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1.
Sci Total Environ ; 838(Pt 3): 156386, 2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-35662599

RESUMO

Endocrine disruption results from exposure to chemicals that alter the function of the endocrine system in animals. Chronic 60 days of exposure to a low dose (0.1 µM) of ioxynil (IOX) or diethylstilbestrol (DES) via food was used to determine the effects of these chemicals on the physiology of the heart and thyroid follicles in juvenile zebrafish. Immunofluorescence analysis and subsequent 3D morphometric analysis of the zebrafish heart revealed that chronic exposure to IOX induced ventricle deformation and significant volume increase (p < 0.001). DES exposure caused a change in ventricle morphology, but volume was unaffected. Alongside, it was found that DES exposure upregulated endothelial related genes (angptl1b, mhc1lia, mybpc2a, ptgir, notch1b and vwf) involved in vascular homeostasis. Both IOX and DES exposure caused a change in thyroid follicle morphology. Notably, in IOX exposed juveniles, thyroid follicle hypertrophy was observed; and in DES-exposed fish, an enlarged thyroid field was present. In summary, chronic exposure of juvenile zebrafish to IOX and DES affected the heart and the thyroid. Given that both chemicals are able to change the morphology of the thyroid it indicates that they behave as endocrine disruptive chemicals (EDCs). Heart function dynamically changes thyroid morphology, and function and hence it is likely that the observed cardiac effects of IOX and DES are the source of altered thyroid status in these fish.


Assuntos
Disruptores Endócrinos , Peixe-Zebra , Animais , Dietilestilbestrol/toxicidade , Iodobenzenos , Nitrilas , Glândula Tireoide , Peixe-Zebra/fisiologia
2.
Artigo em Inglês | MEDLINE | ID: mdl-34639263

RESUMO

BACKGROUND: Psychiatric disorders in children exposed in utero to diethylstilbestrol (DES) are still debated. We report here the impact of DES prescribed to suppress lactation on the children born after such treatment and their progeny, focusing particularly on psychiatric disorders. CASE PRESENTATION: We report here an informative family in which one or more psychiatric problems (e.g., bipolarity, suicide attempts and suicide, eating disorders) were detected in all children of second-generation (DES-exposed children; n = 9), but for II-2 who died at the age of 26 years due to rupture of a congenital brain aneurysm, and were associated with non-psychiatric disorders (particularly, endometriosis and hypospadias). In the third generation, 10 out of 19 DES-exposed grandchildren had psychiatric disorders (autism spectrum disorder, bipolar disorder, dyspraxia and learning disabilities, mood and behavioral disorders, and eating disorders), often associated with comorbidities. In the fourth generation (7 DES-exposed great-grandchildren, aged between 0 and 18 years), one child had dyspraxia and autism spectrum disorder. The first daughter of the second generation (not exposed to DES) and her children and grandchildren did not have any psychiatric symptoms or comorbidities. CONCLUSIONS: To our knowledge, the high prevalence of psychiatric disorders of various severities in two, and likely three generations, including DES-free pregnancies and DES-exposed pregnancies from the same family, has never been reported. This work strengthens the hypothesis that in utero exposure to DES contributes to the pathogenesis of psychiatric disorders. It also highlights a multigenerational, and possibly transgenerational, effect of DES in neurodevelopment and psychiatric disorders.


Assuntos
Transtorno do Espectro Autista , Hipospadia , Transtornos Mentais , Efeitos Tardios da Exposição Pré-Natal , Adolescente , Criança , Pré-Escolar , Dietilestilbestrol/toxicidade , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Transtornos Mentais/induzido quimicamente , Transtornos Mentais/epidemiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
3.
Biomolecules ; 11(7)2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201983

RESUMO

Environmental estrogen is a substance that functions as an endocrine hormone in organisms and can cause endocrine system disruption. A typical environmental estrogen, diethylstilbestrol (DES), can affect normal sexual function and organism development. However, even though the effects of different exposure stages of DES on the endocrine system and gonadal development of zebrafish juveniles are unknown, sex determination is strongly influenced by endocrine-disrupting chemicals (EDCs). From 10-90 days post fertilization (dpf), juvenile zebrafish were exposed to DES (100 and 1000 ng/L) in three different stages (initial development stage (IDS), 10-25 dpf; gonadal differentiation stage (GDS), 25-45 dpf and gonadal maturity stage (GMS), 45-60 dpf). Compared with that of IDS and GMS, the growth indicators (body length, body weight, and others) decreased significantly at GDS, and the proportion of zebrafish females exposed to 100 ng/L DES was significantly higher (by 59.65%) than that of the control; in addition, the zebrafish were biased towards female differentiation. The GDS is a critical period for sex differentiation. Our results show that exposure to environmental estrogen during the critical gonadal differentiation period not only affects the development of zebrafish, but also affects the population development.


