The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Nicolás Olea - One of the best experts on this subject based on the ideXlab platform.
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changes in the total effective xenoestrogen burden texb of breast cancer patients during an 18 month post surgical follow up
Reproductive Toxicology, 2017Co-Authors: Juan P. Arrebola, Mariana F. Fernández, Nicolás Olea, Jose Pumarega, Miquel Porta, Josemanuel MolinamolinaAbstract:Abstract We aimed to assess changes in the total effective xenoestrogen burden (TEXB) −a biomarker of combined effect of mixtures of Xenoestrogens- in breast cancer patients at surgery (breast adipose tissue) and at different time points during an 18-month follow-up (abdominal adipose tissue), and to analyze the potential influence of socio-demographic, reproductive, tumor, and treatment characteristics on TEXB levels. TEXB-alpha (due to persistent organohalogenated chemicals) and TEXB-beta (due mainly to endogenous estrogens) were quantified in 44 women. TEXB values significantly increased over follow-up (p
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Inadvertent exposure to Xenoestrogens in children.
Toxicology and Industrial Health, 2016Co-Authors: Nicolás Olea, Ana Rivas, Fátima Olea-serrano, Pablo Lardelli-claret, Barba-navarro AAbstract:This article reviews previous studies and presents new data on pesticide exposure in order to provide some indications of the extent and significance of childhood exposure to Xenoestrogens, includi...
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In utero exposure to mixtures of Xenoestrogens and child neuropsychological development
Environmental Research, 2014Co-Authors: Nadia Vilahur, Mariana F. Fernández, Mariona Bustamante, Rosa Ramos, Joan Forns, Ferran Ballester, Mario Murcia, Isolina Riaño, Jesús Ibarluzea, Nicolás OleaAbstract:Abstract Background To date, no epidemiological studies have explored the impact and persistence of in utero exposure to mixtures of Xenoestrogens on the developing brain. We aimed to assess whether the cumulative effect of Xenoestrogens in the placenta is associated with altered infant neuropsychological functioning at two and at four years of age, and if associations differ among boys and girls. Methods Cumulative prenatal exposure to Xenoestrogens was quantified in the placenta using the biomarker Total Effective Xenoestrogen Burden (TEXB-alpha) in 489 participants from the INMA (Childhood and the Environment) Project. TEXB-alpha was split in tertiles to test its association with the mental and psychomotor scores of the Bayley Scales of Infant Development (BSID) at 1–2 years of age, and with the McCarthy Scales of Children׳s Abilities (MSCA) general cognitive index and motor scale assessed at 4–5 years of age. Interactions with sex were investigated. Results After adjustment for potential confounders, no association was observed between TEXB-alpha and mental scores at 1–2 years of age. We found a significant interactions with sex for the association between TEXB-alpha and infant psychomotor development (interaction p-value=0.029). Boys in the third tertile of exposure scored on average 5.2 points less than those in the first tertile on tests of motor development at 1-2 years of age (p-value=0.052), while no associations were observed in girls. However, this association disappeared in children at 4-5 years of age and no association between TEXB-alpha and children׳s cognition was found. Conclusions Our results suggest that boys’ early motor development might be more vulnerable to prenatal exposure to mixtures of Xenoestrogens, but associations do not persist in preschool children.
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assessment of the total effective xenoestrogen burden in extracts of human placentas
Biomarkers, 2009Co-Authors: Mariajose Lopezespinosa, Elisabete Silva, Andreas Kortenkamp, Mariana F. Fernández, Josemanuel Molinamolina, Fatima Oleaserrano, Alicia Granada, Clemente Aguilargarduno, Nicolás OleaAbstract:We have standardized a method to assess the total effective xenoestrogen burden (TEXB) in human placentas by the extraction and separation by high-performance liquid chromatography of two fractions containing lipophilic Xenoestrogens (alpha) and endogenous hormones (beta), followed by assessing their estrogenicity in MCF-7 breast cancer cell-based E-Screen and Yeast Estrogen Screen (YES) bioassays. The means of TEXB alpha concentrations (in estradiol equivalent (Eeq) units) were 1.32 and 0.77 Eeq pM g(-1) placenta in the E-Screen and YES, respectively; TEXB beta concentrations were 6.97 and 11.56 Eeq pM g(-1) placenta, respectively. The interclass correlation coefficient was low and a fair level of agreement was observed after kappa test correction. According to the E-Screen and YES, TEXB alpha was > or = LOD in 70.0 and 55.0% of the placentas and 92.5 and 82.5% in beta, respectively. Although both bioassays can be recommended for assessing TEXB, there is greater experience with the use of the E-Screen for estrogenic assessment after extensive extraction of complex human matrices.
