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1.
Toxicol Sci ; 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38995844

RESUMO

Dibutyl phthalate (DBP), di-2-ethylhexyl phthalate (DEHP), and benzyl butyl phthalate (BBP) are used in personal and medical care products. In the ovary, antral follicles are essential for steroidogenesis and ovulation. DBP, BBP, and DEHP are known to inhibit mouse antral follicle growth and ovulation in vitro, and associate with decreased antral follicle counts in women. Given that the in vivo effects of a three-phthalate mixture on antral follicles are unknown, we evaluated the effects of a human relevant mixture of DBP, BBP, and DEHP on ovarian follicles through proteome profiling analysis. Adult CD-1 female mice were fed corn oil (vehicle), or two dose levels of a phthalate mixture based on estimated exposures in general (32 µg/kg/day; PHT 32) and occupationally exposed (500 µg/kg/day; PHT 500) populations for 10 days. Antral follicles (>250 µm) were isolated and subjected to proteome profiling via label-free tandem mass spectrometry. A total of 5,417 antral follicle proteins were detected, of which 194 were differentially abundant between vehicle and PHT 32, and 136 between vehicle and PHT 500. Bioinformatic analysis revealed significantly different responses between the two phthalate doses. Protein abundance differences in the PHT 32 exposure mapped to cytoplasm, mitochondria, and lipid metabolism; while those in the PHT 500 exposure mapped to cytoplasm, nucleus, and phosphorylation. When both doses altered proteins mapped to common processes, the associated predicted transcription factors were different. These findings provide novel mechanistic insight into phthalate-associated, ovary-driven reproductive outcomes in women.

2.
bioRxiv ; 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38464211

RESUMO

Introduction: Dibutyl phthalate (DBP), a phthalate congener, is widely utilized in consumer products and medication coatings. Women of reproductive age have a significant burden of DBP exposure through consumer products, occupational exposure, and medication. Prenatal DBP exposure is associated with adverse pregnancy/fetal outcomes and cardiovascular diseases in the offspring. However, the role of fetal sex and the general mechanisms underlying DBP exposure-associated adverse pregnancy outcomes are unclear. We hypothesize that prenatal DBP exposure at an environmentally relevant low dosage adversely affects fetal-placental development and function during pregnancy in a fetal sex-specific manner. Methods: Adult female CD-1 mice (8-10wks) were orally treated with vehicle (control) or with environmentally relevant low DBP dosages at 0.1 µg/kg/day (refer as DBP0.1) daily from 30 days before pregnancy through gestational day (GD) 18.5. Dam body mass composition was measured non-invasively using the echo-magnetic resonance imaging system. Lipid disposition in fetal labyrinth and maternal decidual area of placentas was examined using Oil Red O staining. Results: DBP0.1 exposure did not significantly affect the body weight and adiposity of non-pregnant adult female mice nor the maternal weight gain pattern and adiposity during pregnancy in adult female mice. DBP0.1 exposure does not affect fetal weight but significantly increased the placental weight at GD18.5 (indicative of decreased placental efficiency) in a fetal sex-specific manner. We further observed that DBP0.1 significantly decreased lipid disposition in fetal labyrinth of female, but not male placentas, while it did not affect lipid disposition in maternal decidual. Conclusions: Prenatal exposure to environmentally relevant low-dosage DBP adversely impacts the fetal-placental efficiency and lipid disposition in a fetal sex-specific manner.