Assuntos
Dietilestilbestrol/toxicidade , Disruptores Endócrinos/toxicidade , Estrogênios não Esteroides/toxicidade , Gônadas/efeitos dos fármacos , Diferenciação Sexual/efeitos dos fármacos , Animais , Tamanho Corporal/efeitos dos fármacos , Tamanho Corporal/fisiologia , Feminino , Masculino , Diferenciação Sexual/fisiologia , Peixe-Zebra
4.
Int J Mol Sci ; 22(8)2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920546

RESUMO

Xenobiotic exposure during pregnancy and lactation has been linked to perinatal changes in male reproductive outcomes and other endocrine parameters. This pilot study wished to assess whether brief maternal exposure of rats to xenobiotics dibutyl phthalate (DBP) or diethylstilbestrol (DES) might also cause long-term changes in hypothalamic gene expression or in reproductive behavior of the resulting offspring. Time-mated female Sprague Dawley rats were given either DBP (500 mg/kg body weight, every second day from GD14.5 to PND6), DES (125 µg/kg body weight at GD14.5 and GD16.5 only), or vehicle (n = 8-12 per group) and mild endocrine disruption was confirmed by monitoring postnatal anogenital distance. Hypothalamic RNA from male and female offspring at PND10, PND24 and PND90 was analyzed by qRT-PCR for expression of aromatase, oxytocin, vasopressin, ER-alpha, ER-beta, kisspeptin, and GnRH genes. Reproductive behavior was monitored in male and female offspring from PND60 to PND90. Particularly, DES treatment led to significant changes in hypothalamic gene expression, which for the oxytocin gene was still evident at PND90, as well as in sexual behavior. In conclusion, maternal xenobiotic exposure may not only alter endocrine systems in offspring but, by impacting on brain development at a critical time, can have long-term effects on male or female sexual behavior.


Assuntos
Dibutilftalato/toxicidade , Dietilestilbestrol/toxicidade , Estrogênios não Esteroides/farmacologia , Hipotálamo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Comportamento Sexual Animal , Animais , Aromatase/genética , Aromatase/metabolismo , Feminino , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Kisspeptinas/genética , Kisspeptinas/metabolismo , Masculino , Ocitocina/genética , Ocitocina/metabolismo , Plastificantes/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Transcriptoma , Vasopressinas/genética , Vasopressinas/metabolismo
5.
Reprod Toxicol ; 101: 9-17, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33571642

RESUMO

Developmental exposure to endocrine disrupting chemicals can have negative consequences for reproductive health in both men and women. Our knowledge about how chemicals can cause adverse health outcomes in females is, however, poorer than our knowledge in males. This is possibly due to lack of sensitive endpoints to evaluate endocrine disruption potential in toxicity studies. To address this shortcoming we carried out rat studies with two well-known human endocrine disruptors, diethylstilbestrol (DES) and ketoconazole (KTZ), and evaluated the sensitivity of a series of endocrine related endpoints. Sprague-Dawley rats were exposed orally from gestational day 7 until postnatal day 22. In a range-finding study, disruption of pregnancy-related endpoints was seen from 0.014 mg/kg bw/day for DES and 14 mg/kg bw/day for KTZ, so doses were adjusted to 0.003; 0.006; and 0.0012 mg/kg bw/day DES and 3; 6; or 12 mg/kg bw/day KTZ in the main study. We observed endocrine disrupting effects on sensitive endpoints in male offspring: both DES and KTZ shortened anogenital distance and increased nipple retention. In female offspring, 0.0012 mg/kg bw/day DES caused slightly longer anogenital distance. We did not see effects on puberty onset when comparing average day of vaginal opening; however, we saw a subtle delay after exposure to both chemicals using a time-curve analysis. No effects on estrous cycle were registered. Our study shows a need for more sensitive test methods to protect the reproductive health of girls and women from harmful chemicals.