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human exposure to endocrine disrupting chemicals and prenatal risk factors for cryptorchidism and hypospadias a nested case control study
Environmental Health Perspectives, 2007Co-Authors: Mariana F. Fernández, Josemanuel Molinamolina, Fatima Oleaserrano, Mariajose Lopezespinosa, Alicia Granada, Begona Olmos, Juan Manuel Fernandez, M Cruz, Nicolás OleaAbstract:BACKGROUND: Exposure to Xenoestrogens during pregnancy may disturb the development and function of male sexual organs. OBJECTIVE: In this study we aimed to determine whether the combined effect of environmental estrogens measured as total effective xenoestrogen burden (TEXB) is a risk factor for male urogenital malformations. METHODS: In a case-control study, nested in a mother-child cohort (n = 702) established at Granada University Hospital, we compared 50 newborns with diagnosis of cryptorchidism and/or hypospadias with 114 boys without malformations matched by gestational age, date of birth, and parity. Controls did not differ from the total cohort in confounding variables. TEXB and levels of 16 organochlorine pesticides were measured in placenta tissues. Characteristics of parents, pregnancy, and birth were gathered by questionnaire. We used conditional and unconditional regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: TEXB from organohalogenated compounds was detectable in 72% and 54% of case and control placentas, respectively. Compared with controls, cases had an OR for detectable versus non-detectable TEXB of 2.82 (95% CI, 1.10-7.24). More pesticides were detected in cases than in controls (9.34 +/- 3.19 vs. 6.97 +/- 3.93). ORs for cases with detectable levels of pesticides, after adjusting for potential confounders in the conditional regression analysis, were o,p'-DDT (OR = 2.25; 95% CI, 1.03-4.89), p,p'-DDT (OR = 2.63; 95% CI, 1.21-5.72), lindane (OR = 3.38; 95% CI, 1.36-8.38), mirex (OR = 2.85; 95% CI, 1.22-6.66), and endosulfan alpha (OR = 2.19; 95% CI, 0.99-4.82). Engagement of mothers in agriculture (OR = 3.47; 95% CI, 1.33-9.03), fathers' occupational exposure to Xenoestrogens (OR = 2.98; 95% CI, 1.11-8.01), and history of previous stillbirths (OR = 4.20; 95% CI, 1.11-16.66) were also associated with risk of malformations. CONCLUSIONS: We found an increased risk for male urogenital malformations related to the combined effect of environmental estrogens in placenta.
Mariana F. Fernández - One of the best experts on this subject based on the ideXlab platform.
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changes in the total effective xenoestrogen burden texb of breast cancer patients during an 18 month post surgical follow up
Reproductive Toxicology, 2017Co-Authors: Juan P. Arrebola, Mariana F. Fernández, Nicolás Olea, Jose Pumarega, Miquel Porta, Josemanuel MolinamolinaAbstract:Abstract We aimed to assess changes in the total effective xenoestrogen burden (TEXB) −a biomarker of combined effect of mixtures of Xenoestrogens- in breast cancer patients at surgery (breast adipose tissue) and at different time points during an 18-month follow-up (abdominal adipose tissue), and to analyze the potential influence of socio-demographic, reproductive, tumor, and treatment characteristics on TEXB levels. TEXB-alpha (due to persistent organohalogenated chemicals) and TEXB-beta (due mainly to endogenous estrogens) were quantified in 44 women. TEXB values significantly increased over follow-up (p
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prenatal exposure to mixtures of Xenoestrogens and genome wide dna methylation in human placenta
Epigenomics, 2016Co-Authors: Nadia Vilahur, Mariana F. Fernández, Mariona Bustamante, Ferran Ballester, Mario Murcia, E. Morales, V. Motta, L.a. Salas, G. Escaramis, A. TardonAbstract:Background: In utero exposure to xenostrogens may modify the epigenome. We explored the association of prenatal exposure to mixtures of Xenoestrogens and genome-wide placental DNA methylation. Materials & methods: Sex-specific associations between methylation changes in placental DNA by doubling the concentration of TEXB-alpha exposure were evaluated by robust multiple linear regression. Two CpG sites were selected for validation and replication in additional male born placentas. Results: No significant associations were found, although the top significant CpGs in boys were located in the LRPAP1, HAGH, PPARGC1B, KCNQ1 and KCNQ1DN genes, previously associated to birth weight, Type 2 diabetes, obesity or steroid hormone signaling. Neither technical validation nor biological replication of the results was found in boys for LRPAP and PPARGC1B. Conclusion: Some suggestive genes were differentially methylated in boys in relation to prenatal xenoestrogen exposure, but our initial findings could not be validated ...
