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1.
Aquat Toxicol ; 223: 105476, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32315829

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used pharmaceuticals to treat pain, fever and inflammation. NSAIDs are also known to have many side effects including adverse effects on reproduction in both humans and animals. As NSAIDs usage is not regulated they are frequently detected at high concentrations in the environment. In order to understand the effect of NSAIDs on zebrafish sex differentiation, we used seven different NSAIDs which were either Cox-1 selective, Cox-1 biased, non-selective or COX-2 selective. We show that at higher concentration, NSAIDs are toxic to zebrafish embryo as they lead to mortality and hatching delay. Gene expression analysis following short term exposure of NSAIDs led to downregulation of female specific genes including zp2, vtg2 foxl2 and wnt4. Long term exposure of larvae to environmentally relevant concentrations of Cox-2 selective and non-selective NSAIDs resulted in male-biased sex ratio which confirmed the qRT-PCR analysis. However, the Cox-1 selective acetylsalicylic acid and the Cox-1 biased ketoprofen did not alter sex ratio. The observed male-biased sex ratio could also be due to induction of apoptosis process as the genes including p21 and casp8 were significantly upregulated following exposure to the Cox-2 selective and the non-selective NSAIDs. The present study indicates that NSAIDs alter sex differentiation in zebrafish, primarily through inhibition of Cox-2. This study clearly demonstrates that the use of NSAIDs and their release into the aquatic environment should be carefully monitored to avoid adverse effects to the aquatic organisms.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Diferenciação Sexual/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Desenvolvimento Embrionário/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Inflamação , Masculino , Diferenciação Sexual/genética , Peixe-Zebra/genética
2.
Aquat Toxicol ; 221: 105441, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32045789

RESUMO

Previous studies have shown that BDE-47, one of the most abundant polybrominated diphenyl ethers (PBDEs) congeners, has a weak estrogenic activity, but it has remained unclear whether BDE-47 disrupts gonadal development and causes male-to-female sex reversal in lower vertebrates, with limited and controversial data. The present study aimed to determine the effects of BDE-47 on gonadal development in Xenopus laevis, a model amphibian species for studying adverse effects of estrogenic chemicals on reproductive development. X. laevis at stage 45/46 were exposed to BDE-47 (0.5, 5, 50 nM) in semi-static system, with 1 nM 17ß-estradiol (E2) as the positive control. When reaching stage 53, tadpoles were examined for gonadal morphology, histology and sex-dimorphic gene expression. The phenotypic sex (gonadal morphology and histology) of each BDE-47-treated tadpole matched its genetic sex, showing no sex-reversal, whereas one half of genetic males treated with E2 displayed ovarian-like features. However, some genetic males (26%) in the 50 nM BDE-47 treatment group were found to contain more germ cells clumping together in the medulla, along with an increasing tendency of the gonad length/kidney length ratio in males, resembling feminizing outcomes of E2. These observations seem to suggest that BDE-47 exerted weak feminizing effects. However, BDE-47 induced increases in expression of both female-biased genes and male-biased genes in two sexes, which disagrees with feminizing outcomes, suggesting complicated effects of BDE-47 on gonadal development. Taken together, all results demonstrate that nanomolar BDE-47 disrupted gonadal development and exerted weak feminizing effects, but not resulted in male-to-female sex reversal in X. laevis.


Assuntos
Gônadas/efeitos dos fármacos , Éteres Difenil Halogenados/toxicidade , Diferenciação Sexual/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Estradiol/toxicidade , Feminino , Gônadas/crescimento & desenvolvimento , Humanos , Larva/efeitos dos fármacos , Masculino , Reprodução/efeitos dos fármacos , Diferenciação Sexual/genética , Xenopus laevis
3.
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
4.
BMC Genomics ; 21(1): 22, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31910818

RESUMO

BACKGROUND: Early sex differentiation genes of zebrafish remain an unsolved mystery due to the difficulty to distinguish the sex of juvenile zebrafish. However, aromatase inhibitors (AIs) could direct juvenile zebrafish sex differentiation to male and even induce ovary-to-testis reversal in adult zebrafish. RESULTS: In order to determine the transcriptomic changes of sex differentiation in juvenile zebrafish and early sex-reversal in adult zebrafish, we sequenced the transcriptomes of juvenile and adult zebrafish treated with AI exemestane (EM) for 32 days, when juvenile zebrafish sex differentiation finished. EM treatment in females up-regulated the expression of genes involved in estrogen metabolic process, female gamete generation and oogenesis, including gsdf, macf1a and paqr5a, while down-regulated the expression of vitellogenin (vtg) genes, including vtg6, vtg2, vtg4, and vtg7 due to the lower level of Estradiol (E2). Furthermore, EM-juveniles showed up-regulation in genes related to cell death and apoptosis, such as bcl2l16 and anax1c, while the control-juveniles exhibited up-regulation of genes involved in positive regulation of reproductive process and oocyte differentiation such as zar1 and zpcx. Moreover, EM-females showed higher enrichment than control females in genes involved in VEGF signaling pathway, glycosaminoglycan degradation, hedgehog signaling pathway, GnRH signaling pathway and steroid hormone biosynthesis. CONCLUSIONS: Our study shows anti-masculinization in EM-treated adult females but not in EM-treated juveniles. This may be responsible for the lower sex plasticity in adults than juveniles.