Assuntos
Dietilestilbestrol/toxicidade , Disruptores Endócrinos/toxicidade , Cetoconazol/toxicidade , Canal Anal/anormalidades , Animais , Feminino , Genitália/anormalidades , Humanos , Masculino , Troca Materno-Fetal , Mamilos/anormalidades , Gravidez , Ratos Sprague-Dawley , Maturidade Sexual , Testes de Toxicidade/métodos
6.
Toxicol In Vitro ; 72: 105088, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33429043

RESUMO

The present study investigated the developmental toxicity of diethylstilbestrol (DES) in the zebrafish embryotoxicity test (ZET). This was done to investigate whether the ZET would better capture the developmental toxicity of DES than the embryonic stem cells test (EST) that was previously shown to underpredict the DES-induced developmental toxicity as compared to in vivo data, potentially because the EST does not capture late events in the developmental process. The ZET results showed DES-induced growth retardation, cumulative mortality and dysmorphisms (i.e. induction of pericardial edema) in zebrafish embryos while the endogenous ERα agonist 17ß-estradiol (E2) showed only growth retardation and cumulative mortality with lower potency compared to DES. Furthermore, the DES-induced pericardial edema formation in zebrafish embryos could be counteracted by co-exposure with ERα antagonist fulvestrant, indicating that the ZET captures the role of ERα in the mode of action underlying the developmental toxicity of DES. Altogether, it is concluded that the ZET differentiates DES from E2 with respect to their developmental toxicity effects, while confirming the role of ERα in mediating the developmental toxicity of DES. Furthermore, comparison to in vivo data revealed that, like the EST, in a quantitative way also the ZET did not capture the relatively high in vivo potency of DES as a developmental toxicant.


Assuntos
Carcinógenos/toxicidade , Dietilestilbestrol/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Estradiol/toxicidade , Estrogênios/toxicidade , Teratógenos/toxicidade , Peixe-Zebra/anormalidades , Animais , Embrião não Mamífero/anormalidades , Feminino , Cabeça/anormalidades , Cardiopatias Congênitas/induzido quimicamente , Masculino , Cauda/anormalidades , Cauda/efeitos dos fármacos , Testes de Toxicidade , Saco Vitelino/anormalidades , Saco Vitelino/efeitos dos fármacos
7.
Differentiation ; 118: 107-131, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33176961

RESUMO

This paper reviews and provides new observations on the ontogeny of estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2) in developing human male and female internal and external genitalia. Included in this study are observations on the human fetal uterine tube, the uterotubal junction, uterus, cervix, vagina, penis and clitoris. We also summarize and report on the ontogeny of estrogen receptors in the human fetal prostate, prostatic urethra and epididymis. The ontogeny of ESR1 and ESR2, which spans from 8 to 21 weeks correlates well with the known "window of susceptibility" (7-15 weeks) for diethylstilbestrol (DES)-induced malformations of the human female reproductive tract as determined through examination of DES daughters exposed in utero to this potent estrogen. Our fairly complete mapping of the ontogeny of ESR1 and ESR2 in developing human male and female internal and external genitalia provides a mechanistic framework for further investigation of the role of estrogen in normal development and of abnormalities elicited by exogenous estrogens.


Assuntos
Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Estrogênios/metabolismo , Genitália Feminina/metabolismo , Genitália Masculina/metabolismo , Dietilestilbestrol/toxicidade , Desenvolvimento Embrionário/genética , Estrogênios/genética , Feminino , Feto , Genitália Feminina/anormalidades , Genitália Feminina/crescimento & desenvolvimento , Genitália Feminina/patologia , Genitália Masculina/anormalidades , Genitália Masculina/crescimento & desenvolvimento , Genitália Masculina/patologia , Humanos , Masculino
9.
Int J Mol Sci ; 21(11)2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32486162

RESUMO

Obstructive voiding disorder (OVD) occurs during aging in men and is often, but not always, associated with increased prostate size, due to benign prostatic hyperplasia (BPH), prostatitis, or prostate cancer. Estrogens are known to impact the development of both OVD and prostate diseases, either during early urogenital tract development in fetal-neonatal life or later in adulthood. To examine the potential interaction between developmental and adult estrogen exposure on the adult urogenital tract, male CD-1 mice were perinatally exposed to bisphenol A (BPA), diethylstilbestrol (DES) as a positive control, or vehicle negative control, and in adulthood were treated for 4 months with Silastic capsules containing testosterone and estradiol (T+E2) or empty capsules. Animals exposed to BPA or DES during perinatal development were more likely than negative controls to have urine flow/kidney problems and enlarged bladders, as well as enlarged prostates. OVD in adult T+E2-treated perinatal BPA and DES animals was associated with dorsal prostate hyperplasia and prostatitis. The results demonstrate a relationship between elevated exogenous estrogen levels during urogenital system development and elevated estradiol in adulthood and OVD in male mice. These findings support the two-hit hypothesis for the development of OVD and prostate diseases.