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In utero exposure to mixtures of Xenoestrogens and child neuropsychological development
Environmental Research, 2014Co-Authors: Nadia Vilahur, Mariana F. Fernández, Mariona Bustamante, Rosa Ramos, Joan Forns, Ferran Ballester, Mario Murcia, Isolina Riaño, Jesús Ibarluzea, Nicolás OleaAbstract:Abstract Background To date, no epidemiological studies have explored the impact and persistence of in utero exposure to mixtures of Xenoestrogens on the developing brain. We aimed to assess whether the cumulative effect of Xenoestrogens in the placenta is associated with altered infant neuropsychological functioning at two and at four years of age, and if associations differ among boys and girls. Methods Cumulative prenatal exposure to Xenoestrogens was quantified in the placenta using the biomarker Total Effective Xenoestrogen Burden (TEXB-alpha) in 489 participants from the INMA (Childhood and the Environment) Project. TEXB-alpha was split in tertiles to test its association with the mental and psychomotor scores of the Bayley Scales of Infant Development (BSID) at 1–2 years of age, and with the McCarthy Scales of Children׳s Abilities (MSCA) general cognitive index and motor scale assessed at 4–5 years of age. Interactions with sex were investigated. Results After adjustment for potential confounders, no association was observed between TEXB-alpha and mental scores at 1–2 years of age. We found a significant interactions with sex for the association between TEXB-alpha and infant psychomotor development (interaction p-value=0.029). Boys in the third tertile of exposure scored on average 5.2 points less than those in the first tertile on tests of motor development at 1-2 years of age (p-value=0.052), while no associations were observed in girls. However, this association disappeared in children at 4-5 years of age and no association between TEXB-alpha and children׳s cognition was found. Conclusions Our results suggest that boys’ early motor development might be more vulnerable to prenatal exposure to mixtures of Xenoestrogens, but associations do not persist in preschool children.
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assessment of the total effective xenoestrogen burden in extracts of human placentas
Biomarkers, 2009Co-Authors: Mariajose Lopezespinosa, Elisabete Silva, Andreas Kortenkamp, Mariana F. Fernández, Josemanuel Molinamolina, Fatima Oleaserrano, Alicia Granada, Clemente Aguilargarduno, Nicolás OleaAbstract:We have standardized a method to assess the total effective xenoestrogen burden (TEXB) in human placentas by the extraction and separation by high-performance liquid chromatography of two fractions containing lipophilic Xenoestrogens (alpha) and endogenous hormones (beta), followed by assessing their estrogenicity in MCF-7 breast cancer cell-based E-Screen and Yeast Estrogen Screen (YES) bioassays. The means of TEXB alpha concentrations (in estradiol equivalent (Eeq) units) were 1.32 and 0.77 Eeq pM g(-1) placenta in the E-Screen and YES, respectively; TEXB beta concentrations were 6.97 and 11.56 Eeq pM g(-1) placenta, respectively. The interclass correlation coefficient was low and a fair level of agreement was observed after kappa test correction. According to the E-Screen and YES, TEXB alpha was > or = LOD in 70.0 and 55.0% of the placentas and 92.5 and 82.5% in beta, respectively. Although both bioassays can be recommended for assessing TEXB, there is greater experience with the use of the E-Screen for estrogenic assessment after extensive extraction of complex human matrices.