Assuntos
Inibidores da Aromatase/farmacologia , Diferenciação Sexual/genética , Vitelogênese/genética , Vitelogeninas/genética , Peixe-Zebra/genética , Androstadienos/farmacologia , Animais , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas Hedgehog/genética , Masculino , Reprodução/genética , Diferenciação Sexual/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Vitelogênese/efeitos dos fármacos
5.
Ecotoxicol Environ Saf ; 189: 110042, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31816500

RESUMO

2,4-Dichlorophenol (2,4-DCP) is ubiquitous in aquatic environment and has potential estrogenic effect on fish. However, the effect of 2,4-DCP on sex differentiation of zebrafish (Danio rerio) and the underlying mechanism are largely unknown. To address these questions, zebrafish larvae at 20 or 30 days post fertilization (dpf) were exposed to 2,4-DCP (0, 80 and 160 µg L-1) with/without 5-aza-2'-deoxycytidine (5AZA, 50 µg L-1) for 10 days. The sex ratios and the expressions of male-related genes including amh, gata4, nr5a1a, nr5a2 and sox9a were analyzed. In addition, the DNA methylation levels of amh, nr5a2 and sox9a were examined. The results showed that 2,4-DCP exposure resulted in significant increase of female ratios both in 20-30 and 30-40 dpf groups. Correspondingly, the expressions of gata4, nr5a1a, nr5a2 and sox9a were decreased by 2,4-DCP exposure in two treatment periods. However, the transcript of amh was decreased by 2,4-DCP exposure only from 30 to 40 dpf. The DNA methylation levels of amh, nr5a2 and sox9a were increased following 2,4-DCP exposure. Moreover, the addition of 5AZA could counteract the effects including feminization, disturbance of gene expression and DNA hypermethylation caused by 2,4-DCP. These results indicated that the feminizing effect of 2,4-DCP was accomplished by regulating the expression of male-related genes through DNA methylation.


Assuntos
Clorofenóis/toxicidade , Metilação de DNA/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Feminização/induzido quimicamente , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/genética , Animais , Regulação para Baixo , Feminino , Feminização/genética , Larva/efeitos dos fármacos , Larva/genética , Masculino , Receptores Citoplasmáticos e Nucleares/genética , Diferenciação Sexual/efeitos dos fármacos , Diferenciação Sexual/genética , Razão de Masculinidade , Proteínas de Peixe-Zebra/genética
6.
Endocrinology ; 161(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31742329

RESUMO

Many neural sex differences are differences in the number of neurons of a particular phenotype. For example, male rodents have more calbindin-expressing neurons in the medial preoptic area (mPOA) and bed nucleus of the stria terminalis (BNST), and females have more neurons expressing estrogen receptor alpha (ERα) and kisspeptin in the ventromedial nucleus of the hypothalamus (VMH) and the anteroventral periventricular nucleus (AVPV), respectively. These sex differences depend on neonatal exposure to testosterone, but the underlying molecular mechanisms are unknown. DNA methylation is important for cell phenotype differentiation throughout the developing organism. We hypothesized that testosterone causes sex differences in neurochemical phenotype via changes in DNA methylation, and tested this by inhibiting DNA methylation neonatally in male and female mice, and in females given a masculinizing dose of testosterone. Neonatal testosterone treatment masculinized calbindin, ERα and kisspeptin cell number of females at weaning. Inhibiting DNA methylation with zebularine increased calbindin cell number only in control females, thus eliminating sex differences in calbindin in the mPOA and BNST. Zebularine also reduced the sex difference in ERα cell number in the VMH, in this case by increasing ERα neuron number in males and testosterone-treated females. In contrast, the neonatal inhibition of DNA methylation had no effect on kisspeptin cell number. We conclude that testosterone normally increases the number of calbindin cells and reduces ERα cells in males through orchestrated changes in DNA methylation, contributing to, or causing, the sex differences in both cell types.