3.
Toxicol Sci ; 195(1): 42-52, 2023 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-37439711

RESUMO

Phthalates are compounds used in consumer and medical products worldwide. Phthalate exposure in women has been demonstrated by detection of phthalate metabolites in their urine and ovarian follicular fluid. High urinary phthalate burden has been associated with reduced ovarian reserve and oocyte retrieval in women undergoing assisted reproduction. Unfortunately, no mechanistic explanation for these associations is available. In short term in vivo and in vitro animal studies modeling human-relevant exposures to di-n-butyl phthalate (DBP), we have identified ovarian folliculogenesis as a target for phthalate exposures. In the present study, we investigated whether DBP exposure negatively influences insulin-like growth factor 1 (IGF1) signaling in the ovary and disrupts ovarian folliculogenesis. CD-1 female mice were exposed to corn oil (vehicle) or DBP (10 µg/kg/day, 100 µg/kg/day, or 1000 mg/kg/day) for 20-32 days. Ovaries were collected as animals reached the proestrus stage to achieve estrous cycle synchronization. Levels of mRNAs encoding IGF1 and 2 (Igf1 and Igf2), IGF1 receptor (Igf1r), and IGF-binding proteins 1-6 (Ifgbp1-6) were measured in whole ovary homogenates. Ovarian follicle counts and immunostaining for phosphorylated IGF1R protein (pIGF1R) were used to evaluate folliculogenesis and IGF1R activation, respectively. DBP exposure, at a realistic dose that some women may experience (100 µg/kg/day for 20-32 days), reduced ovarian Igf1 and Igf1r mRNA expression and reduced small ovarian follicle numbers and primary follicle pIGF1R positivity in DBP-treated mice. These findings reveal that DBP tampers with the ovarian IGF1 system and provide molecular insight into how phthalates could influence the ovarian reserve in females.


Assuntos
Ovário , Ácidos Ftálicos , Humanos , Feminino , Camundongos , Animais , Dibutilftalato/toxicidade , Fator de Crescimento Insulin-Like I/genética
4.
bioRxiv ; 2023 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-36993736

RESUMO

Phthalates are compounds used in consumer and medical products worldwide. Phthalate exposure in women has been demonstrated by detection of phthalate metabolites in their urine and ovarian follicular fluid. High urinary phthalate burden has been associated with reduced ovarian reserve and oocyte retrieval in women undergoing assisted reproduction. Unfortunately, no mechanistic explanation for these associations is available. In short term in vivo and in vitro animal studies modeling human relevant exposures to di-n-butyl phthalate (DBP), we have identified ovarian folliculogenesis as a target for phthalate exposures. In the present study, we investigated whether DBP exposure negatively influences insulin-like growth factor 1 (IGF) signaling in the ovary and disrupts ovarian folliculogenesis. CD-1 female mice were exposed to corn oil (vehicle) or DBP (10 or 100 µg/kg/day) for 20-32 days. Ovaries were collected as animals reached the proestrus stage to achieve estrous cycle synchronization. Levels of mRNAs encoding IGF1 and 2 ( Igf1 and Igf2 ), IGF1 receptor ( Igf1r ), and IGF binding proteins 1-6 ( Ifgbp1-6 ) were measured in whole ovary homogenates. Ovarian follicle counts and immunostaining for phosphorylated IGF1R protein (pIGF1R) were used to evaluate folliculogenesis and IGF1R activation, respectively. DBP exposure, at a realistic dose that some women may experience (100 µg/kg/day for 20-32 days), reduced ovarian Igf1 and Igf1r mRNA expression and reduced small ovarian follicle numbers and primary follicle pIGF1R positivity in DBP-treated mice. These findings reveal that DBP tampers with the ovarian IGF1 system and provide molecular insight into how phthalates could influence the ovarian reserve in females.

5.
6.
Toxicol Sci ; 183(1): 117-127, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34175954

RESUMO

Humans are exposed to phthalates daily via items such as personal care products and medications. Reproductive toxicity has been documented in mice exposed to di-n-butyl phthalate (DBP); however, quantitative evidence of its metabolite, mono-n-butyl phthalate (MBP), reaching the mouse ovary and its effects on hepatic and ovarian biotransformation enzymes in treated mice is still lacking. Liquid chromatography/tandem mass spectrometry (LC-MS/MS) was employed to quantify MBP levels in liver, serum, and ovary from mice treated with a single or repeated exposure to the parent compound, DBP. Adult CD-1 females were pipet fed once or for 10 days with vehicle (tocopherol-stripped corn oil) or DBP at 1, 10, and 1000 mg/kg/day. Tissues and serum were collected at 2, 6, 12, and 24 h after the single or final dose and subjected to LC-MS/MS. Ovaries and livers were processed for qPCR analysis of selected phthalate-associated biotransformation enzymes. Regardless of duration of exposure (single vs repeated), MBP was detected in the tissues of DBP-treated mice. In single dose mice, MBP levels peaked at ≤6 h and fell close to background levels by 24 h post-exposure. Following the last repeated dose, MBP levels peaked at ≤2 h and fell to background levels by 12 h. Hepatic and ovarian expression of Lpl, Aldh1a1, Adh1, Ugt1a6a, and Cyp1b1 were altered in DBP-treated mice in a time- and dose-specific manner. These findings confirm that MBP reaches the mouse liver and ovary after oral exposure to DBP and influences the expression of hepatic and ovarian phthalate-associated biotransformation enzymes.