Assuntos
Compostos Benzidrílicos/toxicidade , Dietilestilbestrol/toxicidade , Estradiol/farmacologia , Fenóis/toxicidade , Testosterona/farmacologia , Obstrução Uretral/fisiopatologia , Animais , Bioensaio , Feminino , Hidronefrose , Rim/patologia , Masculino , Camundongos , Tamanho do Órgão , Gravidez , Prenhez , Efeitos Tardios da Exposição Pré-Natal , Próstata/patologia , Hiperplasia Prostática/patologia , Prostatite/patologia , Bexiga Urinária/patologia
10.
Stem Cell Rev Rep ; 16(5): 893-908, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32592162

RESUMO

Reproductive health of men has declined in recent past with reduced sperm count and increased incidence of infertility and testicular cancers mainly attributed to endocrine disruption in early life. Present study aims to evaluate whether testicular stem cells including very small embryonic-like stem cells (VSELs) and spermatogonial stem cells (SSCs) get affected by endocrine disruption and result in pathologies in adult life. Effect of treatment on mice pups with estradiol (20 µg on days 5-7) and diethylstilbestrol (DES, 2 µg on days 1-5) was studied on VSELs, SSCs and spermatogonial cells in adult life. Treatment affected spermatogenesis, tubules in Stage VIII & sperm count were reduced along with reduction of meiotic (4n) cells and markers (Prohibitin, Scp3, Protamine). Enumeration of VSELs by flow cytometry (2-6 µm, 7AAD-, LIN-CD45-SCA-1+) and qRT-PCR using specific transcripts for VSELs (Oct-4a, Sox-2, Nanog, Stella, Fragilis), SSCs (tOct-4, Gfra-1, Gpr-125) and early germ cells (Mvh, Dazl) showed several-fold increase but transition from c-Kit negative to c-Kit positive spermatogonial cells was blocked on D100 after treatment. Transcripts specific for apoptosis (Bcl2, Bax) remained unaffected but tumor suppressor (p53) and epigenetic regulator (NP95) transcripts showed marked disruption. 9 of 10 mice exposed to DES showed tumor-like changes. To conclude, endocrine disruption resulted in a tilt towards excessive self-renewal of VSELs (leading to testicular cancer after DES treatment) and blocked differentiation (reduced numbers of c-Kit positive cells, meiosis, sperm count and fertility). Understanding the underlying basis for infertility and cancer initiation from endogenous stem cells through murine modelling will hopefully improve human therapies in future.


Assuntos
Envelhecimento/patologia , Carcinogênese/patologia , Células-Tronco Embrionárias/patologia , Disruptores Endócrinos/toxicidade , Fertilidade/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/patologia , Espermatogênese/efeitos dos fármacos , Testículo/patologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinogênese/genética , Dietilestilbestrol/toxicidade , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Embrionárias/metabolismo , Feminino , Fertilidade/genética , Hormônio Foliculoestimulante/genética , Hormônio Foliculoestimulante/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio Luteinizante/genética , Hormônio Luteinizante/metabolismo , Masculino , Camundongos , Modelos Biológicos , Tamanho do Órgão/efeitos dos fármacos , Ploidias , Gravidez , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição SOX9/metabolismo , Espermatogênese/genética
11.
Arch Toxicol ; 94(6): 2081-2095, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32328699

RESUMO

We previously demonstrated the existence of a balance among steroid hormones, i.e. glucocorticoids and androgens, in RACK1 (receptor for activated C kinase 1) expression and innate immunity activation, which may offer the opportunity to use RACK1 expression as marker to evaluate immunotoxicity of hormone-active substances. Because of the existence of close interconnections between the different steroid hormone receptors with overlapping ligand specificities and signaling pathways, in this study, we wanted to investigate a possible effect of estrogenic active compounds, namely 17ß-estradiol, diethylstilbestrol, and zearalenone, on RACK-1 expression and innate immune responses using THP-1 cells as experimental model. All compounds increased RACK1 transcriptional activity as evaluated by reporter luciferase activity, mRNA expression as assessed by real time-PCR and protein expression by western blot analysis, which paralleled an increase in LPS-induced IL-8, TNF-α production, and CD86 expression, which we previously demonstrated to be dependent on RACK1/PKCß activation. As the induction of RACK1 expression can be blocked by the antagonist G15, induced by the agonist G1 and by the non-cell permeable 17ß-estradiol conjugated with BSA, a role of GPER (previously named GPR30) activation in estrogen-induced RACK1 expression could be demonstrated. In addition, a role of androgen receptor (AR) in RACK1 transcription was also demonstrated by the ability of flutamide, a nonsteroidal antiandrogen, to completely prevent diethylstilbestrol-induced RACK1 transcriptional activity and protein expression. Altogether, our data suggest that RACK1 may represent an interesting target of steroid-active compounds, and its evaluation may offer the opportunity to screen the immunotoxic potential of hormone-active substances.


