Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 923
Filtrar
1.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361004

RESUMO

This article reviews evidence suggesting that a common mechanism of initiation leads to the development of many prevalent types of cancer. Endogenous estrogens, in the form of catechol estrogen-3,4-quinones, play a central role in this pathway of cancer initiation. The catechol estrogen-3,4-quinones react with specific purine bases in DNA to form depurinating estrogen-DNA adducts that generate apurinic sites. The apurinic sites can then lead to cancer-causing mutations. The process of cancer initiation has been demonstrated using results from test tube reactions, cultured mammalian cells, and human subjects. Increased amounts of estrogen-DNA adducts are found not only in people with several different types of cancer but also in women at high risk for breast cancer, indicating that the formation of adducts is on the pathway to cancer initiation. Two compounds, resveratrol, and N-acetylcysteine, are particularly good at preventing the formation of estrogen-DNA adducts in humans and are, thus, potential cancer-prevention compounds.


Assuntos
Acetilcisteína/farmacologia , Carcinogênese/efeitos dos fármacos , Estradiol/farmacologia , Estrona/farmacologia , Quinonas/farmacologia , Resveratrol/farmacologia , Animais , Antioxidantes/farmacologia , Carcinogênese/genética , Adutos de DNA , Estradiol/toxicidade , Estrogênios/farmacologia , Estrogênios/toxicidade , Estrona/toxicidade , Humanos , Quinonas/toxicidade
2.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281275

RESUMO

Human estrogens prescribed for hormone replacement therapy (HRT) are known to be potent carcinogens. To find safer estrogens, several chlorinated estrogens were synthesized and their carcinogenic potential were determined. A pellet containing either 2-chloro-17ß-estradiol (2-ClE2) or 4-chloro-17ß-estradiol (4-ClE2) was implanted subcutaneously for 52 weeks into August Copenhagen Irish (ACI) rats, a preferred animal model for human breast cancer. 17ß-Estradiol (E2) frequently induced mammary tumors while both 2-ClE2 and 4-ClE2 did not. Their 17α-ethinyl forms, thought to be orally active estrogens, were also synthesized. Neither 2-chloro-17α-ethinylestradiol (2-ClEE2) nor 4-chloro-17α-ethinylestradiol (4-ClEE2) induced tumors. The less carcinogenic effects were supported by histological examination of mammary glands of ACI rats treated with the chlorinated estrogens. A chlorine atom positioned at the 2- or 4-position of E2 may prevent the metabolic activation, resulting in reducing the carcinogenicity. 2-ClE2 and 4-ClE2 administered subcutaneously and 2-ClEE2 and 4-ClEE2 given orally to ovariectomized rats all showed uterotrophic potency, albeit slightly weaker than that of E2. Our results indicate that less carcinogenic chlorinated estrogens retaining estrogenic potential could be safer alternatives to the carcinogenic estrogens now in use for HRT.


Assuntos
Carcinógenos/toxicidade , Estradiol/análogos & derivados , Terapia de Reposição de Estrogênios/efeitos adversos , Neoplasias Mamárias Experimentais/prevenção & controle , Animais , Testes de Carcinogenicidade , Carcinógenos/síntese química , Dano ao DNA , Estradiol/síntese química , Estradiol/toxicidade , Etinilestradiol/análogos & derivados , Etinilestradiol/síntese química , Etinilestradiol/toxicidade , Feminino , Humanos , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/patologia , Ratos , Ratos Endogâmicos ACI , Útero/efeitos dos fármacos , Útero/patologia
3.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201250

RESUMO

Breast cancer (BC) is a leading cause of cancer deaths in women in less developed countries and the second leading cause of cancer death in women in the U.S. In this study, we report the inhibition of E2-mediated mammary tumorigenesis by Cuminum cyminum (cumin) administered via the diet as cumin powder, as well as dried ethanolic extract. Groups of female ACI rats were given either an AIN-93M diet or a diet supplemented with cumin powder (5% and 7.5%, w/w) or dried ethanolic cumin extract (1%, w/w), and then challenged with subcutaneous E2 silastic implants (1.2 cm; 9 mg). The first appearance of a palpable mammary tumor was significantly delayed by both the cumin powder and extract. At the end of the study, the tumor incidence was 96% in the control group, whereas only 55% and 45% animals had palpable tumors in the cumin powder and extract groups, respectively. Significant reductions in tumor volume (660 ± 122 vs. 138 ± 49 and 75 ± 46 mm3) and tumor multiplicity (4.21 ± 0.43 vs. 1.16 ± 0.26 and 0.9 ± 0.29 tumors/animal) were also observed by the cumin powder and cumin extract groups, respectively. The cumin powder diet intervention dose- and time-dependently offset E2-related pituitary growth, and reduced the levels of circulating prolactin and the levels of PCNA in the mammary tissues. Mechanistically, the cumin powder diet resulted in a significant reversal of E2-associated modulation in ERα, CYP1A1 and CYP1B1. Further, the cumin powder diet reversed the expression levels of miRNAs (miR-182, miR-375, miR-127 and miR-206) that were highly modulated by E2 treatment. We analyzed the composition of the extract by GC/MS and established cymene and cuminaldehyde as major components, and further detected no signs of gross or systemic toxicity. Thus, cumin bioactives can significantly delay and prevent E2-mediated mammary tumorigenesis in a safe and effective manner, and warrant continued efforts to develop these clinically translatable spice bioactives as chemopreventives and therapeutics against BC.