Assuntos
Ovário , Ácidos Ftálicos , Animais , Cromatografia Líquida , Dibutilftalato/toxicidade , Feminino , Fígado , Camundongos , Ácidos Ftálicos/toxicidade , Espectrometria de Massas em Tandem
8.
Data Brief ; 28: 105061, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31956671

RESUMO

Phthalates are industrial chemicals used as plasticizers in food packaging, medical devices, and toys, as well as cosmetics used primarily by women. Epidemiological studies in women and animal studies using rodents have reported associations between phthalate exposures and adverse reproductive health outcomes. Epigenetic mechanisms are thought to be involved in the ability of environmental contaminants to influence development of disease but evidence linking exposure to phthalates and uterine DNA methyltransferase activity are lacking. This article reports the activity of DNA methyltransferase (DNMT) enzymes in uteri from CD-1 mice treated with or without dibutyl phthalate (DBP), a phthalate commonly found in the urine of women of reproductive age. CD-1 mice were orally dosed with tocopherol-stripped corn oil (vehicle) or DBP at 10 µg/kg/day, 100 µg/kg/day and 1000 mg/kg/day daily for 10, 20, and 30 days. These dosages were selected based on estimates of human intake previously reported (10 and 100 µg/kg/day) and included a high dose (1000 mg/kg/day) for comparison with classical toxicity studies. At the end of 10, 20 or 30 days of daily oral dosing, animals were euthanized within 1-2 hours after the final dose. DNMT activity was determined by subjecting uterine nuclear extracts to a commercially-available DNMT activity ELISA assay and measuring optical density with a microplate spectrophotometer at a wavelength of 450 nm. Graph Pad Prism 8 was used for data analysis to determine the activity of DNMT enzymes at different time points and doses versus vehicle. The data presented serves as a resource for researchers working in the field of toxicology because it addresses a gap in knowledge of how exposure to environmental factors such as phthalate esters could produce epigenetic alterations in the uterus, which consequently may increase the risk of developing reproductive disease.

9.
Biol Reprod ; 101(4): 854-867, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31318015

RESUMO

Phthalates have a history of reproductive toxicity in animal models and associations with adverse reproductive outcomes in women. Human exposure to dibutyl phthalate (DBP) occurs via consumer products (7-10 µg/kg/day) and medications (1-233 µg/kg/day). Most DBP toxicity studies have focused on high supraphysiological exposure levels; thus, very little is known about exposures occurring at environmentally relevant levels. CD-1 female mice (80 days old) were treated with tocopherol-stripped corn oil (vehicle control) or DBP dissolved in oil at environmentally relevant (10 and 100 µg/kg/day) or higher (1000 µg/kg/day) levels for 30 days to evaluate effects on DNA damage response (DDR) pathway genes and folliculogenesis. DBP exposure caused dose-dependent effects on folliculogenesis and gene expression. Specifically, animals exposed to the high dose of DBP had more atretic follicles in their ovaries, while in those treated with environmentally relevant doses, follicle numbers were no different from vehicle-treated controls. DBP exposure significantly reduced the expression of DDR genes including those involved in homologous recombination (Atm, Brca1, Mre11a, Rad50), mismatch repair (Msh3, Msh6), and nucleotide excision repair (Xpc, Pcna) in a dose-specific manner. Interestingly, staining for the DNA damage marker, γH2AX, was similar between treatments. DBP exposure did not result in differential DNA methylation in the Brca1 promoter but significantly reduced transcript levels for the maintenance DNA methyltransferase, Dnmt1, in the ovary. Collectively, these findings show that oral exposure to environmentally relevant levels of DBP for 30 days does not significantly impact folliculogenesis in adult mice but leads to aberrant ovarian expression of DDR genes.