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human exposure to endocrine disrupting chemicals and prenatal risk factors for cryptorchidism and hypospadias a nested case control study
Environmental Health Perspectives, 2007Co-Authors: Mariana F. Fernández, Josemanuel Molinamolina, Fatima Oleaserrano, Mariajose Lopezespinosa, Alicia Granada, Begona Olmos, Juan Manuel Fernandez, M Cruz, Nicolás OleaAbstract:BACKGROUND: Exposure to Xenoestrogens during pregnancy may disturb the development and function of male sexual organs. OBJECTIVE: In this study we aimed to determine whether the combined effect of environmental estrogens measured as total effective xenoestrogen burden (TEXB) is a risk factor for male urogenital malformations. METHODS: In a case-control study, nested in a mother-child cohort (n = 702) established at Granada University Hospital, we compared 50 newborns with diagnosis of cryptorchidism and/or hypospadias with 114 boys without malformations matched by gestational age, date of birth, and parity. Controls did not differ from the total cohort in confounding variables. TEXB and levels of 16 organochlorine pesticides were measured in placenta tissues. Characteristics of parents, pregnancy, and birth were gathered by questionnaire. We used conditional and unconditional regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: TEXB from organohalogenated compounds was detectable in 72% and 54% of case and control placentas, respectively. Compared with controls, cases had an OR for detectable versus non-detectable TEXB of 2.82 (95% CI, 1.10-7.24). More pesticides were detected in cases than in controls (9.34 +/- 3.19 vs. 6.97 +/- 3.93). ORs for cases with detectable levels of pesticides, after adjusting for potential confounders in the conditional regression analysis, were o,p'-DDT (OR = 2.25; 95% CI, 1.03-4.89), p,p'-DDT (OR = 2.63; 95% CI, 1.21-5.72), lindane (OR = 3.38; 95% CI, 1.36-8.38), mirex (OR = 2.85; 95% CI, 1.22-6.66), and endosulfan alpha (OR = 2.19; 95% CI, 0.99-4.82). Engagement of mothers in agriculture (OR = 3.47; 95% CI, 1.33-9.03), fathers' occupational exposure to Xenoestrogens (OR = 2.98; 95% CI, 1.11-8.01), and history of previous stillbirths (OR = 4.20; 95% CI, 1.11-16.66) were also associated with risk of malformations. CONCLUSIONS: We found an increased risk for male urogenital malformations related to the combined effect of environmental estrogens in placenta.
Susan C. Nagel - One of the best experts on this subject based on the ideXlab platform.
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Developmental exposure to Xenoestrogens at low doses alters femur length and tensile strength in adult mice
2016Co-Authors: Katherine E. Pelch, Stephanie M. Carleton, Charlotte L. Phillips, Susan C. NagelAbstract:Developmental exposure to high doses of the synthetic xenoestrogen diethylstilbestrol (DES) has been reported to alter femur length and strength in adult mice. However, it is not known if developmental exposure to low, environmentally relevant doses of Xenoestrogens alters adult bone geometry and strength. In this study we investigated the effects of developmental exposure to low doses of DES, bisphenol A (BPA), or ethinyl estradiol (EE2) on bone geometry and torsional strength. C57BL/6 mice were exposed to DES, 0.1 lg/kg/day, BPA, 10 lg/kg/day, EE2, 0.01, 0.1, or 1.0 lg/kg/day, or vehicle from Gestation Day 11 to Postnatal Day 12 via a mini-osmotic pump in the dam. Developmental Xenoestrogen exposure altered femoral geometry and strength, assessed in adulthood by micro-computed tomography and torsional strength analysis, respectively. Low-dose EE2, DES, or BPA increased adult femur length. Exposure to the highest dose of EE2 did not alter femur length, resulting in a nonmonotonic dose response. Exposure to EE2 and DES but not BPA decreased tensile strength. The combined effect of increased femur length and decreased tensile strength resulted in a trend toward decreased torsional ultimate strength and energy to failure. Taken together, these results suggest that exposure to developmental exposure to environ-mentally relevant levels of Xenoestrogens may negatively impact bone length and strength in adulthood. bone, developmental origins of health and disease, endocrine disruptors, environmental contaminants and toxicants, estradiol, estradiol recepto
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Developmental Exposure to Xenoestrogens at Low Doses Alters Femur Length and Tensile Strength in Adult Mice
Biology of Reproduction, 2012Co-Authors: Katherine E. Pelch, Stephanie M. Carleton, Charlotte L. Phillips, Susan C. NagelAbstract:Developmental exposure to high doses of the synthetic xenoestrogen diethylstilbestrol (DES) has been reported to alter femur length and strength in adult mice. However, it is not known if developmental exposure to low, environmentally relevant doses of Xenoestrogens alters adult bone geometry and strength. In this study we investigated the effects of developmental exposure to low doses of DES, bisphenol A (BPA), or ethinyl estradiol (EE2) on bone geometry and torsional strength. C57BL/6 mice were exposed to DES, 0.1 μg/kg/day, BPA, 10 μg/kg/day, EE2, 0.01, 0.1, or 1.0 μg/kg/day, or vehicle from Gestation Day 11 to Postnatal Day 12 via a mini-osmotic pump in the dam. Developmental Xenoestrogen exposure altered femoral geometry and strength, assessed in adulthood by micro-computed tomography and torsional strength analysis, respectively. Low-dose EE2, DES, or BPA increased adult femur length. Exposure to the highest dose of EE2 did not alter femur length, resulting in a nonmonotonic dose response. Exposure to EE2 and DES but not BPA decreased tensile strength. The combined effect of increased femur length and decreased tensile strength resulted in a trend toward decreased torsional ultimate strength and energy to failure. Taken together, these results suggest that exposure to developmental exposure to environmentally relevant levels of Xenoestrogens may negatively impact bone length and strength in adulthood.