Assuntos
Encéfalo/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Diferenciação Sexual/efeitos dos fármacos , Testosterona/farmacologia , Animais , Animais Recém-Nascidos , Encéfalo/citologia , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Calbindinas/metabolismo , Citidina/administração & dosagem , Citidina/análogos & derivados , Citidina/farmacologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Kisspeptinas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Diferenciação Sexual/fisiologia , Fatores Sexuais , Testosterona/administração & dosagem
7.
Ecotoxicol Environ Saf ; 188: 109912, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31706240

RESUMO

Synthetic progestins are emerging contaminants of the aquatic environment with endocrine disrupting potential. The main aim of the present study was to investigate the effects of the synthetic progestins gestodene, and drospirenone on sex differentiation in common carp (Cyprinus carpio) by histological analysis. To gain insights into the mechanisms behind the observations from the in vivo experiment on sex differentiation, we analyzed expression of genes involved in hypothalamus-pituitary-gonad (HPG) and hypothalamus-pituitary-thyroid (HPT) axes, histology of hepatopancreas, and in vitro bioassays. Carp were continuously exposed to concentrations of 2 ng/L of single progestins (gestodene or drospirenone) or to their mixture at concentration 2 ng/L of each. The exposure started 24 h after fertilization of eggs and concluded 160 days post-hatching. Our results showed that exposure of common carp to a binary mixture of drospirenone and gestodene caused increased incidence of intersex (32%) when compared to clean water and solvent control groups (both 3%). Intersex most probably was induced by a combination of multiple modes of action of the studied substances, namely anti-gonadotropic activity, interference with androgen receptor, and potentially also with HPT axis or estrogen receptor.


Assuntos
Androstenos/toxicidade , Carpas/crescimento & desenvolvimento , Disruptores Endócrinos/toxicidade , Norpregnenos/toxicidade , Diferenciação Sexual/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Gônadas/efeitos dos fármacos , Hepatopâncreas/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipófise/efeitos dos fármacos , Diferenciação Sexual/genética
8.
Chemosphere ; 240: 124935, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31563720

RESUMO

Increasing studies have established the toxic effects of BPA on development and reproduction in animals. In present study, we investigated epigenetic effects on the transcription of several ovarian steroidogenic genes in rare minnows Gobiocypris rarus after BPA exposure at 15 µgL-1 for 21, 42 and 63 d. Results showed that short term BPA exposure (21 d) caused significant increase of both estradiol and testerone levels whereas long term exposure (63 d) led to significant decrease of them. The oocytes development was hindered after BPA exposure. BPA treatments for 21 and 42 d resulted in significant increase of genome DNA methylation in ovary while 63-d exposure caused marked decrease. The histone trimethylation levels (H3K4me3, H3K9me3 and H3K27me3) in the ovary were also disturbed by BPA. H3K9me3 was significantly decreased after 21 d whereas it was markedly increased after 42 and 63 d. The 42-d exposure caused significant decrease for H3K4me3. Meanwhile, 42- and 63-d BPA exposure led to significant decrease of H3K27me3. DNA methylation could involve in gene expression regulation of cyp17a1 and cyp19a1a after BPA exposure. After short (21 d) and long term (63 d) BPA exposure, the respective mRNA expression down-regulation and up-regulation of star, cyp11a1, and cyp17a1 were mediated by H3K9me3. This study suggests that epigenetic modulation including DNA and histone methylation could be responsible for the detrimental effects on ovary development upon BPA exposure in G. rarus. It is speculated that BPA exposures for short or long term duration could disturb the steroidogenesis in entirely different mechanisms.


Assuntos
Compostos Benzidrílicos/toxicidade , Cyprinidae/genética , Metilação de DNA/efeitos dos fármacos , Estrogênios não Esteroides/toxicidade , Oócitos/crescimento & desenvolvimento , Ovário/crescimento & desenvolvimento , Fenóis/toxicidade , Animais , Cyprinidae/metabolismo , DNA/metabolismo , Estradiol/metabolismo , Feminino , Regulação da Expressão Gênica , Histonas/genética , Diferenciação Sexual/efeitos dos fármacos , Esteroide 17-alfa-Hidroxilase/genética , Testosterona/metabolismo
9.
PLoS One ; 14(11): e0224628, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31682623