Assuntos
Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Dibutilftalato/farmacologia , Disruptores Endócrinos/farmacologia , Poluentes Ambientais/farmacologia , Ovário/efeitos dos fármacos , Animais , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Ciclo Estral/efeitos dos fármacos , Ciclo Estral/fisiologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Proteína 3 Homóloga a MutS/genética , Proteína 3 Homóloga a MutS/metabolismo , Ovário/metabolismo
10.
Reprod Toxicol ; 89: 100-106, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31306770

RESUMO

Propylparaben is prevalently used in cosmetics, pharmaceuticals, and foods; yet, its direct effects on the mammalian ovary are unknown. We investigated the direct effects of propylparaben on the growth and steroidogenic function of mouse antral follicles. Antral follicles were isolated from the ovaries of Swiss mice (age: 32-42 days) and cultured in media with dimethylsulfoxide vehicle control or propylparaben (0.01-100 µg/mL) for 24-72 h. Follicle diameter was measured every 24 h to assess growth. Follicles and media were collected at 24 and 72 h for gene expression and hormone measurements. Propylparaben (100 µg/mL) significantly inhibited follicle growth (48-72 h). Further, propylparaben exposure increased expression of cell cycle regulators (Cdk4, Cdkn1a), an apoptotic factor (Bax), and a key steroidogenic regulator (Star). In media, propylparaben decreased accumulation of dehydroepiandrosterone-sulfate, but increased testosterone and 17ß-estradiol. Overall, our findings suggest that propylparaben disrupts antral follicle growth and steroidogenic function by altering the cell-cycle, apoptosis, and steroidogenesis pathways.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Hormônios Esteroides Gonadais/biossíntese , Folículo Ovariano/efeitos dos fármacos , Parabenos/toxicidade , Animais , Apoptose/genética , Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Expressão Gênica/efeitos dos fármacos , Técnicas In Vitro , Camundongos , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Regulação para Cima
11.
Comp Med ; 69(1): 16-21, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30591091

RESUMO

Transgenic TgMISIIR-TAg (TAg) mice express the oncogenic virus SV40 in Mullerian epithelial cells. Female TAg mice spontaneously develop epithelial ovarian carcinoma, the most common type of ovarian cancer in women. Female TAg mice are infertile, but the reason has not been determined. We therefore investigated whether female TAg mice undergo puberty, demonstrate follicular development, maintain regular cycles, and ovulate. Ovarian cancers in women commonly develop after menopause. The occupational chemical 4-vinylcyclohexene diepoxide (VCD) accelerates follicle degeneration in the ovaries of rats and mice, causing early ovarian failure. We therefore used VCD dosing of mice to develop an animal model for menopause. The purpose of this study was to characterize reproductive parameters in female TAg mice and to investigate whether the onset of ovarian failure due VCD dosing differed between female TAg and WT C57BL/6 mice. As in WT female mice, TAg female mice underwent puberty (vaginal opening) and developed cyclicity in patterns that were similar between the groups. Vehicle-only TAg mice had fewer ovulations (numbers of corpora lutea) than WT animals. VCD exposure delayed the onset of puberty (day of first estrus) in TAg as compared with WT mice. Morphologic evaluation of ovaries revealed many more degenerating follicles in TAg mice than WT mice, and more VCD-dosed TAg mice were in ovarian failure than VCD-dosed WT mice. These results suggest that despite showing similar onset of sexual maturation, TAg mice have increased follicular degeneration and fewer ovulations than WT. These features may contribute to the inability of female TAg mice to reproduce.