Assuntos
Dietilestilbestrol/toxicidade , Estradiol/toxicidade , Estrogênios/toxicidade , Imunidade Inata/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Receptores de Quinase C Ativada/metabolismo , Zearalenona/toxicidade , Citocinas/metabolismo , Disruptores Endócrinos , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Proteínas de Neoplasias/genética , Estudo de Prova de Conceito , Receptores de Quinase C Ativada/genética , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Células THP-1 , Regulação para Cima
12.
J Toxicol Sci ; 45(3): 131-136, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32147636

RESUMO

Reproductive disorders in birds are the most characteristic effects of DDT contamination of wildlife. Experimental exposure of avian eggs to the estrogenic substance o,p'-DDT causes abnormal development of the reproductive tract (shortening of the left oviduct and aberrant development of the right oviduct) and eggshell thinning in mature birds, but it is still not known how eggshell thinning occurs in the abnormal oviduct. To fill this information gap, we examined the histology of the uterine part of the oviduct in Japanese quail treated in ovo with o,p'-DDT or a synthetic estrogen, diethylstilbestrol (DES), and we performed immunohistochemical staining for the calcium-binding proteins CALB1, SPP1, and TRPV6. Both o,p'-DDT-treated and DES-treated quail had few, and scattered, gland cells in the left uterus, unlike vehicle controls, in which gland cells tightly occupied the lamina propria. The aberrantly developed right uterus retained all the components of the normal left uterus, but in immature form. Immunostaining for CALB1, SPP1, and TRPV6 was greatly reduced by both o,p'-DDT and DES; SPP1 and TRPV6 immunostaining patterns, in particular, differed distinctly from those in the controls. These findings suggest that CALB1, SPP1, and TRPV6 are molecular factors, decreased production of which is responsible for eggshell thinning. Our findings also could contribute to understanding of the eggshell formation mechanism in birds.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , DDT/toxicidade , Casca de Ovo/efeitos dos fármacos , Oviductos/efeitos dos fármacos , Oviductos/metabolismo , Animais , Coturnix , Dietilestilbestrol/toxicidade , Casca de Ovo/patologia , Feminino , Oviductos/patologia
13.
Chemosphere ; 249: 126182, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32078850

RESUMO

An adverse tendency induced by the environmental estrogens in female reproductive health is one serious problem worldwide. Diethylstilbestrol (DES), as a synthetic estrogen, is still used as an animal growth stimulant in terrestrial livestock and aquaculture illegally. It has been reported to negatively affect ovarian function and oogenesis. Nevertheless, the mechanism and toxicity of DES on oocyte meiotic maturation are largely unknown. Herein, we found that DES (40 µM) intervened in mouse oocyte maturation and first polar body extrusion (PBE) was decreased in vitro. Cell cycle analysis showed meiotic process was disturbed with oocytes arrested at metaphase I (MI) stage after DES exposure. Further study showed that DES exposure disrupted the spindle assembly and chromosome alignment, which then continuously provoke the spindle assemble checkpoint (SAC). We also observed that the acetylation levels of α-tubulin were dramatically increased in DES-treated oocytes. In addition, the dynamics of actin were also affected. Moreover, the distribution patterns of estrogen receptor α (ERα) were altered in DES-treated oocyte, as indicated by the significant signals accumulation in the spindle area. However, ERα inhibitor failed to rescue the defects of oocyte maturation caused by DES. Of note, the same phenomenon was observed in estrogen-treated oocytes. Collectively, we showed that DES exposure lead to the oocyte meiotic failure via impairing the spindle assembly and chromosome alignment. Our research is helpful to understand how environmental estrogen affects female germ cells and contribute to design the potential therapies to preserve fertility especially for occupational exposure.