RESUMO

In murine fetal germ cells, retinoic acid (RA) is an extrinsic cue for meiotic initiation that stimulates transcriptional activation of the Stimulated by retinoic acid gene 8 (Stra8), which is required for entry of germ cells into meiotic prophase I. Canonically, the biological activities of RA are mediated by nuclear RA receptors. Recent studies in somatic cells found that RA noncanonically stimulates intracellular signal transduction pathways to regulate multiple cellular processes. In this study, using a germ cell culture system, we investigated (1) whether RA treatment activates any mitogen-activated protein kinase (MAPK) pathways in fetal germ cells at the time of sex differentiation, and (2) if this is the case, whether the corresponding RA-stimulated signaling pathway regulates Stra8 expression in fetal germ cells and their entry into meiosis. When XX germ cells at embryonic day (E) 12.5 were cultured with RA, the extracellular-signal-regulated kinase (ERK) 1/2 pathway was predominantly activated. MEK1/2 inhibitor (U0126) treatment suppressed the mRNA expressions of RA-induced Stra8 and meiotic marker genes (Rec8, Spo11, Dmc1, and Sycp3) in both XX and XY fetal germ cells. Furthermore, U0126 treatment dramatically reduced STRA8 protein levels and numbers of meiotic cells among cultured XX and XY fetal germ cells even in the presence of RA. Taken together, our results suggest the novel concept that the RA functions by stimulating the ERK1/2 pathway and that this activity is critical for Stra8 expression and meiotic progression in fetal germ cells.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Células Germinativas/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Meiose/fisiologia , Tretinoína/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Butadienos/farmacologia , Células Cultivadas , Meios de Cultura/metabolismo , Embrião de Mamíferos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Células Germinativas/efeitos dos fármacos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Meiose/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Nitrilos/farmacologia , Cultura Primária de Células , Diferenciação Sexual/efeitos dos fármacos , Diferenciação Sexual/fisiologia
10.
Mar Biotechnol (NY) ; 21(5): 697-706, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31372794

RESUMO

The availability of sexually mature fish often dictates the success of its captive breeding. In this study, we induced reproductive development in juvenile protogynous tiger grouper through oral administration of a plasmid (p) containing an engineered follicle-stimulating hormone (FSH). An expression construct (pcDNA3.1) was designed to express a single-chain FSH consisting of giant grouper FSH ß-subunit and glycoprotein subunit-α (CGα), linked by the carboxy-terminal peptide (CTP) sequence from the human chorionic gonadotropin (hCG). Single oral delivery of pFSH encapsulated in liposome and chitosan to tiger grouper yielded a significant increase in plasma FSH protein level after 4 days. Weekly pFSH feeding of juvenile tiger groupers for 8 weeks stimulated ovarian development as indicated by a significant increase in oocyte diameter and progression of oocytes to cortical alveolar stage. As the pFSH treatment progressed from 20 to 38 weeks, female to male sex change was initiated, characterized by oocyte regression, proliferation of spermatogonial cells, and occurrence of spermatogenic cysts. It was also associated with significantly lower mRNA expression of steroidogenic genes (cyp11b, cyp19a1a, and foxl2) and basal plasma levels of sex steroid hormones 17ß-estradiol (E2), testosterone (T), and 11-ketotestosterone (11KT). Results suggest that pFSH stimulates ovarian development up to cortical alveolar stage and then initiates sex change in tiger grouper. These findings significantly contribute to our knowledge on the role of FSH in the development of protogynous hermaphroditic fish. This study is the first to demonstrate induction of reproductive development in fish through oral delivery of plasmid gonadotropin.


Assuntos
Gonadotropina Coriônica/genética , Hormônio Foliculoestimulante/genética , Gônadas/efeitos dos fármacos , Organismos Hermafroditas/efeitos dos fármacos , Perciformes/genética , Processos de Determinação Sexual/efeitos dos fármacos , Diferenciação Sexual/efeitos dos fármacos , Administração Oral , Animais , Quitosana/química , Gonadotropina Coriônica/administração & dosagem , Gonadotropina Coriônica/biossíntese , Composição de Medicamentos , Feminino , Proteínas de Peixes/biossíntese , Proteínas de Peixes/genética , Hormônio Foliculoestimulante/administração & dosagem , Hormônio Foliculoestimulante/biossíntese , Hormônios Esteroides Gonadais/biossíntese , Hormônios Esteroides Gonadais/genética , Gônadas/crescimento & desenvolvimento , Gônadas/metabolismo , Organismos Hermafroditas/genética , Humanos , Lipossomos/administração & dosagem , Lipossomos/química , Masculino , Oogênese/efeitos dos fármacos , Oogênese/genética , Perciformes/crescimento & desenvolvimento , Perciformes/metabolismo , Plasmídeos/química , Plasmídeos/metabolismo , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Pré-Seleção do Sexo/métodos , Espermatogênese/efeitos dos fármacos , Espermatogênese/genética
11.
BMC Genomics ; 20(1): 587, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31315571