Assuntos
Cuminum/química , Estradiol/toxicidade , Estrogênios/toxicidade , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Mamárias Experimentais/prevenção & controle , Extratos Vegetais/farmacologia , Animais , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Feminino , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/patologia , MicroRNAs/genética , Ratos , Ratos Endogâmicos ACI
4.
J Environ Pathol Toxicol Oncol ; 40(2): 65-79, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33822518

RESUMO

Environmental pollution (EP) is a well-known threat to wild animals, but its toxicological impact is poorly understood. In vitro toxicity evaluation using cells of lower predators could be a promising way to assess and monitor the effects of EPs on whole wildlife populations that are related in the food web. Here, we describe EPs' toxic effect and mechanism in the primary fibroblast derived from the embryo of the striped field mouse, Apodemus agrarius. Characterization of the primary fibroblast was via morphology, genetics, immunocytochemistry, and stable culture conditions for optimal toxicity screening. Cell viability assays-MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and lactate dehydrogenase (LDH)-were performed to observe cytotoxicity, and quantitative PCR was conducted to confirm gene alteration by EP exposure. MTT and LDH assays confirmed the cytotoxicity of transfluthrin (TF), benzyl butyl phthalate (BBP), and 17ß-estradiol (E2) with IC50 values of 10.56 µM, 10.82 µM, and 24.08 µM, respectively, following 48-h exposures. mRNA expression of androgen-binding protein, growth hormone receptor, cytochrome C oxidase, and cytochrome P450-1A1 was induced after exposure to TF, BBP, and E2. We unveiled new EP mechanisms at the mammalian cellular level and discovered potential biomarker genes for monitoring of EPs. Based on our findings, we propose the primary fibroblast of A. agrarius as a valuable model to assess the toxicological effects of EP on wildlife.


Assuntos
Ciclopropanos/toxicidade , Disruptores Endócrinos/toxicidade , Estradiol/toxicidade , Estrogênios/toxicidade , Fibroblastos/efeitos dos fármacos , Fluorbenzenos/toxicidade , Inseticidas/toxicidade , Ácidos Ftálicos/toxicidade , Proteína de Ligação a Androgênios/genética , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 1/genética , Citocromo P-450 CYP1A1/genética , Embrião de Mamíferos/citologia , Fibroblastos/metabolismo , Murinae , Receptores da Somatotropina/genética
5.
Ecotoxicol Environ Saf ; 216: 112210, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33866271

RESUMO

Bisphenol A (BPA) is a ubiquitous industrial chemical found in everyday plastic products and materials. Due to scientific findings on the reproductive, developmental, and cellular defects caused by BPA and heightened public awareness, manufacturers have begun to use new chemicals in place of BPA in "BPA-free" products. These alternatives are chemical analogs of BPA and include dozens of new compounds that have undergone relatively little testing and oversight, including: bisphenol S (BPS), bisphenol AF (BPAF), and the recently developed tetramethyl bisphenol F (TMBPF; the monomer of valPure V70). Here, we used adult female rat adipose-derived stem cells (rASCs) and human mesenchymal stem cells (hMSCs) to compare the toxicities and potencies of these BPA alternatives in vitro. Rat and human stem cells were exposed to BPA (1-10 µM), 17ß-estradiol (E2; 10 µM), BPS (1-100 µM), BPAF (3×10-4-30 µM), TMBPF (0.01-50 µM), or control media alone (with 0.01% ethanol) for varying time intervals from 10 min to 24 h. We found significantly decreased cell viability and massive apoptosis in rat and human stem cells treated with each BPA analog, as early as 10 min of exposure, and at low, physiologically relevant doses. BPAF showed extreme cytotoxicity in a dose-dependent manner (LC50 =0.014 µM (rASCs) and 0.009 µM (hMSCs)), whereas TMBPF showed a bimodal response, with low and high concentrations being the most toxic (LC50 =0.88 µM (rASCs) and 0.06 µM (hMSCs)). Activated caspase-6 levels increased in nearly all cells treated with the BPA analogs indicating the majority of cell death was due to caspase-6-mediated apoptosis. These results in both rat and human stem cells underscore the toxicity and potency of these BPA analogs, and establish a rank order of potency of: BPAF>TMBPF>BPA>BPS. Further, these and other recent findings indicate that these newer BPA analogs may be 'regrettable substitutions,' being worse than the original parent compound and lacking proper testing and regulation. This work brings to light the need for further toxicological characterization, better regulation, greater public awareness, and the development of safer, more sustainable chemicals and non-plastic products.


