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Neonicotinoids are some of the most widely used insecticides in the world because they broadly target chewing and sucking insects. Neonicotinoids are used in commercial agricultural systems, sold for use in home gardens, and found in veterinary pharmaceuticals in the form of flea and tick preventatives for companion animals. They are also used as crop seed treatments and spread throughout crops as they mature. As a result, humans, wildlife, livestock, and pets are routinely exposed to neonicotinoids through consumption of contaminated food and water as well as through use of some veterinary pharmaceuticals. Although several studies indicate that neonicotinoid exposure causes genotoxicity, neurotoxicity, hepatotoxicity, and immunotoxicity in some non-target species, the impact of neonicotinoid pesticides on the male and female reproductive systems in mammals is largely understudied. This review summarizes current insights on the impact of common neonicotinoid pesticides such as acetamiprid, clothianidin, imidacloprid, and thiacloprid on male and female reproductive health in mammals. The review also summarizes the impacts of exposure to mixtures of neonicotinoids on reproductive endpoints. In addition, this review highlights where gaps in research on neonicotinoid pesticides and reproductive health exist so that future studies can be designed to fill current gaps in knowledge.
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Phthalate monoesters have been identified as endocrine disruptors in a variety of models, yet understanding of their exact mechanisms of action and molecular targets in cells remains incomplete. Here, we set to determine whether epidemiologically relevant mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) can affect biological processes by altering cell plasma membrane fluidity or formation of cell-cell contacts. As a model system, we chose endometrial stromal cell lines, one of which was previously used in a transcriptomic study with MEHHP or MEHHP-containing mixtures. A short-term exposure (1â¯h) of membrane preparations to endocrine disruptors was sufficient to induce changes in membrane fluidity/rigidity, whereas different mixtures showed different effects at various depths of the bilayer. A longer exposure (96â¯h) affected the ability of cells to form spheroids and highlighted issues with membrane integrity in loosely assembled spheroids. Finally, in spheroids assembled from T-HESC cells, MEHHP interfered with the formation of cell-cell contacts as indicated by the immunostaining of zonula occludens 1 protein. Overall, this study emphasized the need to consider plasma membrane, membrane-bound organelles, and secretory vesicles as possible biological targets of endocrine disruptors and offered an explanation for a multitude of endocrine disruptor roles documented earlier.
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Phthalates, synthetic chemicals widely utilized as plasticizers and stabilizers in various consumer products, present a significant concern due to their persistent presence in daily human life. While past research predominantly focused on individual phthalates, real-life human exposure typically encompasses complex mixtures of these compounds. The cumulative effects of prolonged exposure to phthalate mixtures on uterine health remain poorly understood. To address this knowledge gap, we conducted studies utilizing adult female mice exposed to a phthalate mixture for 6 and 12 months through ad libitum chow consumption. We previously reported that continuous exposure to this phthalate mixture for 6 months led to uterine fibrosis. In this study, we show that the exposure, when continued beyond 6 months to 1 year, caused fibrotic uteri to display hyperplasia with a significant increase in gland to stroma ratio. Endometrial hyperplasia is commonly caused by unopposed estrogen action, which promotes increased expression of pro-inflammatory cytokines and chemokines and proliferation of the endometrial epithelial cells. Indeed, RNA sequencing analysis revealed a marked upregulation of several estrogen-regulated genes, Wnt ligands that are involved in oncogenic pathways, as well as chemokines, in phthalate-exposed uterine tissues. Consequently, the exposed uteri exhibited increased proliferation of endometrial epithelial cells, and a heightened inflammatory response indicated by extensive homing of macrophages. Further studies revealed a marked enhancement of the Wnt/ß-Catenin signaling pathway, potentially contributing to the development of endometrial hyperplasia. Collectively, this study underscores the significance of understanding the exposure to environmental factors in the pathogenesis of endometrial disorders.