Assuntos
Variantes Farmacogenômicos , Reprodução/efeitos dos fármacos , Reprodução/genética , Animais , Cicloexenos/toxicidade , Estro/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Folículo Ovariano/efeitos dos fármacos , Compostos de Vinila/toxicidade
12.
Toxicol Sci ; 162(2): 349-360, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29281099

RESUMO

Personal care products (PCP) contain a myriad of chemicals generally formulated to provide a safe and beneficial use. Nonetheless, an increasing amount of laboratory animal and human studies indicate that some chemicals in PCP are associated with decreased hormone production, diminished ovarian reserve, ovarian cancer, and early pregnancy loss. The ovary is key to female fertility by providing the eggs and sex steroid hormones for fertilization and maintenance of reproductive function, respectively. Thus, understanding how chemicals in PCP affect the ovary will shed some light on their potential effects on female fertility. In this review, we provide an overview of: (1) ovarian function as a determinant of fertility in females, (2) the status of knowledge regarding the effects of seven common chemicals in PCP on the ovary, and (3) significant gaps in the literature along with opportunities to eliminate some of the gaps. Findings from the limited existing data suggest that chemicals in PCP such as dibutyl phthalate can reach the ovary in humans and impact its function in animal models. Unfortunately, it is still difficult to assess how relevant findings of experimental studies are to women because of lack of human exposure data for most of these chemicals and the lack of studies that mimic real-life exposures. In contrast to chemicals such as bisphenol A and dioxin, the investigation of the effects of chemicals in PCP on reproductive function is still limited and warrants further investigation to fill existing data gaps.


Assuntos
Cosméticos , Disruptores Endócrinos/toxicidade , Ovário/efeitos dos fármacos , Animais , Cosméticos/química , Cosméticos/normas , Feminino , Fertilidade/efeitos dos fármacos , Humanos , Ovário/patologia
13.
Biol Reprod ; 96(5): 1105-1117, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28486587

RESUMO

Dibutyl phthalate (DBP) is present in consumer products and the coating of some oral medications. Acetyl tributyl citrate (ATBC) has been proposed as an alternative to DBP because DBP causes endocrine disruption in animal models. Following ingestion, DBP is converted to its main metabolite mono-butyl phthalate (MBP) which has been detected in >90% of human follicular fluid samples. Previous studies show that DBP reduces the number of antral follicles present in the ovaries of mice. Thus, this study was designed to evaluate the effects of DBP, MBP, and ATBC on in vitro growth and viability of mouse ovarian antral follicles. Antral follicles were isolated from CD-1 females (PND32-37) and treated with vehicle, DBP, MBP, or ATBC (starting at 0.001 and up to 1000 µg/ml for DBP; 24-72 h). Follicle diameter, ATP production, qPCR, and TUNEL were used to measure follicle growth, viability, cell cycle and apoptosis gene expression, and cell death-associated DNA fragmentation, respectively. While MBP did not cause toxicity, DBP exposure at ≥10 µg/ml resulted in growth inhibition followed by cytoxicity at ≥500 µg/ml. ATBC increased the number of nongrowing follicles at 0.01 µg/ml and did not affect ATP production, but increased TUNEL positive area in treated follicles. Gene expression results suggest that cytotoxicity in DBP-treated follicles occurs via activation of cell cycle arrest prior to follicular death. These findings suggest that concentrations of DBP ≥10 µg/ml are detrimental to antral follicles and that ATBC should be examined further as it may disrupt antral follicle function at low concentrations.


Assuntos
Citratos/toxicidade , Dibutilftalato/toxicidade , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/crescimento & desenvolvimento , Plastificantes/toxicidade , Trifosfato de Adenosina/biossíntese , Animais , Proteínas Reguladoras de Apoptose/biossíntese , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Camundongos
14.
J Appl Toxicol ; 37(6): 668-675, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27866379