Assuntos
Poluentes Ambientais/toxicidade , Fenóis/toxicidade , Testes de Toxicidade , Animais , Apoptose/fisiologia , Compostos Benzidrílicos/toxicidade , Sobrevivência Celular , Estradiol/toxicidade , Feminino , Humanos , Ratos , Células-Tronco , Sulfonas/toxicidade
6.
Artigo em Inglês | MEDLINE | ID: mdl-33753303

RESUMO

Vitellogenin has been regarded as an acceptable indicator for evaluating the endocrine-disrupting property of chemicals using fish. However, the endocrine-disrupting property of chemicals has been rarely evaluated using soil species. This study aimed to find evidence that endocrine-disrupting chemicals (including the natural hormones estradiol and dihydrotestosterone) can affect the reproductive organs of earthworms. Earthworms were exposed to 17ß-estradiol, dihydrotestosterone, bisphenol A, and methylparaben for seven days. The four EDCs inhibited normal oogenesis and maturation of oocytes in earthworm ovary, and dihydrotestosterone and bisphenol A were observed to damage earthworm seminal vesicle tissues and inhibit normal spermatogenesis. The evidence showed that the tested EDCs have an adverse effect on female and male reproductive systems of soil invertebrates. The results suggest that the evaluations of oogenesis and spermatogenesis in the ovary and seminal vesicles of earthworms are useful indicators for investigating the endocrine-disrupting property of chemicals. Additionally, our results encourage further studies on developing novel indicators using soil invertebrates to evaluate the effects of the toxicity of endocrine-disrupting chemicals on the soil ecosystem.


Assuntos
Disruptores Endócrinos/toxicidade , Genitália/efeitos dos fármacos , Oligoquetos/efeitos dos fármacos , Poluentes do Solo/toxicidade , Animais , Compostos Benzidrílicos/toxicidade , Di-Hidrotestosterona/toxicidade , Estradiol/toxicidade , Feminino , Masculino , Parabenos/toxicidade , Fenóis/toxicidade
7.
Toxicol Sci ; 181(2): 187-198, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33769548

RESUMO

Estrogen receptor alpha (ERα) belongs to the nuclear hormone receptor family of ligand-inducible transcription factors and regulates gene networks in biological processes such as cell growth and proliferation. Disruption of these networks by chemical compounds with estrogenic activity can result in adverse outcomes such as unscheduled cell proliferation, ultimately culminating in tumor formation. To distinguish disruptive activation from normal physiological responses, it is essential to quantify relationships between different key events leading to a particular adverse outcome. For this purpose, we established fluorescent protein MCF7 reporter cell lines for ERα-induced proliferation by bacterial artificial chromosome-based tagging of 3 ERα target genes: GREB1, PGR, and TFF1. These target genes are inducible by the non-genotoxic carcinogen and ERα agonist 17ß-estradiol in an ERα-dependent manner and are essential for ERα-dependent cell-cycle progression and proliferation. The 3 GFP reporter cell lines were characterized in detail and showed different activation dynamics upon exposure to 17ß-estradiol. In addition, they demonstrated specific activation in response to other established reference estrogenic compounds of different potencies, with similar sensitivities as validated OECD test methods. This study shows that these fluorescent reporter cell lines can be used to monitor the spatial and temporal dynamics of ERα pathway activation at the single-cell level for more mechanistic insight, thereby allowing a detailed assessment of the potential carcinogenic activity of estrogenic compounds in humans.


Assuntos
Receptor alfa de Estrogênio , Estrogênios , Carcinógenos , Linhagem Celular Tumoral , Estradiol/toxicidade , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio , Estrogênios/toxicidade , Humanos
8.
Aquat Toxicol ; 234: 105796, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33713916