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In brief: This review article highlights the associations between endocrine-disrupting chemicals, reproductive aging, and menopause. Collectively, the current literature indicates that phthalates, bisphenols, parabens, per- and poly-fluoroalkyl substances, polychlorinated biphenyls, dioxins, and pesticides are associated with reproductive aging in women and animal models. Abstract: Menopause marks the end of a woman's reproductive lifetime and can have a significant effect on a woman's quality of life. Menopause naturally occurs at 51 years of age on average, but recent literature suggests that endocrine-disrupting chemicals (EDCs) in our environment can accelerate reproductive aging, causing women to reach menopause at earlier ages. This is concerning as menopause can significantly alter a woman's quality of life and is associated with increased risks of conditions such as depression, osteoporosis, and cardiovascular disease. EDC exposures have also been associated with more intense menopausal symptoms, making the menopausal transition more difficult for some women. This review highlights the associations between EDC exposure, early menopause, and reproductive aging, using both epidemiological and experimental studies.
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Envelhecimento , Disruptores Endócrinos , Exposição Ambiental , Menopausa , Reprodução , Humanos , Disruptores Endócrinos/efeitos adversos , Disruptores Endócrinos/toxicidade , Feminino , Menopausa/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Animais , Reprodução/efeitos dos fármacos , Envelhecimento/fisiologia , Poluentes Ambientais/toxicidade , Poluentes Ambientais/efeitos adversosRESUMO
Phthalates are endocrine disrupting chemicals (EDCs) found in common consumer products such as soft plastics and cosmetics. Although the knowledge regarding the adverse effects of phthalates on female fertility are accumulating, information on the hormone sensitive endometrium is still scarce. Here, we studied the effects of phthalates on endometrial cell proliferation and gene expression. Human endometrial primary epithelial and stromal cells were isolated from healthy fertile-aged women (n=3), and were compared to endometrial cell lines T-HESC and Ishikawa. Three different epidemiologically relevant phthalate mixtures were used, defined by urine samples in the Midlife Women Health Study (MWHS) cohort. Mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) was used as a single phthalate control. Cells were harvested for proliferation testing and transcriptomic analyses after 24â¯h exposure. Even though all cell models responded differently to the phthalate exposures, many overlapping differentially expressed genes (DEGs, FDR<0.1), related to cell adhesion, cytoskeleton and mitochondria were found in all cell types. The qPCR analysis confirmed that MEHHP significantly affected cell adhesion gene vinculin (VCL) and NADH:ubiquinone oxidoreductase subunit B7 (NDUFB7), important for oxidative phosphorylation. Benchmark dose modelling showed that MEHHP had significant concentration-dependent effects on cytoskeleton gene actin-beta (ACTB). In conclusion, short 24â¯h phthalate exposures significantly altered gene expression cell-specifically in human endometrial cells, with six shared DEGs. The mixture effects were similar to those of MEHHP, suggesting MEHHP could be the main driver in the mixture. Impact of phthalate exposures on endometrial functions including receptivity should be addressed.
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Proliferação de Células , Citoesqueleto , Disruptores Endócrinos , Endométrio , Mitocôndrias , Ácidos Ftálicos , Humanos , Feminino , Endométrio/efeitos dos fármacos , Endométrio/citologia , Endométrio/metabolismo , Citoesqueleto/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Mitocôndrias/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Adulto , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Linhagem Celular , Células Cultivadas , Poluentes Ambientais/toxicidade , Expressão Gênica/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Pessoa de Meia-IdadeRESUMO
Phthalates are used as plasticizers and solvents in consumer products. Virtually 100% of the US population has measurable exposure levels to phthalates, however, the mechanisms by which prenatal exposure to phthalate mixtures affects reproductive health in the offspring remain unclear. Thus, this study tested the hypothesis that prenatal exposure to an environmentally relevant phthalate mixture promotes inflammation in F1 ovarian tissue. Pregnant CD-1 dams were dosed orally with vehicle control (corn oil) or phthalate mixture (20 µg/kg/d, 200 µg/kg/d, 200 mg/kg/d, 500 mg/kg/d). Pregnant dams delivered pups naturally and ovaries and sera from the F1 females were collected at postnatal day (PND) 21, PND 60, 3 mo, and 6 mo. Sera were used to measure levels of C-reactive protein (CRP). Ovaries and sera were used for cytokine array analysis. RNA was isolated from F1 ovaries and used to quantify expression of selected cytokine genes. Prenatal exposure to the mixture significantly increased the levels of CRP at 200 µg/kg/d on PND 21 compared with controls. The mixture altered 6 immune factors in sera at PND 21 and 33 immune factors in the ovary and sera at 6 mo compared with controls. The mixture increased ovarian expression of cytokines at PND 21 and decreased ovarian expression of cytokines at 6 mo compared with controls. These data suggest that prenatal exposure to a phthalate mixture interferes with the immune response in F1 female mice long after initial exposure.