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developmental effects of estrogenic chemicals are predicted by an in vitro assay incorporating modification of cell uptake by serum
The Journal of Steroid Biochemistry and Molecular Biology, 1999Co-Authors: Susan C. Nagel, Frederick Vom S Saal, Wade V WelshonsAbstract:Many estrogenic chemicals found in the environment (Xenoestrogens) show a lower affinity for plasma estrogen binding proteins relative to the natural estrogens such as estradiol. These binding proteins, which include alphafetoprotein in rats and mice, sex hormone binding globulin in humans, and albumin in all species, regulate estrogen uptake into tissues. Therefore, the in vivo estrogenic potency relative to estradiol of Xenoestrogens that show lower binding to these serum proteins will thus be underestimated in assays that compare the potency of Xenoestrogens to estradiol and do not take serum binding into account. We have examined the effects of the binding components in serum on the uptake of a number of Xenoestrogens into intact MCF-7 human breast cancer cells. Since most estrogenic chemicals are not available in radiolabeled form, their uptake is determined by competition with [3H]estradiol for binding to estrogen receptors (ER) in an 18-h assay. Serum modified access (SMA) of cell uptake of Xenoestrogens is calculated as the RBA in serum-free-medium divided by the RBA in serum, and the bioactive free fraction of xenoestrogen in serum is then also calculated. We predicted the concentration of two Xenoestrogens, bisphenol A and octylphenol, required to alter development of the prostate in male mouse fetuses. Whereas octylphenol was predicted to be a more potent estrogen than bisphenol A when tested in serum-free medium, our assay predicted that bisphenol A would be over 500-times more potent than octylphenol in fetal mice. The finding that administration of bisphenol A at a physiologically relevant dose predicted from our in vitro assay to pregnant mice from gestation day 11 to 17 increased adult prostate weight in male offspring relative to controls (similar to the effect of estradiol), while the same doses of octylphenol did not alter prostate development, provided support for our hypothesis.