RESUMO

BACKGROUND: Atrazine is widely used in agriculture and is a known endocrine disrupting chemical. Atrazine can seep into the water body through surface, posing a potential threat to the aquatic ecological environment and human drinking water source. In vertebrate, studies have shown that it can affect reproduction and development seriously, but its molecular mechanism for aquatic animals is unknown. Aquaculture is very common in China, especially common carp, whose females grow faster than males. However, the effects of atrazine on the reproduction of carp, especially miRNA, have not been investigated. RESULTS: In this study, common carp (Cyprinus carpio) at two key developmental stages were exposed to atrazine in vitro. Sex ratio was observed to analyze the effect of atrazine on the sex. MiRNA expression profiles were analysed to identify miRNAs related to gonad development and to reveal the atrazine mechanisms interfering with gonad differentiation. The results showed that the sex ratio was biased towards females. Atrazine exposure caused significant alteration of multiple miRNAs. Predicted targets of differently-expressed miRNAs were involved in many reproductive biology signalling pathways. CONCLUSIONS: Our results indicate that atrazine promoted the expression of female-biased genes by decreasing miRNAs in primordial gonad. In addition, our results indicate that atrazine can up-regulate aromatase expression through miRNAs, which supports the hypothesis that atrazine has endocrine-disrupting activity by altering the gene expression profile of the Hypothalamus-Pituitary-Gonad axis through its corresponding miRNAs.


Assuntos
Atrazina/toxicidade , Carpas/genética , Disruptores Endócrinos/toxicidade , Gônadas/efeitos dos fármacos , MicroRNAs/genética , Diferenciação Sexual/efeitos dos fármacos , Animais , Aromatase/genética , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Gônadas/embriologia , Masculino , Razão de Masculinidade , Transcriptoma/efeitos dos fármacos
12.
Aquat Toxicol ; 214: 105242, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31319296

RESUMO

Some progestins, including the widely used dydrogesterone (DDG), have been shown to cause male-biased sex ratio in teleost. However, there is a gap to fully understand the mechanisms of the sex differentiation disturbance by progestins, particularly from the metabolic aspect. We thus aimed to examine the sex changes by exposing zebrafish embryos to 4.4 (L), 44 (M) and 440 (H) ng/L DDG for up to 140 days, and investigated metabolomic profile changes during the critical period of sex differentiation at fry stage (35 dpf). DDG increased the percentage of male zebrafish in a dose-dependent manner, with 98% male fish in the high concentration group. In zebrafish fry, DDG increased the levels of some free fatty acids, monoglycerides, acylcarnitines, organic acids, free amino acids, while decreased lysophospholipids, uric acid and bile acids. DDG exposure also decreased the nucleoside monophosphates and UDP-sugars while increased nucleosides and their bases. These metabolite changes, namely increase in n-3 PUFAs (polyunsaturated fatty acids), myo-inositol, taurine, palmitoleic acid, oleic acid, lactic acid, fumaric acid, and uracil, and decrease in uric acid and bile acids, might account for the male-biased sex ratio in zebrafish. It appears that many of these metabolites could inhibit several pathways that regulate zebrafish gonad differentiation, including NF-κB/COX-2 and Wnt/ß-catenin pathways, and activate p53 pathway. Thus we proposed a hypothesis that DDG might induce oocytes apoptosis through the above pathways and finally lead to female-to-male sex reversal. The results from this study suggest that DDG at environmentally relevant concentrations could affect zebrafish metabolomic profiles and finally disturb fish sex differentiation.


Assuntos
Didrogesterona/toxicidade , Metabolômica , Diferenciação Sexual , Peixe-Zebra/metabolismo , Peixe-Zebra/fisiologia , Animais , Feminino , Masculino , Metaboloma , Modelos Biológicos , Análise Multivariada , Diferenciação Sexual/efeitos dos fármacos , Razão de Masculinidade , Poluentes Químicos da Água/toxicidade
13.
Environ Res ; 177: 108564, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31306987

RESUMO

Bifenthrin (BF) is a pyrethroid insecticide used in urban and agricultural applications. Previous studies in early life stages of fish have indicated anti-estrogenic activity; however, estrogenic activity has been observed in adults. To test the hypothesis that BF impairs sex differentiation, larval Japanese Medaka were exposed to BF during a critical developmental window for phenotypic sexual differentiation. Fish were exposed to environmentally relevant concentrations of BF (0.15 µg/L and 1.5 µg/L), a single concentration (0.3 mg/L) of an estrogen receptor (ER) antagonist (ICI 182,780), and an ER agonist (0.2 ug/L) (17ß-estradiol). Fish were exposed at 8 days post hatch (dph) larvae for 30 days. Phenotypic sex, secondary sexual characteristics (SSC) and genotypic sex were investigated at sexual maturity (8 weeks). A trend towards masculinization (p = 0.06) based on the presence of papillary processes in anal fin rays of Japanese Medaka was observed in fish exposed to the lowest concentration of BF. However, genotypic gender ratios were not altered. These results show sex differentiation was not significantly altered by larval exposure to BF in Japanese medaka.