RESUMO

Acetyl tributyl citrate (ATBC), is a phthalate substitute used in food and medical plastics, cosmetics and toys. Although systemically safe up to 1000 mg kg-1 day-1 , its ability to cause reproductive toxicity in females at levels below 50 mg kg-1 day-1 has not been examined. This study evaluated the effects of lower ATBC exposures on female reproduction using mice. Adult CD-1 females (n = 7-8 per treatment) were dosed orally with tocopherol-stripped corn oil (vehicle), 5 or 10 mg kg-1 day-1 ATBC daily for 15 days, and then bred with a proven breeder male. ATBC exposure did not alter body weights, estrous cyclicity, and gestational and litter parameters. Relative spleen weight was slightly increased in the 5 mg kg-1 day-1 group. ATBC at 10 mg kg-1 day-1 targeted ovarian follicles and decreased the number of primordial, primary and secondary follicles present in the ovary. These findings suggest that low levels of ATBC may be detrimental to ovarian function, thus, more information is needed to understand better the impact of ATBC on female reproduction. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Citratos/toxicidade , Exposição Materna/efeitos adversos , Ovário/efeitos dos fármacos , Plastificantes/toxicidade , Reprodução/efeitos dos fármacos , Administração Oral , Animais , Relação Dose-Resposta a Droga , Feminino , Camundongos Endogâmicos , Tamanho do Órgão/efeitos dos fármacos , Ovário/patologia
15.
Reprod Toxicol ; 53: 15-22, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25765776

RESUMO

Di-n-butyl phthalate (DBP) is present in many beauty and medical products. Human exposure estimates range from 0.007-0.01 mg/kg/day in the general population and up to 0.233 mg/kg/day in patients taking DBP-coated medications. Levels of phthalates tend to be higher in women, thus, evaluating ovarian effects of DBP exposure is of great importance. Mice were given corn oil (vehicle) or DBP at 0.01, 0.1, and 1000 mg/kg/day (high dose) for 10 days to test whether DBP causes ovarian toxicity. Estrous cyclicity, steroidogenesis, ovarian morphology, and apoptosis and steroidogenesis gene expression were evaluated. DBP exposure decreased serum E2 at all doses, while 0.1DBP increased FSH, decreased antral follicle numbers, and increased mRNA encoding pro-apoptotic genes (Bax, Bad, Bid). Interestingly, mRNAs encoding the steroidogenic enzymes Hsd17b1, Cyp17a1 and Cyp19a1 were increased in all DBP-treated groups. These novel findings show that DBP can disrupt ovarian function in mice at doses relevant to humans.


Assuntos
Dibutilftalato/toxicidade , Ovário/efeitos dos fármacos , Plastificantes/toxicidade , 17-Hidroxiesteroide Desidrogenases/genética , Animais , Proteínas Reguladoras de Apoptose/genética , Sistema Enzimático do Citocromo P-450/genética , Estradiol/sangue , Ciclo Estral/efeitos dos fármacos , Feminino , Hormônio Foliculoestimulante/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio Luteinizante/sangue , Camundongos , Ovário/patologia , Fosfoproteínas/genética
16.
Reprod Toxicol ; 45: 45-51, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24412242

RESUMO

Mono-2-ethyhexyl phthalate (MEHP) is a metabolite of a plasticizer found in many consumer products. MEHP inhibits mouse ovarian follicle growth by reducing 17ß-estradiol (E2) production. Yet, whether MEHP causes follicle death (atresia) is unclear. We hypothesized that MEHP causes atresia by altering apoptosis gene expression, and that E2 co-treatment blocks these effects. Follicles were exposed to MEHP (0.36-36µM)±E2 for 48-96h to determine the effect of MEHP±E2 on atresia and gene expression. MEHP increased atresia, but this effect was blocked by co-treatment with E2. MEHP increased the expression of the pro-apoptotic gene Aifm1, but decreased that of the pro-apoptotic gene Bok and the anti-apoptotic gene Bcl2l10. E2 interfered with MEHP-induced changes in Aifm1 and Bcl2l10. Our findings suggest that decreased E2 levels are required for MEHP-induced follicle atresia and that Aifm1, Bok, and Bcl2l10 are involved in this process.