RESUMO

This study leveraged the Japanese medaka fish embryo model for the assessment of effects of select contaminants on early development in fish. Fish embryos were exposed to various pharmaceutical contaminants including synthetic hormones and non-steroidal anti-inflammatory drugs and their effects on development were observed. Initial screening determined that swim bladder inflation failure was the most common endpoint detected. Swim bladder inflation failure was first explored in a study demonstrating that medaka require access to the air-water interphase to inflate their swim bladders in a time-dependent manner, and swim bladder inflation failure was correlated with mortality. Fish embryos were exposed 24-hours post fertilization until hatch to concentration ranges of various pharmaceutical contaminants including: 17ß-estradiol, 17α-ethinylestradiol, and levonorgestrel (1 to 1000 µg/L), or diclofenac (0.32 to 100 mg/L). The main effect observed across all four compounds was a significant increase in failure of swim bladder inflation with increasing exposure concentration (24 to 72-hours post-hatch). Following single compound experiments combinatorial exposures using no-observed-effect concentrations were conducted. The main effect observed was a significant decrease in inflation success 24-hours post-hatch following a binary mixture of levonorgestrel and 17α-ethinylestradiol, as well as a significant decrease in swim bladder inflation success at all times following exposure to a quaternary mixture of all four compounds. This study demonstrated that embryonic exposure to pharmaceutical compounds, both alone and in combination, resulted in failure of swim bladder inflation in larval Japanese medaka.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Oryzias/crescimento & desenvolvimento , Bexiga Urinária/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Diclofenaco/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/fisiologia , Estradiol/toxicidade , Oryzias/fisiologia , Bexiga Urinária/fisiologia
9.
J Ovarian Res ; 14(1): 26, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33546719

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common complex endocrine disorder affecting approximately 2-20% of reproductive aged females. Tumour Treating Fields (100-300 kHz) is a recent innovative, non-invasive therapeutic approach to cancer therapy. This frequency as an alternative therapy for the management of polycystic ovaries has not yet been explored. OBJECTIVES: To explore the effect of full-body exposure of 150 kHz Electromagnetic Radiation (EMR), on the development of polycystic ovaries in an estradiol valerate-induced PCO rat model. METHOD: Twenty-one female adult rats were divided into three groups (n = 7 each): control, Estradiol Valerate (EV) and EV + EMR groups. The EV + EMR group was subjected to full body exposure at 150 kHz EMR continuously for eight consecutive weeks. Estradiol valerate was administered orally to induce polycystic ovaries in EV and EV + EMR groups. Body and ovarian weights were recorded and analysed. The regularity of the estrous cycle was assessed in all three groups. The histological study of ovarian tissue was carried out by haematoxylin and eosin staining. The serum concentration levels of Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH) and testosterone were measured using the ELISA method. RESULTS: The body and ovary weights did not differ significantly between the EV and EV + EMR groups. The estrous cycle was found to be irregular in both the EV and EV + EMR groups. Ovarian histology revealed near normal morphology with little or no degenerative and morphological changes in developing follicles in the exposed group. Histometrical analysis showed an increased number of developing follicles and a significant reduction in the number and size of follicular cysts (p < 0.05) in the EV + EMR group. Hormonal analysis revealed no significant difference in the testosterone and FSH levels between the EV + EMR and EV groups. However, the LH, LH/FSH ratio decreased significantly in the EV + EMR group compares to the EV group. CONCLUSION: The 150 kHz EMR appear to have little or no degenerative and morphological changes in the developing follicles, an increased number of typical developing follicles and a significant reduction in the number and size of the follicular cysts (p < 0.05).


Assuntos
Radiação Eletromagnética , Ciclo Estral/efeitos da radiação , Folículo Ovariano/efeitos da radiação , Ovário/efeitos da radiação , Síndrome do Ovário Policístico/patologia , Animais , Peso Corporal , Modelos Animais de Doenças , Estradiol/toxicidade , Estrogênios/toxicidade , Ciclo Estral/efeitos dos fármacos , Feminino , Hormônio Foliculoestimulante/sangue , Hormônio Luteinizante/sangue , Tamanho do Órgão , Folículo Ovariano/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/patologia , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/radioterapia , Ratos , Ratos Sprague-Dawley , Testosterona/sangue
10.
Ecotoxicol Environ Saf ; 208: 111566, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396095

RESUMO

Androgens and estrogens often co-exist in aquatic environments and pose potential risks to fish populations. However, little is known about the endocrine disrupting effects of the mixture of androgens and estrogens in fish. In this study, transcriptional level of target genes related to the hypothalamic-pituitary-gonadal-liver (HPGL) axis, sex hormone level, VTG protein concentration, histology and secondary sex characteristic were assessed in the ovaries and livers of adult female western mosquitofish (Gambusia affinis) exposed to 17ß-estradiol (E2), testosterone (T), and mixtures of E2 and T for 91 days. The results showed that the transcriptional expression of cytochrome P450, family 19, subfamily A, polypeptide 1a (Cyp19a1a) was suppressed in the 200 ng/L T treatment and the 50 ng/L E2 + 200 ng/L T treatment in the ovaries. Steroidogenic acute regulatory protein (Star) and Cyp11a1 showed a similar expression pattern in the T treatment to its corresponding T + E2 mixtures. In the ovaries, the concentrations of 17ß-estradiol and testosterone were decreased in most treatments compared with the solvent control. VTG protein was induced in all steroid treatment. However, exposure to T or E2 + T mixture did not cause the abnormal cells of the ovaries and livers and an extension of the anal fins in female G. affinis. This study demonstrates that chronic exposure to E2, T and their mixtures affects the transcripts of genes in the HPGL axis, steroid hormone level and VTG protein concentration in the ovaries and livers, but fails to cause the histopathological effect of the ovaries and livers and alter the morphology of the anal fins in G. affinis.