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Citocinas , Ovário , Ácidos Ftálicos , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Gravidez , Ovário/efeitos dos fármacos , Ovário/metabolismo , Citocinas/sangue , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/sangue , Ácidos Ftálicos/toxicidade , Camundongos , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Exposição Materna/efeitos adversos , Poluentes Ambientais/toxicidadeRESUMO
BACKGROUND: The menopausal transition involves significant sex hormone changes. Environmental chemicals, such as urinary phthalate metabolites, are associated with sex hormone levels in cross-sectional studies. Few studies have assessed longitudinal associations between urinary phthalate metabolite concentrations and sex hormone levels during menopausal transition. METHODS: Pre- and perimenopausal women from the Midlife Women's Health Study (MWHS) (n = 751) contributed data at up to 4 annual study visits. We quantified 9 individual urinary phthalate metabolites and 5 summary measures (e.g., phthalates in plastics (∑Plastic)), using pooled annual urine samples. We measured serum estradiol, testosterone, and progesterone collected at each study visit, unrelated to menstrual cycling. Linear mixed-effects models and hierarchical Bayesian kernel machine regression analyses evaluated adjusted associations between individual and phthalate mixtures with sex steroid hormones longitudinally. RESULTS: We observed associations between increased concentrations of certain phthalate metabolites and lower testosterone and higher sub-ovulatory progesterone levels, e.g., doubling of monoethyl phthalate (MEP), monobenzyl phthalate (MBzP), di-2-ethylhexyl phthalate (∑DEHP) metabolites, ∑Plastic, and ∑Phthalates concentrations were associated with lower testosterone (e.g., for ∑DEHP: -4.51%; 95% CI: -6.72%, -2.26%). For each doubling of MEP, certain DEHP metabolites, and summary measures, we observed higher mean sub-ovulatory progesterone (e.g., ∑AA (metabolites with anti-androgenic activity): 6.88%; 95% CI: 1.94%, 12.1%). Higher levels of the overall time-varying phthalate mixture were associated with lower estradiol and higher progesterone levels, especially for 2nd year exposures. CONCLUSIONS: Phthalates were longitudinally associated with sex hormone levels during the menopausal transition. Future research should assess such associations and potential health impacts during this understudied period.