Assuntos
Apoptose/efeitos dos fármacos , Dietilexilftalato/análogos & derivados , Estradiol/farmacologia , Estrogênios/farmacologia , Folículo Ovariano/efeitos dos fármacos , Animais , Apoptose/genética , Fator de Indução de Apoptose/genética , Dietilexilftalato/toxicidade , Feminino , Expressão Gênica/efeitos dos fármacos , Camundongos , Folículo Ovariano/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética
17.
Toxicol Appl Pharmacol ; 272(3): 780-6, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23948739

RESUMO

Mono-hydroxy methoxychlor (mono-OH MXC) is a metabolite of the pesticide, methoxychlor (MXC). Although MXC is known to decrease antral follicle numbers, and increase follicle death in rodents, not much is known about the ovarian effects of mono-OH MXC. Previous studies indicate that mono-OH MXC inhibits mouse antral follicle growth, increases follicle death, and inhibits steroidogenesis in vitro. Further, previous studies indicate that CYP11A1 expression and production of progesterone (P4) may be the early targets of mono-OH MXC in the steroidogenic pathway. Thus, this study tested whether supplementing pregnenolone, the precursor of progesterone and the substrate for HSD3B, would prevent decreased steroidogenesis, inhibited follicle growth, and increased follicle atresia in mono-OH MXC-treated follicles. Mouse antral follicles were exposed to vehicle (dimethylsulfoxide), mono-OH MXC (10 µg/mL), pregnenolone (1 µg/mL), or mono-OH MXC and pregnenolone together for 96 h. Levels of P4, androstenedione (A), testosterone (T), estrone (E1), and 17ß-estradiol (E2) in media were determined, and follicles were processed for histological evaluation of atresia. Pregnenolone treatment alone stimulated production of all steroid hormones except E2. Mono-OH MXC-treated follicles had decreased sex steroids, but when given pregnenolone, produced levels of P4, A, T, and E1 that were comparable to those in vehicle-treated follicles. Pregnenolone treatment did not prevent growth inhibition and increased atresia in mono-OH MXC-treated follicles. Collectively, these data support the idea that the most upstream effect of mono-OH MXC on steroidogenesis is by reducing the availability of pregnenolone, and that adding pregnenolone may not be sufficient to prevent inhibited follicle growth and survival.


Assuntos
Atresia Folicular/efeitos dos fármacos , Inibidores do Crescimento/toxicidade , Inseticidas/toxicidade , Metoxicloro/análogos & derivados , Pregnenolona/administração & dosagem , Animais , Células Cultivadas , Feminino , Atresia Folicular/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Inibidores do Crescimento/administração & dosagem , Inibidores do Crescimento/antagonistas & inibidores , Humanos , Inseticidas/administração & dosagem , Metoxicloro/administração & dosagem , Metoxicloro/toxicidade , Camundongos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Resultado do Tratamento
18.
Reprod Toxicol ; 42: 58-67, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23928317

RESUMO

Bisphenol A (BPA) is an endocrine disruptor that inhibits growth of mouse ovarian follicles and disrupts steroidogenesis at a dose of 438µM. However, the effects of lower doses of BPA and its mechanism of action in ovarian follicles are unknown. We hypothesized that low doses of BPA inhibit follicular growth and decrease estradiol levels through the aryl hydrocarbon receptor (AHR) pathway. Antral follicles from wild-type and Ahr knock-out (AhrKO) mice were cultured for 96h. Follicle diameters and estradiol levels then were compared in wild-type and AhrKO follicles ± BPA (0.004-438µM). BPA inhibited follicle growth (110-438µM) and decreased estradiol levels (43.8-438µM) in wild-type and AhrKO follicles. However, at BPA 110µM, inhibition of growth in AhrKO follicles was attenuated compared to wild-type follicles. These data suggest that BPA may inhibit follicle growth partially via the AHR pathway, whereas its effects on estradiol synthesis likely involve other mechanisms.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Estradiol/metabolismo , Folículo Ovariano/efeitos dos fármacos , Fenóis/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Folículo Ovariano/crescimento & desenvolvimento , Folículo Ovariano/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptores de Hidrocarboneto Arílico/genética , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/genética
19.
Biol Reprod ; 88(1): 23, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23242528