Assuntos
Ciprinodontiformes/fisiologia , Disruptores Endócrinos/toxicidade , Estradiol/toxicidade , Androgênios/metabolismo , Animais , Ciprinodontiformes/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Disruptores Endócrinos/metabolismo , Estradiol/metabolismo , Estrogênios/metabolismo , Feminino , Hormônios Esteroides Gonadais/metabolismo , Fígado/efeitos dos fármacos , Masculino , Ovário/efeitos dos fármacos , Testosterona/metabolismo , Vitelogeninas/metabolismo
11.
Life Sci ; 265: 118792, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33220286

RESUMO

AIMS: In the cyclic rat in estrus, the vasoactive intestinal peptide (VIP) has an impact on ovarian function, which depends on the endocrine status of the animal. In this work, we aimed to clarify the participation of VIP in the pathophysiological condition of polycystic ovary syndrome (PCOS) using a model of PCOS induced by estradiol valerate (EV-PCOS) in rats. MAIN METHODS: In the cyclic rat in estrus and in the EV-PCOS model, we analyzed the acute effects of blocking VIP receptors with the use of an antagonist (Ant-VIP) injected into the left or right ovarian bursa on the steroidogenic response and ovarian catecholamine levels. KEY FINDINGS: In the cyclic animal in estrus, the treatment with Ant-VIP in the left ovarian bursa resulted in a reduction in testosterone serum levels and in ovarian levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), without changes in 4-hydroxy-3-methoxyphenyl (MHPG) and norepinephrine (NE). When the treatment was applied on the right side, only MHPG levels increased. In the EV-PCOS model, the treatment with Ant-VIP in the left ovarian bursa increased testosterone, estradiol, MHPG, and NE levels. When the treatment was performed on the right side, progesterone levels decreased and estradiol increased, without changes in ovarian catecholamines. SIGNIFICANCE: The binding of VIP to its receptors differentially regulates steroidogenesis in the cyclic animal in estrus and in the EV-PCOS model. The blocking of VIP signaling produces changes in ovarian catecholamines.


Assuntos
Modelos Animais de Doenças , Ovário/metabolismo , Síndrome do Ovário Policístico/metabolismo , Receptores de Peptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores de Peptídeo Intestinal Vasoativo/metabolismo , Animais , Catecolaminas/metabolismo , Estradiol/metabolismo , Estradiol/toxicidade , Feminino , Ovário/efeitos dos fármacos , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/tratamento farmacológico , Ratos , Testosterona/metabolismo , Peptídeo Intestinal Vasoativo/antagonistas & inibidores , Peptídeo Intestinal Vasoativo/metabolismo
12.
Toxicol Mech Methods ; 31(1): 43-52, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32967526

RESUMO

Early detection and treatment of endometrial hyperplasia (EH) is mandatory for endometrial cancer prevention. Several bioactive agents of plant origin have been shown to elicit their chemotherapeutic effect against tumors and cancer via induction of mitochondrial permeability transition(mPT) pore opening. This research was therefore aimed at evaluating the potential chemopreventive effect of methyl palmitate (MP), on estradiol benzoate(EB)-induced EH, looking at the mitochondrial-mediated pathway and other possible mechanisms of action. Mitochondria were isolated using differential centrifugation. The mPT pore, mitochondrial ATPase (mATPase) activity, lipid peroxidation and cytochrome c release were determined by standard methods using spectrophotometer. Uterine interleukin 1b, MDA levels and SOD, GSH activities, were determined using commercially available kits. The uterine histological and immunohistochemical assessment of estrogen receptor (ERα), IL-1b and caspas-3 were carried out. The fibroblast cell count density was determined using histomorphometry. At all the concentrations of MP used, there was no significant induction of mPT pore opening, neither any enhancement of mATPase activity nor release of cytochrome c when compared to the control. Similar pattern of results were recorded for the in vivo study. However, there was marked increase in the uterine MDA and interleukin 1b levels, with concurrent decrease in SOD and GSH activities, in the EB-treated group, which was significantly reversed by MP co-administration. Endometrial Hyperplasia observed in the EB-treated group was ameliorated by MP co-administration. The immunoexpression of ERα and IL-1b in the EB-treated group was reversed by MP co-administration. This study suggests anti-inflammatory, antioxidant and anti-proliferative potential of MP against EB-induced EH.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Hiperplasia Endometrial/prevenção & controle , Endométrio/efeitos dos fármacos , Estradiol/análogos & derivados , Mitocôndrias/efeitos dos fármacos , Palmitatos/farmacologia , Animais , Citocromos c/metabolismo , Hiperplasia Endometrial/induzido quimicamente , Hiperplasia Endometrial/metabolismo , Hiperplasia Endometrial/patologia , Endométrio/metabolismo , Endométrio/patologia , Estradiol/toxicidade , Receptor alfa de Estrogênio/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Interleucina-1beta/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais
13.
J Toxicol Sci ; 45(8): 435-447, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741896