Assuntos
Oryzias/fisiologia , Piretrinas/toxicidade , Diferenciação Sexual/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Estradiol
14.
Environ Toxicol ; 34(11): 1255-1262, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31298479

RESUMO

Progesterone (P4) is a biologically active steroid hormone that is involved in the regulation of oocyte growth and maturation, as well as development of the endometrium and implantation in the uterus of humans. It can also stimulate oocyte maturation in female fish, as well as spermatogenesis and sperm motility in male fish. Thus, P4 has been extensively used in human and animal husbandry as a typical progestin. However, P4 remaining in the water environment will pose a potential hazard to aquatic organisms. For example, it can interfere with sex differentiation and reproduction in aquatic vertebrates such as fish. Therefore, we investigated the effects of prolonged progesterone exposure on the expression of genes related to circadian rhythm signaling and the hypothalamic-pituitary-gonadal (HPG) axes in Yellow River Carp, which may have a potential impact on their sex differentiation. Our results suggested that P4 exposure altered the expression of genes related to circadian rhythm signaling, which can lead to disorders in the endocrine system and regulate the HPG axes-related activities. Furthermore, the expression of genes related to the HPG axes was also altered, which might affect gonadal development and the reproductive systems of Yellow River Carp. In addition, these changes may provide a plausible mechanism for the observed shifts in their sex ratio toward females.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Progesterona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Carpas/crescimento & desenvolvimento , Carpas/metabolismo , Feminino , Gônadas/efeitos dos fármacos , Gônadas/patologia , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Diferenciação Sexual/efeitos dos fármacos , Razão de Masculinidade , Transcrição Genética/efeitos dos fármacos
15.
Reprod Biol Endocrinol ; 17(1): 53, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292004

RESUMO

BACKGROUND: Bisphenol A is well known endocrine-disrupting chemical while Bisphenol S was considered a safe alternative. The present study aims to examine the comparative effects of xenobiotic bisphenol-A (BPA) and its substitute bisphenol-S (BPS) on spermatogenesis and development of sexually dimorphic nucleus population of dopaminergic neurons in the anteroventral periventricular nucleus (AVPV) of the hypothalamus in male pups. METHODS: Sprague Dawley rat's pups were administered subcutaneously at the neonatal stage from postnatal day PND1 to PND 27. Thirty animals were divided into six experimental groups (6 animals/group). The first group served as control and was provided with normal olive oil. The four groups were treated with 2 µg/kg and 200 µg/kg of BPA and BPS, respectively. The sixth group was given with 50 µg/kg of estradiol dissolved in olive oil as a standard to find the development of dopaminergic tyrosine hydroxylase neurons in AVPV regions. Histological analysis for testicular tissues and immunohistochemistry for brain tissues was performed. RESULTS: The results revealed adverse histopathological changes in testis after administration of different doses of BPA and BPS. These degenerative changes were marked by highly significant (p < 0.001) decrease in tubular and luminal diameters of seminiferous tubule and epithelial height among bisphenols treated groups as compared to control. Furthermore, significantly increased (p < 0.001) TH-ir cell bodies in the AVPV region of the brain with 200 µg/kg dose of BPA and BPS was evident. CONCLUSION: It is concluded that exposure of BPA and BPS during a critical developmental period can structural impairments in testes and affects sexual differentiation of a dimorphic dopaminergic population of AVPV region of hypothalamus in the male brain.


Assuntos
Compostos Benzidrílicos/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Hipotálamo Anterior/efeitos dos fármacos , Fenóis/farmacologia , Diferenciação Sexual/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Sulfonas/farmacologia , Animais , Animais Recém-Nascidos , Neurônios Dopaminérgicos/metabolismo , Disruptores Endócrinos/farmacologia , Poluentes Ambientais/farmacologia , Estradiol/farmacologia , Estrogênios/farmacologia , Feminino , Hipotálamo Anterior/patologia , Masculino , Ratos Sprague-Dawley , Túbulos Seminíferos/efeitos dos fármacos , Túbulos Seminíferos/patologia , Fatores Sexuais
16.
BMC Genomics ; 20(1): 583, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307399