RESUMO

Di-n-butyl phthalate (DBP) is present in many consumer products, such as infant, beauty, and medical products. Several studies have shown that DBP causes reproductive toxicity in rodents, but no studies have evaluated its effects on ovarian follicles. Therefore, we used a follicle culture system to evaluate the effects of DBP on antral follicle growth, cell cycle and apoptosis gene expression, cell cycle staging, atresia, and 17ß-estradiol (E(2)) production. Antral follicles were isolated from adult CD-1 mice and exposed to DBP at 1, 10, 100, and 1000 µg/ml for 24 or 168 h. Follicles treated with vehicle or DBP at 1-100 µg/ml grew over time, but DBP at 1000 µg/ml significantly suppressed follicle growth. Regardless of effect on follicle growth, DBP-treated follicles had decreased mRNA for cyclins D2, E1, A2, and B1 and increased p21. Levels of the proapoptotic genes Bax, Bad, and Bok were not altered by DBP treatment, but DBP 1000 µg/ml increased levels of Bid and decreased levels of the antiapoptotic gene Bcl2. DBP-treated follicles contained significantly more cells in G(1) phase, significantly less cells in S, and exhibited a trend for fewer cells in G(2). Although DBP did not affect E(2) production and atresia at 24 h, follicles treated with DBP had reduced levels of E(2) at 96 h and underwent atresia at 168 h. These data suggest that DBP targets antral follicles and alters the expression of cell cycle and apoptosis factors, causes cell cycle arrest, decreases E(2), and triggers atresia, depending on dose.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Dibutilftalato/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Animais , Relação Dose-Resposta a Droga , Poluentes Ambientais/toxicidade , Feminino , Camundongos , Folículo Ovariano/citologia , Plastificantes/toxicidade
20.
Biol Reprod ; 87(6): 152, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23077170

RESUMO

Mono-(2-ethylhexyl) phthalate (MEHP) is the active metabolite of the most commonly used plasticizer, di-(2-ethylhexyl) phthalate, and is considered to be a reproductive toxicant. However, little is known about the effects of MEHP on ovarian antral follicles. Thus, the present study tested the hypothesis that MEHP inhibits follicle growth via oxidative stress pathways. The data indicate that MEHP increases reactive oxygen species (ROS) levels and inhibits follicle growth in antral follicles, whereas N-acetylcysteine (NAC; an antioxidant) restores ROS levels to control levels and rescues follicles from MEHP-induced inhibition of follicle growth. To further analyze the mechanism by which MEHP induces oxidative stress and inhibits follicle growth, the expression and activities of various key antioxidant enzymes (copper/zinc superoxide dismutase [SOD1], glutathione peroxidase [GPX], and catalase [CAT]) and the expression of key cell-cycle regulators (Ccnd2, Ccne1, and Cdk4) and apoptotic regulators (Bcl-2 and Bax) were compared in control and MEHP-treated follicles. The data indicate that MEHP inhibits the expression and activities of SOD1 and GPX; does not inhibit Cat expression; inhibits the expression of Ccnd2, Ccne1, Cdk4, and Bcl-2; but increases the expression of Bax compared to controls. Furthermore, NAC blocks these toxic effects of MEHP. Collectively, these data suggest that MEHP induces oxidative stress by disrupting the activities of antioxidant enzymes. This may lead to decreased expression of cell-cycle regulators and antiapoptotic regulators and increased expression of proapoptotic factors, which then may lead to inhibition of follicle growth.


Assuntos
Dietilexilftalato/análogos & derivados , Disruptores Endócrinos/toxicidade , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/patologia , Estresse Oxidativo/efeitos dos fármacos , Plastificantes/toxicidade , Acetilcisteína/uso terapêutico , Animais , Proteínas Reguladoras de Apoptose/agonistas , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Ciclo Celular/agonistas , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Dietilexilftalato/antagonistas & inibidores , Dietilexilftalato/toxicidade , Regulação para Baixo/efeitos dos fármacos , Disruptores Endócrinos/química , Feminino , Sequestradores de Radicais Livres/uso terapêutico , Infertilidade Feminina/induzido quimicamente , Infertilidade Feminina/metabolismo , Infertilidade Feminina/patologia , Infertilidade Feminina/prevenção & controle , Camundongos , Camundongos Endogâmicos , Folículo Ovariano/metabolismo , Oxirredutases/antagonistas & inibidores , Oxirredutases/química , Oxirredutases/metabolismo , RNA Mensageiro/metabolismo , Distribuição Aleatória , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos
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