RESUMO

The imbalance of testosterone to estradiol ratio has been related to the development of prostate diseases. Although rat models of prostate diseases induced by endocrine-disrupting chemicals (EDCs) and/or hormone exposure are commonly used to analyze gene expression profiles in the prostate, most studies utilize a single endpoint. In this study, microarray analysis was used for gene expression profiling in rat prostate tissue after exposure to EDCs and sex hormones over multiple time points (prepubertal through adulthood). We used dorsolateral prostate tissues from Sprague-Dawley rats (male offspring) and postnatally administered estradiol benzoate (EB) on postnatal days (PNDs) 1, 3, and 5, followed by treatment with additional hormones [estradiol (E) and testosterone (T)] on PNDs 90-200, as described by Ho et al. Microarray analysis was performed for gene expression profiling in the dorsolateral prostate, and the results were validated via qRT-PCR. The genes in cytokine-cytokine receptor interaction, cell adhesion molecules, and chemokines were upregulated in the EB+T+E group on PNDs 145 and 200. Moreover, early-stage downregulation of anti-inflammatory gene: bone morphogenetic protein 7 gene was observed. These findings suggest that exposure to EB, T, and E activates multiple pathways and simultaneously downregulates anti-inflammatory genes. Interestingly, these genes are reportedly expressed in prostate cancer tissues/cell lines. Further studies are required to elucidate the mechanism, including analyses using human prostate tissues.


Assuntos
Disruptores Endócrinos/toxicidade , Estradiol/análogos & derivados , Estradiol/toxicidade , Perfilação da Expressão Gênica/métodos , Expressão Gênica , Próstata/metabolismo , Puberdade , Testosterona/toxicidade , Transcriptoma , Fatores Etários , Animais , Proteína Morfogenética Óssea 7/genética , Proteína Morfogenética Óssea 7/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Disruptores Endócrinos/efeitos adversos , Estradiol/efeitos adversos , Inflamação/genética , Masculino , Análise em Microsséries , Ratos Sprague-Dawley , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Testosterona/efeitos adversos
14.
Aquat Toxicol ; 226: 105557, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32645606

RESUMO

Extensive studies have shown that estrogenic endocrine-disrupting chemicals (EDCs) can disrupt testis differentiation and even cause feminization in vertebrates. However, little is known about the mechanisms by which estrogenic EDCs disrupt testis differentiation. Here, we employed Xenopus laevis, a model amphibian species sensitive to estrogenic EDCs, to explore the molecular and cellular events by which 17ß-estradiol (E2) disrupts testis differentiation and causes feminization. Following waterborne exposure to E2 from stage 45/46, genetically male X. laevis were confirmed to undergo testis differentiation inhibition and ovary differentiation activation at stages 52 and 53, ultimately displaying gonadal feminization at stage 66. Using a time-course RNA sequencing approach, we then identified thousands of differentially expressed transcripts (DETs) in genetically male gonad-mesonephros complexes at stages 48, 50 and 52 (the window for testis differentiation) between E2 treatment and the control. Enrichment analysis suggests alterations in cell proliferation, extracellular matrix, and cell motility following E2 exposure. Further verification by multiple methods demonstrated that E2 inhibited cell proliferation, disrupted extracellular matrix, and altered cell motility in the genetically male gonads compared with controls, implying that these events together contributed to testis differentiation disruptions and feminization in X. laevis. This study for the first time uncovered some of the early molecular and cellular events by which estrogen disrupts testicular differentiation and causes feminization in X. laevis. These new findings improve our understanding of the mechanisms by which estrogenic EDCs disrupt testicular differentiation in vertebrates.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Estradiol/toxicidade , Feminização , Testículo/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Feminino , Feminização/induzido quimicamente , Feminização/genética , Perfilação da Expressão Gênica , Humanos , Larva/efeitos dos fármacos , Larva/genética , Masculino , Ovário/efeitos dos fármacos , Xenopus laevis
15.
Artigo em Inglês | MEDLINE | ID: mdl-32450338

