereals and foods. We propose that detoxification enzymes are a valuable source of new catalytic functions and SPG, a standalone enzyme catalyzing complex reactions, has potential for toxin degradation, crop engineering and design of novel aromatics.


Assuntos
Aromatase/metabolismo , Lactoilglutationa Liase/química , Lactoilglutationa Liase/metabolismo , Aromatase/química , Produtos Biológicos , Catálise , Citosol/metabolismo , Glutationa/metabolismo , Gossypium/metabolismo , Complexos Multienzimáticos , Aldeído Pirúvico/química , Aldeído Pirúvico/metabolismo
17.
J Morphol ; 281(3): 302-315, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31904879

RESUMO

Artibeus lituratus is a frugivorous bat that directly assists in the restoration of degraded habitats through the effective dispersion of seeds and fruits. Given its great importance, this work aimed to evaluate the uterine hormonal control of A. lituratus during its different reproductive phases. The uteri of 30 sexually mature adult females, five specimens for each of the six sample groups (NON, nonreproductive; P1, initial pregnancy; P2, intermediate pregnancy; P3, advanced pregnancy; LAC, lactating; P + LAC, pregnant-lactating), were submitted to analyses of serum estradiol and progesterone concentrations, in addition to immunohistochemical analyses. Both estradiol and progesterone, gradually increased during pregnancy, with a marked significant increase in P3 females. Both returned to low levels in LAC-females; however, estradiol levels decreased further in P + LAC-females, while progesterone increased in the same group. In general, signs indicative of aromatase expression were observed in the endometrium of all analyzed groups and in the placenta of bats in the gestation groups. Similarly, ERα and PR were expressed in the myometrium, endometrium and placenta at varying levels of intensity. The results indicate that the uterine microenvironment of A. lituratus is directly regulated by serum concentrations of estradiol and progesterone, and fluctuations in these concentrations control morphological and physiological changes of this organ during different phases of the reproductive cycle. RESEARCH HIGHLIGHTS: Increases in serum concentrations of estradiol and progesterone coordinate the gestational period of A. lituratus. Estradiol activates ERα, stimulating cell proliferation in the uterus, in addition to activating the expression of PR, which trigger the quiescence of the myometrium and stimulation of the secretion and differentiation of the endometrium. Results showed several similarities to humans, indicating the use of A. lituratus as an animal model in reproductive studies.


Assuntos
Quirópteros/fisiologia , Hormônios/farmacologia , Reprodução/fisiologia , Útero/fisiologia , Animais , Aromatase/metabolismo , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Feminino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Receptores de Progesterona/metabolismo , Útero/anatomia & histologia , Útero/citologia , Útero/efeitos dos fármacos
18.
Nat Commun ; 11(1): 185, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924771

RESUMO

Developing insight into tissue-specific transcriptional mechanisms can help improve our understanding of how genetic variants exert their effects on complex traits and disease. In this study, we apply the principles of Mendelian randomization to systematically evaluate transcriptome-wide associations between gene expression (across 48 different tissue types) and 395 complex traits. Our findings indicate that variants which influence gene expression levels in multiple tissues are more likely to influence multiple complex traits. Moreover, detailed investigations of our results highlight tissue-specific associations, drug validation opportunities, insight into the likely causal pathways for trait-associated variants and also implicate putative associations at loci yet to be implicated in disease susceptibility. Similar evaluations can be conducted at http://mrcieu.mrsoftware.org/Tissue_MR_atlas/.


Assuntos
Análise da Randomização Mendeliana , Fenômica , Transcriptoma , Aromatase/genética , Fibrilina-2/genética , Regulação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Proteínas Ribossômicas/genética , Doenças da Glândula Tireoide/genética , Doenças da Glândula Tireoide/metabolismo
19.
Eur J Histochem ; 64(1)2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31988532

RESUMO

The goal of this study was to evaluate P450 aromatase localization in the epididymis of two different vertebrates: the lizard Podarcis sicula, a seasonal breeder, and Rattus rattus, a continuous breeder. P450 aromatase is a key enzyme involved in the local control of spermatogenesis and steroidogenesis and we proved for the first time that this enzyme is represented in the epididymis of both P. sicula and R. rattus. In details, P450 aromatase was well represented in epithelial and myoid cells and in the connective tissue of P. sicula epididymis during the reproductive period; instead, during autumnal resumption this enzyme was absent in the connective tissue. During the non-reproductive period, P450 aromatase was localized only in myoid cells of P. sicula epididymis, whereas in R. rattus it was localized both in myoid cells and connective tissue. Our findings, the first on the epididymis aromatase localization in the vertebrates, suggest a possible role of P450 aromatase in the control of male genital tract function, particularly in sperm maturation.


Assuntos
Aromatase/fisiologia , Epididimo/enzimologia , Animais , Tecido Conjuntivo/enzimologia , Imuno-Histoquímica , Lagartos , Masculino , Ratos , Reprodução/fisiologia
20.
J Phys Chem Lett ; 11(4): 1189-1193, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31986051

RESUMO

Cytochromes P450 enzymes (CYP450s) promote the oxidative metabolism of a variety of substrates via the electrons supplied by the cytochrome P450 reductase (CPR) and upon formation of a CPR/CYP450 adduct. In spite of the pivotal regulatory importance of this process, the impact of CPR binding on the functional properties of its partner CYP450 remains elusive. By performing multiple microsecond-long all-atom molecular dynamics simulations of a 520 000-atom model of a CPR/CYP450 adduct embedded in a membrane mimic, we disclose the molecular terms for their interactions, considering the aromatase (HA) enzyme as a proxy of the CYP450 family. Our study strikingly unveils that CPR binding alters HA's functional motions, bolstering a change in the shape and type of the channels traveled by substrates/products during their access/egress to/from the enzyme's active site. Our outcomes unprecedentedly contribute to extricate the many entangled facets of the CYP450 metabolon, redrafting its intricate panorama from an atomic-level perspective.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Aromatase/química , Aromatase/metabolismo , Sistema Enzimático do Citocromo P-450/química , Transporte de Elétrons , Humanos , Simulação de Dinâmica Molecular , NADPH-Ferri-Hemoproteína Redutase/química , Ligação Proteica , Especificidade por Substrato
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