Assuntos
Dietilestilbestrol/toxicidade , Estrogênios não Esteroides/toxicidade , Animais , Processos de Crescimento Celular , Cromossomos , Feminino , Pontos de Checagem da Fase M do Ciclo Celular , Meiose/efeitos dos fármacos , Metáfase , Camundongos , Oócitos/metabolismo , Oogênese/efeitos dos fármacos , Fuso Acromático , Testes de Toxicidade , Tubulina (Proteína)/metabolismo
14.
Cell Biol Toxicol ; 36(5): 417-435, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32088792

RESUMO

Diethylstilbestrol (DES) is a synthetic estrogen and proven human teratogen and carcinogen reported to act via the estrogen receptor α (ERα). Since the endogenous ERα ligand 17ß-estradiol (E2) does not show these adverse effects to a similar extent, we hypothesized that DES' interaction with the ERα differs from that of E2. The current study aimed to investigate possible differences between DES and E2 using in vitro assays that detect ERα-mediated effects, including ERα-mediated reporter gene expression, ERα-mediated breast cancer cell (T47D) proliferation and ERα-coregulator interactions and gene expression in T47D cells. Results obtained indicate that DES and E2 activate ERα-mediated reporter gene transcription and T47D cell proliferation in a similar way. However, significant differences between DES- and E2-induced binding of the ERα to 15 coregulator motifs and in transcriptomic signatures obtained in the T47D cells were observed. It is concluded that differences observed in binding of the ERα with several co-repressor motifs, in downregulation of genes involved in histone deacetylation and DNA methylation and in upregulation of CYP26A1 and CYP26B1 contribute to the differential effects reported for DES and E2.


Assuntos
Dietilestilbestrol/toxicidade , Estradiol/farmacologia , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica , Coativadores de Receptor Nuclear/metabolismo , Motivos de Aminoácidos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dietilestilbestrol/química , Estradiol/química , Receptor alfa de Estrogênio/química , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Genes Reporter , Humanos , Ligação Proteica/efeitos dos fármacos , Transcriptoma/genética
15.
Toxicol Sci ; 173(1): 19-31, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31626307

RESUMO

The present study assessed the potential of a generic physiologically based kinetic (PBK) model to convert in vitro data for estrogenicity to predict the in vivo uterotrophic response in rats for diethylstibestrol (DES), ethinylestradiol (EE2), genistein (GEN), coumestrol (COU), and methoxychlor (MXC). PBK models were developed using a generic approach and in vitro concentration-response data from the MCF-7 proliferation assay and the yeast estrogen screening assay were translated into in vivo dose-response data. Benchmark dose analysis was performed on the predicted data and available in vivo uterotrophic data to evaluate the model predictions. The results reveal that the developed generic PBK model adequate defines the in vivo kinetics of the estrogens. The predicted dose-response data of DES, EE2, GEN, COU, and MXC matched the reported in vivo uterus weight response in a qualitative way, whereas the quantitative comparison was somewhat hampered by the variability in both in vitro and in vivo data. From a safety perspective, the predictions based on the MCF-7 proliferation assay would best guarantee a safe point of departure for further risk assessment although it may be conservative. The current study indicates the feasibility of using a combination of in vitro toxicity data and a generic PBK model to predict the relative in vivo uterotrophic response for estrogenic chemicals.


Assuntos
Bioensaio/métodos , Estrogênios/toxicidade , Útero/fisiologia , Animais , Cumestrol/toxicidade , Dietilestilbestrol/toxicidade , Relação Dose-Resposta a Droga , Estrona , Etinilestradiol/toxicidade , Feminino , Genisteína/toxicidade , Cinética , Metoxicloro/toxicidade , Modelos Biológicos , Fenóis , Ratos , Útero/efeitos dos fármacos
16.
Mol Cancer Res ; 17(12): 2369-2382, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31597742

RESUMO

Early-life exposure to estrogenic chemicals can increase cancer risk, likely by disrupting normal patterns of cellular differentiation. Female mice exposed neonatally to the synthetic estrogen diethylstilbestrol (DES) develop metaplastic and neoplastic uterine changes as adults. Abnormal endometrial glands express the oncofetal protein sine oculis homeobox 1 (SIX1) and contain cells with basal [cytokeratin (CK)14+/18-] and poorly differentiated features (CK14+/18+), strongly associating SIX1 with aberrant differentiation and cancer. Here, we tested whether SIX1 expression is necessary for abnormal endometrial differentiation and DES-induced carcinogenesis by using Pgr-cre to generate conditional knockout mice lacking uterine Six1 (Six1 d/d). Interestingly, corn oil (CO) vehicle-treated Six1 d/d mice develop focal endometrial glandular dysplasia and features of carcinoma in situ as compared with CO wild-type Six1 (Six1 +/+) mice. Furthermore, Six1 d/d mice neonatally exposed to DES had a 42% higher incidence of endometrial cancer relative to DES Six1 +/+ mice. Although DES Six1 d/d mice had >10-fold fewer CK14+/18- basal cells within the uterine horns as compared with DES Six1 +/+ mice, the appearance of CK14+/18+ cells remained a feature of neoplastic lesions. These findings suggest that SIX1 is required for normal endometrial epithelial differentiation, CK14+/18+ cells act as a cancer progenitor population, and SIX1 delays DES-induced endometrial carcinogenesis by promoting basal differentiation of CK14+/18+ cells. In human endometrial biopsies, 35% of malignancies showed CK14+/18+ expression, which positively correlated with tumor stage and grade and was not present in normal endometrium. IMPLICATIONS: Aberrant epithelial differentiation is a key feature in both the DES mouse model of endometrial cancer and human endometrial cancer. The association of CK14+/18+ cells with human endometrial cancer provides a novel cancer biomarker and could lead to new therapeutic strategies.