RESUMO

The effect of estrogens on Oryzias curvinotus juveniles were investigated by sequencing the transcriptome of O. curvinotus juveniles exposed to 17 ß - estradiol for 24 h. A total of 69,071,524 and 71,210,528 raw reads were obtained for the control group (NC) and 17 ß - estradiol exposure group (E2), respectively. After de novo assembly, total 133,210 unigenes were identified, and 85,837 unigenes (64.44% of 133,210) were annotated. Analysis of the transcriptome showed that exposure to 2 µg/L 17 ß - estradiol led to the up-regulation of 19 genes and down-regulation of 18 genes. The eef1b and rps4x was most suitable as controls for quantitative real-time PCR (qPCR) using Reffinder. Different expression genes enrichment analysis found that exposed to 2 µg/L 17 ß - estradiol affected various physiological processes, including spliceosome, phototransduction, amino sugar and nuclear sugar metabolism, hypotaurine metabolism, and renin-angiotensin system, etc. Exposing O. curvinotus juveniles to increasing concentrations of 17 ß - estradiol (2 ng/L, 20 ng/L, 200 ng/L and 2 µg/L) led to significant up-regulation of vitellogenins (vtgs) and choriogenins (chgs) mRNA expression. The present study is the first high-throughput transcriptome sequencing of O. curvinotus juveniles, which will be useful for future functional analysis of genes related to environmental estrogen exposed, and development of biomarkers.


Assuntos
Proteínas do Ovo/metabolismo , Estradiol/toxicidade , Proteínas de Peixes/metabolismo , Oryzias/metabolismo , Precursores de Proteínas/metabolismo , Vitelogeninas/metabolismo , Animais , Biomarcadores/metabolismo , Proteínas do Ovo/genética , Proteínas de Peixes/genética , Precursores de Proteínas/genética , Transcriptoma , Vitelogeninas/genética
16.
Artigo em Inglês | MEDLINE | ID: mdl-32352404

RESUMO

Background 3-(Para-fluorobenzoyl)-propionic acid (3PFBPA) is one of the metabolites of haloperidol used in the treatment of psychotic disorders. 3PFBPA is an inhibitor of mitogen-activated protein kinase (MAPK), implicated in the development of uterine fibroids (UFs) and cellular proliferation. In this study, the effect of 3PFBPA on oestradiol valerate (OV)-induced uterine hyperplasia was investigated. Methods Uterine hyperplasia was induced by intraperitoneal (i.p.) injection of OV (3 mg/kg for 12 weeks). Expression of oestrogen receptor (ER) α, ß-catenin and E-cadherin were investigated via immunohistochemistry. The histology and fibroblast cell count/µm2 (using histomorphometry) were carried out. Results There was a significant increase in the levels of oestrogen, progesterone and total cholesterol in the OV-treated group when compared with the control, assessed by enzyme-linked immunosorbent assay (ELISA) kits. Oestrogen and total cholesterol were markedly reduced in the OV + 3PFBPAtreated group when compared with the OV-treated group. The OV-induced overexpression of ß-catenin and ER were also ameliorated by 3PFBPA. Also, the loss of E-cadherin function in the OV-treated group was restored by 3PFBPA. The histological findings and histomorphometric results revealed the presence of uterine hyperplasia in the OV-treated rats which was significantly reversed by 3PFBPA. Histological studies revealed a protective role against OV-induced uterine damage that was found after OV + 3PFBPA co-administration. Conclusion This study demonstrated that 3PFBPA ameliorates OV-induced uterine hyperplasia in the female Wistar rat model. The findings warrant further investigation of the antifibrotic effects of 3PFBPA in humans.


Assuntos
Estradiol/toxicidade , Haloperidol/farmacologia , Propionatos/farmacologia , Receptores de Estrogênio/metabolismo , Útero/efeitos dos fármacos , Útero/patologia , Animais , Antipsicóticos/farmacologia , Proliferação de Células/efeitos dos fármacos , Estrogênios/toxicidade , Feminino , Hiperplasia/metabolismo , Hiperplasia/patologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Útero/metabolismo
17.
J Hazard Mater ; 394: 122537, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32203715