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Poluentes Ambientais , Perimenopausa , Ácidos Ftálicos , Humanos , Ácidos Ftálicos/urina , Feminino , Pessoa de Meia-Idade , Estudos Longitudinais , Perimenopausa/sangue , Poluentes Ambientais/sangue , Poluentes Ambientais/urina , Estradiol/sangue , Adulto , Hormônios Esteroides Gonadais/sangue , Progesterona/sangue , Progesterona/urina , Exposição Ambiental/estatística & dados numéricos , Saúde da Mulher , Testosterona/sangueRESUMO
Neonicotinoids are the most widely used insecticides in the world. They are synthetic nicotine derivatives that act as nicotinic acetylcholine receptor agonists. Although parent neonicotinoids have low affinity for the mammalian nicotinic acetylcholine receptor, they can be activated in the environment and the body to positively charged metabolites with high affinity for the mammalian nicotinic acetylcholine receptor. Imidacloprid, the most popular neonicotinoid, and its bioactive metabolite desnitro-imidacloprid differentially interfere with ovarian antral follicle physiology in vitro, but their effects on ovarian nicotinic acetylcholine receptor subunit expression are unknown. Furthermore, ovarian nicotinic acetylcholine receptor subtypes have yet to be characterized in the ovary. Thus, this work tested the hypothesis that ovarian follicles express nicotinic acetylcholine receptors and their expression is differentially modulated by imidacloprid and desnitro-imidacloprid in vitro. We used polymerase chain reaction, RNA in situ hybridization, and immunohistochemistry to identify and localize nicotinic acetylcholine receptor subunits (α2, 4, 5, 6, 7 and ß1, 2, 4) expressed in neonatal ovaries (NO) and antral follicles. Chrnb1 was expressed equally in NO and antral follicles. Chrna2 and Chrnb2 expression was higher in antral follicles compared to NO and Chrna4, Chrna5, Chrna6, Chrna7, and Chrnb4 expression was higher in NO compared to antral follicles. The α subunits were detected throughout the ovary, especially in oocytes and granulosa cells. Imidacloprid and desnitro-imidacloprid dysregulated the expression of multiple nicotinic acetylcholine receptor subunits in NO, but only dysregulated one subunit in antral follicles. These data indicate that mammalian ovaries contain nicotinic acetylcholine receptors, and their susceptibility to imidacloprid and desnitro-imidacloprid exposure varies with the stage of follicle maturity.
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Inseticidas , Neonicotinoides , Folículo Ovariano , Receptores Nicotínicos , Feminino , Animais , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/genética , Neonicotinoides/farmacologia , Camundongos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Inseticidas/farmacologia , Nitrocompostos/farmacologia , Ovário/efeitos dos fármacos , Ovário/metabolismoRESUMO
BACKGROUND: The European Food Safety Authority (EFSA) recommended lowering their estimated tolerable daily intake (TDI) for bisphenol A (BPA) 20,000-fold to 0.2 ng/kg body weight (BW)/day. BPA is an extensively studied high production volume endocrine disrupting chemical (EDC) associated with a vast array of diseases. Prior risk assessments of BPA by EFSA as well as the US Food and Drug Administration (FDA) have relied on industry-funded studies conducted under good laboratory practice protocols (GLP) requiring guideline end points and detailed record keeping, while also claiming to examine (but rejecting) thousands of published findings by academic scientists. Guideline protocols initially formalized in the mid-twentieth century are still used by many regulatory agencies. EFSA used a 21st century approach in its reassessment of BPA and conducted a transparent, but time-limited, systematic review that included both guideline and academic research. The German Federal Institute for Risk Assessment (BfR) opposed EFSA's revision of the TDI for BPA. OBJECTIVES: We identify the flaws in the assumptions that the German BfR, as well as the FDA, have used to justify maintaining the TDI for BPA at levels above what a vast amount of academic research shows to cause harm. We argue that regulatory agencies need to incorporate 21st century science into chemical hazard identifications using the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) nonguideline academic studies in a collaborative government-academic program model. DISCUSSION: We strongly endorse EFSA's revised TDI for BPA and support the European Commission's (EC) apparent acceptance of this updated BPA risk assessment. We discuss challenges to current chemical risk assessment assumptions about EDCs that need to be addressed by regulatory agencies to, in our opinion, become truly protective of public health. Addressing these challenges will hopefully result in BPA, and eventually other structurally similar bisphenols (called regrettable substitutions) for which there are known adverse effects, being eliminated from all food-related and many other uses in the EU and elsewhere. https://doi.org/10.1289/EHP13812.