Assuntos
Dietilestilbestrol/toxicidade , Hiperplasia Endometrial/genética , Neoplasias do Endométrio/genética , Estrogênios/toxicidade , Proteínas de Homeodomínio/genética , Animais , Animais Recém-Nascidos , Carcinogênese/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Óleo de Milho/farmacologia , Dietilestilbestrol/farmacologia , Modelos Animais de Doenças , Hiperplasia Endometrial/induzido quimicamente , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/induzido quimicamente , Neoplasias do Endométrio/patologia , Endométrio/efeitos dos fármacos , Endométrio/patologia , Células Epiteliais/efeitos dos fármacos , Estrogênios/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Queratina-14/genética , Camundongos
17.
Artigo em Inglês | MEDLINE | ID: mdl-31561897

RESUMO

Phenolic groups of steroidal or nonsteroidal estrogens can redox cycle, leading to oxidative stress, where creation of reactive oxygen species are recognized as the main mechanism of their DNA damage properties. Dry olive (Olea europaea L.) leaf extract is known to contain bioactive and antioxidative components and to have an ability to modulate the effects of various oxidants in cells. The main goal of this study was to investigate antigenotoxic potential of a standardized dry olive leaf extract on DNA damage induced by 17ß-estradiol and diethylstilbestrol in human whole blood cells in vitro, using comet assay. Our results indicated that both hormones showed a genotoxic effect at a concentration of 100 µM (P < 0.05, n = 6). Dry olive leaf extract was efficient in reducing number of cells with estrogen-induced DNA damage at tested concentrations (0.125, 0.5 and 1 mg/mL) (P < 0.05, n = 6) and under two experimental protocols, pre-treatment and post-treatment, exhibiting antigenotoxic properties. Analysis of antioxidant properties of the extract revealed moderate ABTS radical scavenging properties and reducing power. Overall, our results suggested that the protective potential of dry olive leaf extract could arise from the synergistic effect of its scavenging activity and enhancement of the cells' antioxidant capacity.


Assuntos
Antioxidantes/farmacologia , Células Sanguíneas/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Dietilestilbestrol/antagonistas & inibidores , Estradiol/toxicidade , Antagonistas de Estrogênios/farmacologia , Sequestradores de Radicais Livres/farmacologia , Olea/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Adulto , Ensaio Cometa , Dietilestilbestrol/toxicidade , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Oxirredução , Estresse Oxidativo , Extratos Vegetais/isolamento & purificação , Espécies Reativas de Oxigênio , Adulto Jovem
18.
Epidemiology ; 30(5): 679-686, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31259848

RESUMO

BACKGROUND: Prenatal exposure to diethylstilbestrol (DES), an endocrine-disrupting chemical, may be associated with depression in adulthood, but previous findings are inconsistent. METHODS: Women (3,888 DES exposed and 1,729 unexposed) and men (1,021 DES exposed and 1,042 unexposed) participating in the National Cancer Institute (NCI) DES Combined Cohort Follow-up Study were queried in 2011 for any history of depression diagnosis or treatment. Hazard ratios (HRs; 95% confidence intervals [CIs]) estimated the associations between prenatal DES exposure and depression risk. RESULTS: Depression was reported by 993 (26%) exposed and 405 (23%) unexposed women, and 177 (17%) exposed and 181 (17%) unexposed men. Compared with the unexposed, HRs for DES and depression were 1.1 (95% CI = 0.9, 1.2) in women and 1.0 (95% CI = 0.8, 1.2) in men. For medication-treated depression, the HRs (CIs) were 1.1 (0.9, 1.2) in women and 0.9 (0.7, 1.2) in men. In women, the HR (CI) for exposure to a low cumulative DES dose was 1.2 (1.0, 1.4), and for DES exposure before 8 weeks' gestation was 1.2 (1.0, 1.4). In men, the HR for low dose was 1.2 (95% CI = 0.9, 1.6) and there was no association with timing. In women, associations were uninfluenced by the presence of DES-related vaginal epithelial changes or a prior diagnosis of DES-related adverse outcomes. CONCLUSIONS: Prenatal DES exposure was not associated overall with risk of depression in women or men. In women, exposure in early gestation or to a low cumulative dose may be weakly associated with an increased depression risk.