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the effective free fraction of estradiol and Xenoestrogens in human serum measured by whole cell uptake assays physiology of delivery modifies estrogenic activity
Experimental Biology and Medicine, 1998Co-Authors: Susan C. Nagel, Frederick Vom S Saal, Wade V WelshonsAbstract:The biological activity of natural estrogens is influenced by the degree to which they bind to serum proteins. To determine directly how serum affected the uptake of estradiol, we compared the whole cell uptake of [3H]estradiol in intact MCF-7 human breast cancer cells from serum-free medium with the uptake from 100% serum from adult men. In estrogen receptor saturation assays, 28.9 times more estradiol was required in serum to occupy the same number of estrogen receptors as was required in serum-free medium (SFM), suggesting that the effective free fraction of estradiol in adult male serum was 3.46% (1/28.9). Since most Xenoestrogens are not available in tritium-labeled form, the cell uptake of unlabeled Xenoestrogens could not be measured directly with saturation analysis. Therefore, we developed the relative binding affinity-serum modified access (RBA-SMA) assay to determine the effect of serum on the access of nonradioactive Xenoestrogens to estrogen receptors within intact MCF-7 cells. Serum modified access (SMA) was calculated by dividing the relative binding affinity (RBA, relative to estradiol) measured in 100% serum, by the RBA measured in serum-free medium. An SMA > 1 indicated that the xenoestrogen had greater access to estrogen receptors than estradiol from serum. In contrast, an SMA < 1 indicated that the xenoestrogen had less access to estrogen receptors from serum than did estradiol. The synthetic estrogen diethylstilbestrol (DES) binds poorly to sex hormone binding globulin (SHBG), and DES showed enhanced access in serum, SMA = 6.2. Additional calculations through the Ki (inhibition constant) indicated that this corresponded to an effective free fraction of 26.9% for DES in serum. The phytoestrogens, coumestrol, genistein, and equol, showed substantial enhanced access in serum, over 10-fold relative to estradiol (SMA = 12.1, 10.3, and 11.3, respectively), and effective free fractions in serum of 47.8, 45.8, and 49.7%, respectively. Since most in vitro assays of Xenoestrogens do not address how serum influences their bioactivity, the estrogenic activity of these phytoestrogens would be underestimated. Conversely, biochanin A showed decreased access from serum (SMA = 0.44) and had an effective free fraction of 2.4%; its estrogenic activity would be overestimated in serum-free assays.
Cheryl S Watson - One of the best experts on this subject based on the ideXlab platform.
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mixtures of Xenoestrogens disrupt estradiol induced non genomic signaling and downstream functions in pituitary cells
Environmental Health, 2013Co-Authors: Rene Vinas, Cheryl S WatsonAbstract:Our study examines the effects of xenoestrogen mixtures on estradiol-induced non-genomic signaling and associated functional responses. Bisphenol-A, used to manufacture plastic consumer products, and nonylphenol, a surfactant, are estrogenic by a variety of assays, including altering many intracellular signaling pathways; bisphenol-S is now used as a bisphenol-A substitute. All three compounds contaminate the environment globally. We previously showed that bisphenol-S, bisphenol-A, and nonylphenol alone rapidly activated several kinases at very low concentrations in the GH3/B6/F10 rat pituitary cell line. For each assay we compared the response of individual Xenoestrogens at environmentally relevant concentrations (10-15 -10-7 M), to their mixture effects on 10-9 M estradiol-induced responses. We used a medium-throughput plate immunoassay to quantify phosphorylations of extracellular signal-regulated kinases (ERKs) and c-Jun-N-terminal kinases (JNKs). Cell numbers were assessed by crystal violet assay to compare the proliferative effects. Apoptosis was assessed by measuring caspase 8 and 9 activities via the release of the fluorescent product 7-amino-4-trifluoromethylcoumarin. Prolactin release was measured by radio-immunoassay after a 1 min exposure to all individual and combinations of estrogens. Individual Xenoestrogens elicited phospho-activation of ERK in a non-monotonic dose- (fM-nM) and mostly oscillating time-dependent (2.5-60 min) manner. When multiple Xenoestrogens were combined with nM estradiol, the physiologic estrogen’s response was attenuated. Individual bisphenol compounds did not activate JNK, while nonylphenol did; however, the combination of two or three Xenoestrogens with estradiol generated an enhanced non-monotonic JNK dose–response. Estradiol and all xenoestrogen compounds induced cell proliferation individually, while the mixtures of these compounds with estradiol suppressed proliferation below that of the vehicle control, suggesting a possible apoptotic response. Extrinsic caspase 8 activity was suppressed by estradiol, elevated by bisphenol S, and unaffected by mixtures. Intrinsic caspase 9 activity was inhibited by estradiol, and by xenoestrogen combinations (at 10-14 and 10-8 M). Mixtures of Xenoestrogens impeded the estradiol-induced release of prolactin. In mixtures expected to be found in contaminated environments, Xenoestrogens can have dramatic disrupting effects on hormonal mechanisms of cell regulation and their downstream functional responses, altering cellular responses to physiologic estrogens.