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Compostos Benzidrílicos , Fenóis , Humanos , Inocuidade dos Alimentos , Nível de Efeito Adverso não Observado , Revisões Sistemáticas como AssuntoRESUMO
Purpose: To investigate follicular fluid (FF) phthalate levels in adolescents undergoing fertility preservation compared to oocyte donors and explore its association with ovarian reserve and cumulus cell gene expression. Methods: 20 Adolescents (16.7 ± 0.6 years old) and 24 oocyte donors (26.2 ± 0.4 years old) undergoing fertility preservation were included in the study. Patient demographics, ovarian stimulation and oocyte retrieval outcomes were analyzed for each group. FF levels of 9 phthalate metabolites were assessed individually and as molar sums representative of common compounds (all phthalates: ΣPhthalates; DEHP: ΣDEHP), exposure sources (plastics: ΣPlastic; personal care products: ΣPCP), and modes of action (anti-androgenic: ΣAA) and compared between the two groups. Results: Follicular fluid ΣPlastic and ΣPCP levels were significantly higher in adolescents compared to oocyte donors (p<0.05). Follicular fluid ΣDEHP, ΣPlastic, ΣPCP, ΣAA, and ΣPhthalates levels were positively associated with antral follicle count (AFC) (p<0.05) in oocyte donors when adjusted for age, BMI, and race/ethnicity. RNA-seq analysis revealed 248 differentially expressed genes (DEGs) in cumulus cells of adolescents within the top quartile (n=4) of FF ΣPhthalates levels compared to the adolescents within the bottom half (n=9). Genes enriched in pathways involved in cell motility and development were significantly downregulated. Conclusion: Adolescents undergoing fertility preservation cycles demonstrate higher levels of phthalate metabolites in their follicular fluid compared to oocyte donors. Phthalate metabolite levels in FF are associated with higher AFC levels in oocyte donors. Higher phthalate levels in FF are associated with alterations in the cumulus cells transcriptome in adolescents.
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Prenatal exposure to Di (2-ethylhexyl) phthalate (DEHP) impairs the reproductive system and causes fertility defects in male offspring. Additionally, high-fat (HF) diet is a risk factor for reproductive disorders in males. In this study, we tested the hypothesis that prenatal exposure to a physiologically relevant dose of DEHP in conjunction with HF diet synergistically impacts reproductive function and fertility in male offspring. Female mice were fed a control or HF diet 7 days prior to mating and until their litters were weaned on postnatal day 21. Pregnant dams were exposed to DEHP or vehicle from gestational day 10.5 until birth. The male offspring's gross phenotype, sperm quality, serum hormonal levels, testicular histopathology, and testicular gene expression pattern were analyzed. Male mice born to dams exposed to DEHP + HF had smaller testes, epididymides, and shorter anogenital distance compared with those exposed to HF or DEHP alone. DEHP + HF mice had lower sperm concentration and motility compared with DEHP mice. Moreover, DEHP + HF mice had more apoptotic germ cells, fewer Leydig cells, and lower serum testosterone levels than DEHP mice. Furthermore, testicular mRNA expression of Dnmt1 and Dnmt3a was two to eight-fold higher than in DEHP mice by qPCR, suggesting that maternal HF diet and prenatal DEHP exposure additively impact gonadal function by altering the degree of DNA methylation in the testis. These results suggest that the combined exposure to DEHP and high-fat synergistically impairs reproductive function in male offspring, greater than exposure to DEHP or HF diet alone.