RESUMO

The synthetic 17α-ethinylestradiol (EE2) is a common estrogenic pollutant that has been suspected to affect the demography of river-dwelling salmonids. One possibility is that exposure to EE2 tips the balance during initial steps of sex differentiation, so that male genotypes show female-specific gene expression and gonad formation. Here we study EE2 effects on gene expression around the onset of sex differentiation in a population of European grayling (Thymallus thymallus) that suffers from sex ratio distortions. We exposed singly-raised embryos to one dose of 1 ng/L EE2, studied gene expression 10 days before hatching, at the day of hatching, and around the end of the yolk-sac stage, and related it to genetic sex (sdY genotype). We found that exposure to EE2 affects expression of a large number of genes, especially around hatching. These effects were strongly sex-dependent. We then raised fish for several months after hatching and found no evidence of sex reversal in the EE2-exposed fish. We conclude that ecologically relevant (i.e. low) levels of EE2 pollution do not cause sex reversal by simply tipping the balance at early stages of sex differentiation, but that they interfere with sex-specific gene expression.


Assuntos
Disruptores Endócrinos/toxicidade , Estrogênios/toxicidade , Etinilestradiol/toxicidade , Expressão Gênica/efeitos dos fármacos , Salmonidae/genética , Diferenciação Sexual/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Feminino , Masculino , Salmonidae/embriologia , Diferenciação Sexual/genética , Razão de Masculinidade
17.
Anim Reprod Sci ; 207: 44-51, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31208847

RESUMO

The number of Sertoli cells has a major effect on adult testis size and sperm production capacity. Mechanisms that regulate the number of Sertoli cells in livestock are at best nebulously understood; however, with lesser testicular estrogen production, proliferation of Sertoli cells is prolonged compared with vehicle-treated littermates. Decreased WISP2 gene expression in testes as a result of less endogenous estrogen is similar to altered WISP2 gene expression following corticosteroid treatment of some cultured cells. Taken together, these findings indicate decreased testicular cortisol might be in the signaling pathway between reduced endogenous estrogens and the prolonged interval of Sertoli cell proliferation. Hence, in these studies, potential actions of testicular corticosteroid on Sertoli cell numbers were evaluated. Testicular cortisol concentrations were reduced at 6.5 weeks of age (P < 0.05) in littermates treated with the aromatase inhibitor, letrozole, compared with littermates treated with vehicle. Letrozole treatment leads to reduced testicular estradiol and greater Sertoli cell numbers during the early juvenile interval in pigs. The inverse relationship between testicular glucocorticoid and Sertoli cell proliferation was also tested by increasing local testicular glucocorticoids using the synthetic compound, dexamethasone. Local administration beginning at 1.5 weeks of age (osmotic pump and catheter (n = 3) or a silastic implant (n = 5)) reduced Sertoli cell numbers at 6.5 weeks of age compared with littermates that received the vehicle treatment (P< 0.05). In summary, testicular glucocorticoid concentration was inversely correlated with Sertoli cell numbers during the first wave of Sertoli cell proliferation.


Assuntos
Proteínas de Sinalização Intercelular CCN/fisiologia , Proliferação de Células/efeitos dos fármacos , Estrogênios/farmacologia , Hidrocortisona/fisiologia , Células de Sertoli/efeitos dos fármacos , Testículo/metabolismo , Animais , Proteínas de Sinalização Intercelular CCN/genética , Dexametasona/farmacologia , Fulvestranto/farmacologia , Expressão Gênica/efeitos dos fármacos , Hidrocortisona/metabolismo , Letrozol/farmacologia , Masculino , Células de Sertoli/fisiologia , Diferenciação Sexual/efeitos dos fármacos , Diferenciação Sexual/genética , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Suínos
18.
Environ Pollut ; 249: 1049-1059, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31146311

RESUMO

Tebuconazole is a widely used fungicide that has been detected in water ecosystems, of which the concentrations may affect the endocrine function of aquatic organisms. At present study, tissue-specific bioaccumulation of tebuconazole was found in ovary of adult zebrafish, indicating a potential risk of endocrine disruption. In order to evaluate the potential endocrine disrupting effects, three life stages (2 hpf (hours post-fertilization) -60 dpf (days post-fertilization), Stage I; 60-120 dpf, Stage II; 180-208 dpf, Stage III) of zebrafish (Danio rerio) were chronically exposed to tebuconazole at the concentrations ranging from 0.05 mg/L to 1.84 mg/L. Result showed that exposed to tebuconazole could lead to a male-biased sex differentiation in juvenile zebrafish and significant decrease of the percentage of germ cells in sexually-mature zebrafish. Egg production was significantly inhibited by 57.8% and 19.2% after Stage II- and Stage III-exposures, respectively. The contents of 17ß-estradiol in gonad decreased by 63.5% when exposed to 0.20 mg/L tebuconazole at Stage II and by 49.5% after exposed to 0.18 mg/L tebuconazole at Stage III, respectively. For all stages exposure, reductions in 17ß-estradiol/testosterone ratio were observed, indicating an imbalance in steroids synthesis. Additionally, tebuconazole reduced the expression of cyp19a, which was consistent with the decrease of E2 level. In overall, the present findings indicated that, playing as an anti-estrogen-like chemical, tebuconazole inhibited the expression of Cyp19, thereby impairing steroid hormones biosynthesis, leading to a diminished fecundity of zebrafish.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Fungicidas Industriais/toxicidade , Gônadas/efeitos dos fármacos , Triazóis/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/crescimento & desenvolvimento , Animais , Aromatase/metabolismo , Embrião não Mamífero/metabolismo , Disruptores Endócrinos/metabolismo , Feminino , Fungicidas Industriais/metabolismo , Gônadas/embriologia , Diferenciação Sexual/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos , Triazóis/metabolismo , Poluentes Químicos da Água/metabolismo , Peixe-Zebra/metabolismo
19.
Horm Behav ; 113: 38-46, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31047887