Assuntos
Depressão/induzido quimicamente , Dietilestilbestrol/toxicidade , Disruptores Endócrinos/toxicidade , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Idoso , Depressão/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Efeitos Tardios da Exposição Pré-Natal/psicologia , Estudos Retrospectivos , Fatores de Risco , Autorrelato
19.
Arch Toxicol ; 93(7): 2021-2033, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31119342

RESUMO

In the present study, we evaluated an alternative testing strategy to quantitatively predict the in vivo developmental toxicity of the synthetic hormone diethylstilbestrol (DES). To this end, a physiologically based kinetic (PBK) model was defined that was subsequently used to translate concentration-response data for the in vitro developmental toxicity of DES, obtained in the ES-D3 cell differentiation assay, into predicted in vivo dose-response data for developmental toxicity. The previous studies showed that the PBK model-facilitated reverse dosimetry approach is a useful approach to quantitatively predict the developmental toxicity of several developmental toxins. The results obtained in the present study show that the PBK model adequately predicted DES blood concentrations in rats. Further studies revealed that DES tested positive in the ES-D3 differentiation assay and that DES-induced inhibition of the ES-D3 cell differentiation could be counteracted by the estrogen receptor alpha (ERα) antagonist fulvestrant, indicating that the in vitro ES-D3 cell differentiation assay was able to mimic the role of ERα reported in the mode of action underlying the developmental toxicity of DES in vivo. In spite of this, combining these in vitro data with the PBK model did not adequately predict the in vivo developmental toxicity of DES in a quantitative way. It is concluded that although the EST qualifies DES as a developmental toxin and detects the role of ERα in this process, the ES-D3 cell differentiation assay of the EST apparently does not adequately capture the processes underlying DES-induced developmental toxicity in vivo.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Dietilestilbestrol/toxicidade , Células-Tronco Embrionárias/efeitos dos fármacos , Modelos Biológicos , Animais , Linhagem Celular , Dietilestilbestrol/administração & dosagem , Dietilestilbestrol/farmacocinética , Relação Dose-Resposta a Droga , Células-Tronco Embrionárias/citologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley
20.
Biol Reprod ; 101(2): 392-404, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141131

RESUMO

Both membrane and nuclear fractions of estrogen receptor 1 (ESR1) mediate 17ß-estradiol (E2) actions. Mice expressing nuclear (n)ESR1 but lacking membrane (m)ESR1 (nuclear-only estrogen receptor 1 [NOER] mice) show reduced E2 responsivity and reproductive abnormalities culminating in adult male and female infertility. Using this model, we investigated whether reproductive pathologies caused by the synthetic estrogen diethylstilbestrol (DES) are mitigated by mESR1 ablation. Homozygous and heterozygous wild-type (WT and HET, respectively) and NOER male and female mice were subcutaneously injected with DES (1 mg/kg body weight [BW]) or vehicle daily from postnatal day (PND) 1-5. Uterine histology was assessed in select DES-treated females at PND 5, whereas others were ovariectomized at PND 60 and treated with E2 (10 µg/kg BW) or vehicle 2 weeks later. Neonatal DES exposure resulted in ovary-independent epithelial proliferation in the vagina and uterus of WT but not NOER females. Neonatal DES treatment also induced ovary-independent adult expression of classical E2-induced transcripts (e.g., lactoferrin [Ltf] and enhancer of zeste homolog 2 [Ezh2]) in WT but not NOER mice. At PND 90, DES-treated WT and HET males showed smaller testes and a high incidence of bacterial pyogranulomatous inflammation encompassing the testes, epididymis and occasionally the ductus deferens with spread to lumbar lymph nodes; such changes were largely absent in NOER males. Results indicate that male and female NOER mice are protected from deleterious effects of neonatal DES, and thus mESR1 signaling is required for adult manifestation of DES-induced reproductive pathologies in both sexes.


Assuntos
Dietilestilbestrol/toxicidade , Receptor alfa de Estrogênio/genética , Estrogênios não Esteroides/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Doenças dos Genitais Masculinos/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Útero/metabolismo
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