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Dieta Hiperlipídica , Dietilexilftalato , Efeitos Tardios da Exposição Pré-Natal , Testículo , Animais , Feminino , Masculino , Dietilexilftalato/toxicidade , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Dieta Hiperlipídica/efeitos adversos , Testículo/efeitos dos fármacos , Testículo/patologia , Espermatozoides/efeitos dos fármacosRESUMO
Di(2-ethylhexyl) phthalate and diisononyl phthalate are widely used as plasticizers in polyvinyl chloride products. Short-term exposures to phthalates affect hormone levels, ovarian follicle populations, and ovarian gene expression. However, limited data exist regarding the effects of long-term exposure to phthalates on reproductive functions. Thus, this study tested the hypothesis that short-term and long-term exposure to di(2-ethylhexyl) phthalate or diisononyl phthalate disrupts follicle dynamics, ovarian and pituitary gene expression, and hormone levels in female mice. Adult CD-1 female mice were exposed to vehicle, di(2-ethylhexyl) phthalate, or diisononyl phthalate (0.15 ppm, 1.5 ppm, or 1500 ppm) via the chow for 1 or 6 months. Short-term exposure to di(2-ethylhexyl) phthalate (0.15 ppm) and diisononyl phthalate (1.5 ppm) decreased serum follicle-stimulating hormone levels compared to control. Long-term exposure to di(2-ethylhexyl) phthalate and diisononyl phthalate (1500 ppm) increased the percentage of primordial follicles and decreased the percentages of preantral and antral follicles compared to control. Both phthalates increased follicle-stimulating hormone levels (di(2-ethylhexyl) phthalate at 1500 ppm; diisononyl phthalate at 1.5 ppm) and decreased luteinizing hormone levels (di(2-ethylhexyl) phthalate at 0.15 and 1.5 ppm; diisononyl phthalate at 1.5 ppm and 1500 ppm) compared to control. Furthermore, both phthalates altered the expression of pituitary gonadotropin subunit genes (Cga, Fshb, and Lhb) and a transcription factor (Nr5a1) that regulates gonadotropin synthesis. These data indicate that long-term exposure to di(2-ethylhexyl) phthalate and diisononyl phthalate alters follicle growth dynamics in the ovary and the expression of gonadotropin subunit genes in the pituitary and consequently luteinizing hormone and follicle-stimulating hormone synthesis.
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Dietilexilftalato , Ácidos Ftálicos , Camundongos , Animais , Feminino , Ácidos Ftálicos/toxicidade , Dietilexilftalato/toxicidade , Folículo Ovariano/metabolismo , Hormônio Foliculoestimulante/farmacologia , Hormônio Luteinizante/metabolismoRESUMO
Di(2-ethylhexyl) phthalate (DEHP) is a pervasive environmental toxicant used in the manufacturing of numerous consumer products, medical supplies, and building materials. DEHP is metabolized to mono(2-ethylhexyl) phthalate (MEHP). MEHP is an endocrine disruptor that adversely affects folliculogenesis and steroidogenesis in the ovary, but its mechanism of action is not fully understood. Thus, we tested the hypothesis that the aryl hydrocarbon receptor (AHR) plays a functional role in MEHP-mediated disruption of folliculogenesis and steroidogenesis. CD-1 mouse antral follicles were isolated and cultured with MEHP (0-400 µM) in the presence or absence of the AHR antagonist CH223191 (1 µM). MEHP treatment reduced follicle growth over a 96-h period, and this effect was partially rescued by co-culture with CH223191. MEHP exposure alone increased expression of known AHR targets, cytochrome P450 (CYP) enzymes Cyp1a1 and Cyp1b1, and this induction was blocked by CH223191. MEHP reduced media concentrations of estrone and estradiol compared to control. This effect was mitigated by co-culture with CH223191. Moreover, MEHP reduced the expression of the estrogen-sensitive genes progesterone receptor (Pgr) and luteinizing hormone/choriogonadotropin receptor (Lhcgr) and co-treatment with CH223191 blocked this effect. Collectively, these data indicate that MEHP activates the AHR to impair follicle growth and reduce estrogen production and signaling in ovarian antral follicles.