RESUMO

Environmental estrogens, including bisphenol A (BPA) and 17ß-estradiol (E2), which are widely used in industries and medicine, pose a severe ecological threat to fish due to feminization induction. However, the related metabolic basis for reproductive feminization in male fish has not been well addressed. We first found that female zebrafish exhibited higher lipid accumulation and lipogenesis activity than males. Next, we exposed male and female zebrafish to E2 (200 ng/L) or BPA (100 µg/L) for six weeks, and observed an early-phase reproductive feminization in males, accompanied with reduced spermatids, significant fat deposition and lipogenic gene expressions that mimicked female patterns. Cellular signaling assays revealed that, E2 or BPA modulated lipid metabolism in males mainly through lowering 5' AMP-activated protein kinase (AMPK) and upregulating the lipogenic mechanistic target of rapamycin (mTOR) pathways. For the first time, we show that environmental estrogens could alter lipid metabolism in male fish to a female pattern (metabolic feminization) prior to gonad feminization in male fish, to allows males to accumulate efficiently lipids to harmonize with the feminized gonads. This study suggests that negative effects of environmental estrogens, as hazardous materials, on vertebrate health are more complicated than originally thought.


Assuntos
Compostos Benzidrílicos/toxicidade , Estradiol/toxicidade , Estrogênios não Esteroides/toxicidade , Feminização/induzido quimicamente , Metabolismo dos Lipídeos/efeitos dos fármacos , Fenóis/toxicidade , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Feminino , Peixes , Gônadas/efeitos dos fármacos , Masculino , Serina-Treonina Quinases TOR/metabolismo , Transcrição Genética/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade
18.
Environ Pollut ; 261: 114208, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32097791

RESUMO

The molecular mechanism of evaluating 17ß-estradiol (E2)-induced toxicity in female Daphnia magna has not been determined. In this study, the transcriptome of D. magna was analyzed after exposure to three different concentrations (0, 10, and 100 ng L-1) of E2 at 3, 6, and 12 h. The results showed 351-17,221 significantly up-regulated and 505-10,282 significantly down-regulated genes (P < 0.05). Overall, the selected largest 10,282 (10 ng L-1vs control at 12 h) down-regulated and 17,221 (100 vs 10 ng L-1) up-regulated genes were identified; following annotation, pathways in cancer and RNA transport were found to be enriched according to the interaction network. Among all completed comparisons, KEGG pathways related to the immune system, cancer, disease infection, and active compound metabolism were identified by short time series expression miner analysis. A different set of genes fluctuated in a "U"-shaped pattern over time and at different concentrations of E2, whereas some genes associated with disintoxication showed a reverse "U"-shaped response as E2 administration was increased. These results suggest that E2 exposure caused transcriptional changes in the immune system, disintoxication, disease prevention, and the protein degradation pathway.


Assuntos
Daphnia , Exposição Ambiental , Estradiol , Transcriptoma , Animais , Daphnia/efeitos dos fármacos , Estradiol/toxicidade , Feminino , Transcriptoma/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade
19.
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
20.
Environ Toxicol Chem ; 39(4): 842-851, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32004384

RESUMO

Gonadal development in medaka (Oryzias latipes) is dependent on the synergy between estrogens and androgens. Disruption of steroid hormone levels can lead to ovo-testis. To determine the sensitive windows for hormonally induced sex reversal in medaka, we developed a novel 42sp50-GFP_ChgH-GFP transgenic medaka line, allowing the identification of female gonadal tissue by fluorescence present in developing oocytes. Germinal transgenesis resulted in a stable line exhibiting a strong green fluorescent protein signal constitutively in the ovaries and in the liver in response to estrogens. The sensitivity of this line to disruption of sex determination following 16-d chronic exposures was in the nanograms per liter range. To identify the developmental period sensitive to exogenous agents, fry were exposed to 24-h pulses of high concentrations of 17ß-estradiol (E2) or 5α-dihydrotestosterone (DHT) at various time points between days postfertilization (dpf) 0 and 12. Evaluation of phenotype followed by genotyping at 16 dpf revealed sensitivity to E2 between 1 and 8 dpf as well as 2 periods of susceptibility to DHT between 0 and 1 dpf and 4 and 8 dpf. No phenotypic sex reversal was detected after exposure to DHT or E2 on 11 or 12 dpf. The observed effects persisted to at least 24 dpf. The identified sensitive embryonic time periods for disruption of sex determination will aid future research on sex determination and the development of screening assays using early embryonic life stages. Environ Toxicol Chem 2020;39:842-851. © 2020 SETAC.


Assuntos
Animais Geneticamente Modificados/embriologia , Disruptores Endócrinos/toxicidade , Organogênese/efeitos dos fármacos , Oryzias/embriologia , Ovário/embriologia , Processos de Determinação Sexual/efeitos dos fármacos , Animais , Di-Hidrotestosterona/toxicidade , Estradiol/toxicidade , Feminino , Proteínas de Fluorescência Verde/genética , Masculino , Oryzias/metabolismo , Ovário/efeitos dos fármacos , Ovário/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...