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combinations of physiologic estrogens with Xenoestrogens alter calcium and kinase responses prolactin release and membrane estrogen receptor trafficking in rat pituitary cells
Environmental Health, 2010Co-Authors: Yow Jiun Jeng, Mikhail Y Kochukov, Cheryl S WatsonAbstract:Background Xenoestrogens such as alkylphenols and the structurally related plastic byproduct bisphenol A have recently been shown to act potently via nongenomic signaling pathways and the membrane version of estrogen receptor-α. Though the responses to these compounds are typically measured individually, they usually contaminate organisms that already have endogenous estrogens present. Therefore, we used quantitative medium-throughput screening assays to measure the effects of physiologic estrogens in combination with these Xenoestrogens.
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Combinations of physiologic estrogens with Xenoestrogens alter ERK phosphorylation profiles in rat pituitary cells.
Environmental Health Perspectives, 2010Co-Authors: Yow Jiun Jeng, Cheryl S WatsonAbstract:BackgroundEstrogens are potent nongenomic phospho-activators of extracellular-signal–regulated kinases (ERKs). A major concern about the toxicity of Xenoestrogens (XEs) is potential alteration of r...
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Xenoestrogens are potent activators of nongenomic estrogenic responses.
Steroids, 2006Co-Authors: Cheryl S Watson, Nataliya N Bulayeva, Ann L Wozniak, Rebecca A. AlyeaAbstract:Studies of the nuclear transcriptional regulatory activities of non-physiological estrogens have not explained their actions in mediating endocrine disruption in animals and humans at the low concentrations widespread in the environment. However, Xenoestrogens have rarely been tested for their ability to participate in the plethora of nongenomic steroid signaling pathways elucidated over the last several years. Here we review what is known about such responses in comparison to our recent evidence that Xenoestrogens can rapidly and potently elicit signaling through nongenomic pathways culminating in functional endpoints. Both estradiol (E(2)) and compounds representing various classes of Xenoestrogens (diethylstilbestrol, coumestrol, bisphenol A, DDE, nonylphenol, endosulfan, and dieldrin) act via a membrane version of the estrogen receptor-alpha on pituitary cells, and can provoke Ca(2+) influx via L-type channels, leading to prolactin (PRL) secretion. These hormones and mimetics can also cause the oscillating activation of extracellular regulated kinases (ERKs). However, individual estrogen mimetics differ in their potency and temporal phasing of these activations compared to each other and to E(2). It is perhaps in these ways that they disrupt some endocrine functions when acting in combination with physiological estrogens. Our quantitative assays allow comparison of these outcomes for each mimetic, and let us build a detailed picture of alternative signaling pathway usage. Such an understanding should allow us to determine the estrogenic or antiestrogenic potential of different types of Xenoestrogens, and help us to develop strategies for preventing xenoestrogenic disruption of estrogen action in many tissues.
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signaling from the membrane via membrane estrogen receptor α estrogens Xenoestrogens and phytoestrogens
Steroids, 2005Co-Authors: Cheryl S Watson, Nataliya N Bulayeva, Ann L Wozniak, Celeste C FinnertyAbstract:Abstract Estrogen mimetics in the environment and in foods can have important consequences for endocrine functions. When previously examined for action via genomic steroid signaling mechanisms, most of these compounds were found to be very weak agonists. We have instead tested their actions via several membrane-initiated signaling mechanisms in GH3/B6 pituitary tumor cells extensively selected for high (responsive) or low (nonresponsive) expression of the membrane version of estrogen receptor-α (mERα). We found many estrogen mimetic compounds to be potently active in our quantitative extracellular-regulated kinase (ERK) activation assays, to increase cellular Ca++ levels, and to cause rapid prolactin release. However, these compounds may activate one or both mechanisms with different potencies. For instance, some compounds activate ERKs in both pM and nM concentration ranges, while others are only active at nM and higher concentrations. Compounds also show great differences in their temporal activation patterns. While estradiol causes a bimodal time-dependent ERK activation (peaking at both 3 and 30 min), most estrogen mimetics cause either an early phase activation, a late phase activation, or an early sustained activation. One xenoestrogen known to be a relatively potent activator of estrogen response element-mediated actions (bisphenol A) is inactive as an ERK activator, and only a modest inducer of Ca++ levels and prolactin release. Many different signaling machineries culminate in ERK activation, and Xenoestrogens differentially affect various pathways. Clearly individual Xenoestrogens must be individually investigated for their differing abilities to activate distinct membrane-initiated signal cascades that lead to a variety of cellular functions.
Wade V Welshons - One of the best experts on this subject based on the ideXlab platform.