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Compostos Azo , Dietilexilftalato , Dietilexilftalato/análogos & derivados , Ácidos Ftálicos , Pirazóis , Camundongos , Animais , Feminino , Dietilexilftalato/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , EstrogêniosRESUMO
BACKGROUND: Humans are widely exposed to phthalates, which are metabolized in the body and excreted in urine. Phthalate metabolites are excreted within hours of exposure, making urinary phthalate biomarker concentrations highly variable. OBJECTIVE: The goal of this study was to characterize the long-term variability in phthalate biomarker concentrations in women across the midlife transition and to identify factors that may be associated with increased variability in those phthalate biomarker concentrations by analyzing longitudinal urinary phthalate metabolite data from the Midlife Women's Health Study (2006-2015). METHODS: A total of 741 women were enrolled in the study for a period of up to 4 years, during which they each provided 2-4 urine samples per year over 4 consecutive weeks that were pooled for analysis (1876 total pools). Nine phthalate metabolites were assessed individually and as molar sums representative of common compounds (all phthalates: Æ©Phthalates; DEHP: Æ©DEHP), exposure sources (plastics: Æ©Plastic; personal care products: Æ©PCP), and modes of action (anti-androgenic: Æ©AA). Phthalate metabolites were analyzed by quartile using generalized linear models. In addition, the impact of explanatory variables (race, annual family income, and type of work) on phthalate quartile was examined using ordinal logistic regression models. IMPACT STATEMENT: Phthalate biomarker concentrations are highly variable among midlife women over time, and annual sampling may not be sufficient to fully characterize long-term exposure.
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Phthalates are chemicals ubiquitously used in industry. Individual phthalates have been found to adversely affect female reproduction; however, humans are exposed to a mixture of phthalates daily, primarily through ingestion. Previous studies show that exposure to an environmentally relevant mixture of phthalates (Mix) can affect female reproduction. Little research, however, has been conducted on the effects of short-term (1 month) and long-term (6 months) exposure to Mix on ovarian functions. Thus, this study tested the hypothesis that short-term and long-term exposure to Mix alters ovarian folliculogenesis, serum hormone concentrations, pituitary gene expression, and ovarian expression of genes involved in steroidogenesis, apoptosis, cell cycle regulation, and oxidative stress. Adult CD-1 female mice were exposed to vehicle control (corn oil) or Mix (0.15-1500 ppm) in the chow for 1 or 6 months. Exposure to Mix for 1 month increased the number of atretic follicles (0.15 ppm), altered ovarian gene expression (0.15 ppm, 1500 ppm), and decreased serum testosterone (1.5 ppm) compared to control. Exposure to Mix for 6 months increased serum follicle-stimulating hormone (FSH) (0.15 ppm), decreased serum luteinizing hormone (LH) (0.15 ppm, 1.5 ppm, and 1500 ppm), decreased serum estradiol (1500 ppm), altered pituitary gene expression (1500 ppm), increased the number (1500 ppm) and percentage (1.5 ppm and 1500 ppm) of primordial follicles, and decreased the percentage of preantral (1500 ppm) and antral (1.5 ppm and 1500 ppm) follicles compared to control. These data indicate that exposure to Mix can alter folliculogenesis, steroidogenesis, and gene expression in female mice.
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Exposição Dietética , Folículo Ovariano , Adulto , Humanos , Camundongos , Feminino , Animais , Hormônio Luteinizante , Hormônio Foliculoestimulante , Expressão Gênica , EstradiolRESUMO
Phthalates are synthetic chemicals widely used as plasticizers and stabilizers in various consumer products. Because of the extensive production and use of phthalates, humans are exposed to these chemicals daily. While most studies focus on a single phthalate, humans are exposed to a mixture of phthalates on a regular basis. The impact of continuous exposure to phthalate mixture on uterus is largely unknown. Thus, we conducted studies in which adult female mice were exposed for 6 months to 0.15 ppm and 1.5 ppm of a mixture of phthalates via chow ad libitum. Our studies revealed that consumption of phthalate mixture at 0.15 ppm and 1.5 ppm for 6 months led to a significant increase in the thickness of the myometrial layer compared to control. Further investigation employing RNA-sequencing revealed an elevated transforming growth factor beta (TGF-ß) signaling in the uteri of mice fed with phthalate mixture. TGF-ß signaling is associated with the development of fibrosis, a consequence of excessive accumulation of extracellular matrix components, such as collagen fibers in a tissue. Consistent with this observation, we found a higher incidence of collagen deposition in uteri of mice exposed to phthalate mixture compared to unexposed controls. Second Harmonic Generation (SHG) imaging showed disorganized collagen fibers and nanoindentation indicated a local increase in uterine stiffness upon exposure to phthalate mixture. Collectively, our results demonstrate that chronic exposure to phthalate mixture can have adverse eï¬ects on uterine homeostasis.