RESUMO

Gonadal steroids play an integral role in male sexual behavior, and in most rodent models, this relationship is tightly coupled. However, many other species, including humans, continue to demonstrate male sex behavior in the absence of gonadal steroids, and the mechanisms that regulate steroid-independent male sex behavior are not well understood. Approximately 30% of castrated male B6D2F1 hybrid mice display male sex behavior many months after castration, allowing for the investigation of individual variation in steroidal regulation of male sex behavior. During both the perinatal and peripubertal periods of development, the organizational effects of gonadal steroids on sexual differentiation of the neural circuits controlling male sex behavior are well-documented. Several factors can alter the normal range of gonadal steroids or their receptors which may lead to the disruption of the normal processes of masculinization and defeminization. It is unknown whether the organizational effects of gonadal hormones during puberty are necessary for steroid-independent male sex behavior. However, gonadal steroids during puberty were not necessary for either testosterone or estradiol to activate male sex behavior in adulthood. Furthermore, activation of male sex behavior was initiated sooner in hybrid male mice castrated prior to puberty that were administered estradiol in adulthood compared to those that were provided testosterone. The underlying mechanisms by which gonadal hormones, during both the perinatal and peripubertal developmental periods of sexual differentiation, organize the normal maturation of neural circuitry that regulates steroid-independent male sex behavior in adult castrated B6D2F1 male mice warrants further investigation.


Assuntos
Hormônios Esteroides Gonadais/fisiologia , Comportamento Sexual Animal , Maturidade Sexual/fisiologia , Animais , Estradiol/farmacologia , Feminino , Hormônios Esteroides Gonadais/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Orquiectomia , Diferenciação Sexual/efeitos dos fármacos , Comportamento Sexual Animal/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos , Esteroides/farmacologia , Esteroides/fisiologia , Testosterona/farmacologia , Testosterona/fisiologia
20.
Aquat Toxicol ; 212: 70-76, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31077968

RESUMO

Medroxyprogesterone acetate (MPA) is a widely used synthetic progestin and it has been frequently detected in aquatic environments. However, its effects on aquatic organisms remain largely unknown. Here we investigated the chronic effects of MPA on sex differentiation and gonad development in zebrafish. Zebrafish larvae at 20 days post fertilization (dpf) were exposed to 4.32, 42.0, and 424 ng L-1 of MPA until they reached 140 dpf. The results showed that chronic exposure to 42.0 ng L-1 of MPA caused 60% proportion of males as well as significant up-regulation of dmrt1 (˜1.79 fold) and hsd17b3 (˜1.92 fold). Histological analysis showed MPA significantly increased the frequency of immature spermatocytes accompanied with the increased transcription of dmrt1 (˜2.06 fold) and ar (˜1.73 fold) in the testes. Meanwhile, MPA exposure significantly increased the transcription of lhb at all exposure concentrations in the males. In contrast, it significantly suppressed the transcription of lhb (˜-8.06-fold) and fshb (˜-6.35-fold) at 42.0 ng L-1 in the females. Collectively our results demonstrated that MPA had androgenic activity, and could affect sex differentiation and spermatogenesis in zebrafish at environmentally relevant concentrations. The findings from this study suggest that MPA in the aquatic environment may pose potential androgenic risks to fish populations.


Assuntos
Acetato de Medroxiprogesterona/farmacologia , Diferenciação Sexual/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Peixe-Zebra/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Gônadas/efeitos dos fármacos , Hormônios/sangue , Masculino , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Razão de Masculinidade , Transcrição Genética/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/sangue , Peixe-Zebra/crescimento & desenvolvimento
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