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developmental effects of estrogenic chemicals are predicted by an in vitro assay incorporating modification of cell uptake by serum
The Journal of Steroid Biochemistry and Molecular Biology, 1999Co-Authors: Susan C. Nagel, Frederick Vom S Saal, Wade V WelshonsAbstract:Many estrogenic chemicals found in the environment (Xenoestrogens) show a lower affinity for plasma estrogen binding proteins relative to the natural estrogens such as estradiol. These binding proteins, which include alphafetoprotein in rats and mice, sex hormone binding globulin in humans, and albumin in all species, regulate estrogen uptake into tissues. Therefore, the in vivo estrogenic potency relative to estradiol of Xenoestrogens that show lower binding to these serum proteins will thus be underestimated in assays that compare the potency of Xenoestrogens to estradiol and do not take serum binding into account. We have examined the effects of the binding components in serum on the uptake of a number of Xenoestrogens into intact MCF-7 human breast cancer cells. Since most estrogenic chemicals are not available in radiolabeled form, their uptake is determined by competition with [3H]estradiol for binding to estrogen receptors (ER) in an 18-h assay. Serum modified access (SMA) of cell uptake of Xenoestrogens is calculated as the RBA in serum-free-medium divided by the RBA in serum, and the bioactive free fraction of xenoestrogen in serum is then also calculated. We predicted the concentration of two Xenoestrogens, bisphenol A and octylphenol, required to alter development of the prostate in male mouse fetuses. Whereas octylphenol was predicted to be a more potent estrogen than bisphenol A when tested in serum-free medium, our assay predicted that bisphenol A would be over 500-times more potent than octylphenol in fetal mice. The finding that administration of bisphenol A at a physiologically relevant dose predicted from our in vitro assay to pregnant mice from gestation day 11 to 17 increased adult prostate weight in male offspring relative to controls (similar to the effect of estradiol), while the same doses of octylphenol did not alter prostate development, provided support for our hypothesis.
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the effective free fraction of estradiol and Xenoestrogens in human serum measured by whole cell uptake assays physiology of delivery modifies estrogenic activity
Experimental Biology and Medicine, 1998Co-Authors: Susan C. Nagel, Frederick Vom S Saal, Wade V WelshonsAbstract:The biological activity of natural estrogens is influenced by the degree to which they bind to serum proteins. To determine directly how serum affected the uptake of estradiol, we compared the whole cell uptake of [3H]estradiol in intact MCF-7 human breast cancer cells from serum-free medium with the uptake from 100% serum from adult men. In estrogen receptor saturation assays, 28.9 times more estradiol was required in serum to occupy the same number of estrogen receptors as was required in serum-free medium (SFM), suggesting that the effective free fraction of estradiol in adult male serum was 3.46% (1/28.9). Since most Xenoestrogens are not available in tritium-labeled form, the cell uptake of unlabeled Xenoestrogens could not be measured directly with saturation analysis. Therefore, we developed the relative binding affinity-serum modified access (RBA-SMA) assay to determine the effect of serum on the access of nonradioactive Xenoestrogens to estrogen receptors within intact MCF-7 cells. Serum modified access (SMA) was calculated by dividing the relative binding affinity (RBA, relative to estradiol) measured in 100% serum, by the RBA measured in serum-free medium. An SMA > 1 indicated that the xenoestrogen had greater access to estrogen receptors than estradiol from serum. In contrast, an SMA < 1 indicated that the xenoestrogen had less access to estrogen receptors from serum than did estradiol. The synthetic estrogen diethylstilbestrol (DES) binds poorly to sex hormone binding globulin (SHBG), and DES showed enhanced access in serum, SMA = 6.2. Additional calculations through the Ki (inhibition constant) indicated that this corresponded to an effective free fraction of 26.9% for DES in serum. The phytoestrogens, coumestrol, genistein, and equol, showed substantial enhanced access in serum, over 10-fold relative to estradiol (SMA = 12.1, 10.3, and 11.3, respectively), and effective free fractions in serum of 47.8, 45.8, and 49.7%, respectively. Since most in vitro assays of Xenoestrogens do not address how serum influences their bioactivity, the estrogenic activity of these phytoestrogens would be underestimated. Conversely, biochanin A showed decreased access from serum (SMA = 0.44) and had an effective free fraction of 2.4%; its estrogenic activity would be overestimated in serum-free assays.