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Poluentes Ambientais , Leiomioma , Ácidos Ftálicos , Fator de Crescimento Transformador beta , Animais , Feminino , Camundongos , Colágeno , Exposição Ambiental/efeitos adversos , Poluentes Ambientais/toxicidade , Ácidos Ftálicos/toxicidade , Plastificantes/toxicidade , Fator de Crescimento Transformador beta/genética , Leiomioma/induzido quimicamenteRESUMO
Neonicotinoid insecticides are synthetic nicotine derivatives that have high affinity for invertebrate nicotine receptors and low affinity for mammalian nicotine receptors. However, imidacloprid (IMI), the most commonly used neonicotinoid, can be bioactivated by the liver in mammals to desnitro-imidacloprid, an intermediate metabolite that effectively binds and activates mammalian receptors. However, it is not known if other tissues such as the ovaries can metabolize IMI. Thus, the present study tested the hypothesis that ovarian antral follicles metabolize and bioactivate IMI. Antral follicles were dissected from the ovaries of CD-1 mice and cultured in media containing dimethyl sulfoxide or IMI (0.2-200 µg/ml) for 48 and 96 h. Media were subjected to liquid chromatography-mass spectrometry for detection of phase I IMI metabolites. Follicles from the cultures were used for gene expression analysis of metabolic enzymes associated with IMI metabolism. All IMI metabolites were detected at 48 and 96 h. Oxidized IMI intermediates were detected in media from cultured follicles, but not environmental controls. Reduced IMI intermediates were detected in media from cultured follicles and the environmental controls. At 48 h, IMI did not affect expression of any metabolic enzymes compared with control. At 96 h, IMI induced Cyp2e1 and Cyp4f18 compared with control. These data indicate that mouse ovarian follicles metabolize IMI and that IMI induces ovarian Cyp expression over time.
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Inseticidas , Nicotina , Feminino , Camundongos , Animais , Nicotina/farmacologia , Neonicotinoides/toxicidade , Inseticidas/toxicidade , Inseticidas/metabolismo , Nitrocompostos/toxicidade , Folículo Ovariano , Mamíferos/metabolismoRESUMO
The use of zinc oxide nanoparticles (ZnO NP) in consumer products is increasing, raising concern about their potential toxicity to human health. Nanoparticles have endocrine disrupting effects and can induce oxidative stress, leading to biomolecule oxidation and cell dysfunction. The ovary is one of the most important endocrine organs in female reproduction. Nanoparticles accumulate in the ovary, but it is unknown whether and how exposure to these materials disrupts antral follicle functions. Thus, this study tested the hypothesis that the in vitro exposure to ZnO NPs affects the steroidogenic pathway and induces oxidative stress in ovarian antral follicles. Antral follicles from CD-1 mice were cultured with ZnO NPs (5, 10, and 15 µg/mL) for 96 h. ZnO NP exposure did not affect apoptosis and cell cycle regulators at any of the tested concentrations. ZnO NP exposure at low levels (5 µg/mL) increased aromatase levels, leading to increased estradiol levels and decreased estrogen receptor alpha (Esr1) expression. ZnO NP exposure at 15 µg/mL induced an antioxidant response in the antral follicles as evidenced by changes in expression of antioxidant molecules (Nrf2, Cat, Sod1, Gsr, Gpx) and decreased levels of reactive oxygen species. Interestingly, ZnO NPs dissolve up to 50% in media and are internalized in cells as soon as 1 h after culture. In conclusion, ZnO NPs are internalized in antral follicles, leading to increased estrogen production and an antioxidant response.