The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Michael K. Skinner - One of the best experts on this subject based on the ideXlab platform.
-
Transgenerational sperm DNA methylation epimutation developmental origins following ancestral Vinclozolin exposure
2019Co-Authors: Michael K. Skinner, Millissia Ben Maamar, Daniel Beck, Eric Nilsson, Ingrid Sadler-riggleman, John R. MccarreyAbstract:A number of environmental factors from nutrition to toxicants have been shown to promote the epigenetic transgenerational inheritance of disease and phenotypic variation. This requires alterations in the germline (sperm or egg) epigenome. Previously, the agricultural fungicide Vinclozolin was found to promote the transgenerational inheritance of sperm differential DNA methylation regions (DMRs) termed epimutations that help mediate this epigenetic inheritance. The current study was designed to investigate the developmental origins of the transgenerational DMRs during gametogenesis. Male control and Vinclozolin lineage F3 generation rats were used as a source of embryonic day 13 (E13) primordial germ cells, embryonic day 16 (E16) prospermatogonia, postnatal day 10 (P10) spermatogonia, adult pachytene spermatocytes, round spermatids, caput epididymal spermatozoa, and caudal sperm. The DMRs between the control versus Vinclozolin lineage samples were determined for each developmental stage. The top 100 statistically significant DMRs for each stage were compared. The developmental origins of the caudal epididymal sperm DMRs were assessed. The chromosomal locations and genomic features of the different stage DMRs were investigated. In addition, the DMR associated genes were identified. Previous studies have demonstrated alterations in the DMRs of primordial germ cells (PGCs). Interestingly, the majority of the DMRs identified in the current study for the caudal sperm originated during the spermatogenic process in the testis. A cascade of epigenetic alterations initiated in the PGCs appears to be required to alter the epigenetic programming during spermatogenesis to modify the sperm epigenome involved in the transgenerational epigenetic inheritance phenomenon.
-
alterations in sperm dna methylation non coding rna expression and histone retention mediate Vinclozolin induced epigenetic transgenerational inheritance of disease
Environmental Epigenetics, 2018Co-Authors: Millissia Ben Maamar, Eric E Nilsson, Wei Yan, Ingrid Sadlerriggleman, Daniel Beck, Margaux Mcbirney, Rachel Klukovich, Yeming Xie, Chong Tang, Michael K. SkinnerAbstract:Epigenetic transgenerational inheritance of disease and phenotypic variation can be induced by several toxicants, such as Vinclozolin. This phenomenon can involve DNA methylation, non-coding RNA (ncRNA) and histone retention, and/or modification in the germline (e.g. sperm). These different epigenetic marks are called epimutations and can transmit in part the transgenerational phenotypes. This study was designed to investigate the Vinclozolin-induced concurrent alterations of a number of different epigenetic factors, including DNA methylation, ncRNA, and histone retention in rat sperm. Gestating females (F0 generation) were exposed transiently to Vinclozolin during fetal gonadal development. The directly exposed F1 generation fetus, the directly exposed germline within the fetus that will generate the F2 generation, and the transgenerational F3 generation sperm were studied. DNA methylation and ncRNA were altered in each generation rat sperm with the direct exposure F1 and F2 generations being distinct from the F3 generation epimutations. Interestingly, an increased number of differential histone retention sites were found in the F3 generation Vinclozolin sperm, but not in the F1 or F2 generations. All three different epimutation types were affected in the Vinclozolin lineage transgenerational sperm (F3 generation). The direct exposure generations (F1 and F2) epigenetic alterations were distinct from the transgenerational sperm epimutations. The genomic features and gene pathways associated with the epimutations were investigated to help elucidate the integration of these different epigenetic processes. Our results show that the three different types of epimutations are involved and integrated in the mediation of the epigenetic transgenerational inheritance phenomenon.
-
ancestral Vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding rnas
Environmental Epigenetics, 2016Co-Authors: Andrew Schuster, Michael K. Skinner, Wei YanAbstract:Exposure to the agricultural fungicide Vinclozolin during gestation promotes a higher incidence of various diseases in the subsequent unexposed F3 and F4 generations. This phenomenon is termed epigenetic transgenerational inheritance and has been shown to in part involve alterations in DNA methylation, but the role of other epigenetic mechanisms remains unknown. The current study investigated the alterations in small noncoding RNA (sncRNA) in the sperm from F3 generation control and Vinclozolin lineage rats. Over 200 differentially expressed sncRNAs were identified and the tRNA-derived sncRNAs, namely 5′ halves of mature tRNAs (5′ halves), displayed the most dramatic changes. Gene targets of the altered miRNAs and tRNA 5′ halves revealed associations between the altered sncRNAs and differentially DNA methylated regions. Dysregulated sncRNAs appear to correlate with mRNA profiles associated with the previously observed Vinclozolin-induced disease phenotypes. Data suggest potential connections between sperm-borne RNAs and the Vinclozolin-induced epigenetic transgenerational inheritance phenomenon.
-
sexually dimorphic effects of ancestral exposure to Vinclozolin on stress reactivity in rats
Endocrinology, 2014Co-Authors: Ross Gillette, Michael K. Skinner, Eric E Nilsson, Andrea C Gore, Isaac Millercrews, David CrewsAbstract:How an individual responds to the environment depends upon both personal life history as well as inherited genetic and epigenetic factors from ancestors. Using a 2-hit, 3 generations apart model, we tested how F3 descendants of rats given in utero exposure to the environmental endocrine-disrupting chemical (EDC) Vinclozolin reacted to stress during adolescence in their own lives, focusing on sexually dimorphic phenotypic outcomes. In adulthood, male and female F3 Vinclozolin- or vehicle-lineage rats, stressed or nonstressed, were behaviorally characterized on a battery of tests and then euthanized. Serum was used for hormone assays, and brains were used for quantitative PCR and transcriptome analyses. Results showed that the effects of ancestral exposure to Vinclozolin converged with stress experienced during adolescence in a sexually dimorphic manner. Debilitating effects were seen at all levels of the phenotype, including physiology, behavior, brain metabolism, gene expression, and genome-wide transcriptome modifications in specific brain nuclei. Additionally, females were significantly more vulnerable than males to transgenerational effects of Vinclozolin on anxiety but not sociality tests. This fundamental transformation occurs in a manner not predicted by the ancestral exposure or the proximate effects of stress during adolescence, an interaction we refer to as synchronicity.
-
epigenetic transgenerational inheritance of Vinclozolin induced mouse adult onset disease and associated sperm epigenome biomarkers
Reproductive Toxicology, 2012Co-Authors: Carlos Guerrerobosagna, Matthew D. Anway, Eric E Nilsson, Trevor R Covert, Muksitul M Haque, Matthew L Settles, Michael K. SkinnerAbstract:The endocrine disruptor Vinclozolin has previously been shown to promote epigenetic transgenerational inheritance of adult onset disease in the rat. The current study was designed to investigate the transgenerational actions of Vinclozolin on the mouse. Transient exposure of the F0 generation gestating female during gonadal sex determination promoted transgenerational adult onset disease in F3 generation male and female mice, including spermatogenic cell defects, testicular abnormalities, prostate abnormalities, kidney abnormalities and polycystic ovarian disease. Pathology analysis demonstrated 75% of the Vinclozolin lineage animals developed disease with 34% having two or more different disease states. Interestingly, the Vinclozolin induced transgenerational disease was observed in the outbred CD-1 strain, but not the inbred 129 mouse strain. Analysis of the F3 generation sperm epigenome identified differential DNA methylation regions that can potentially be utilized as epigenetic biomarkers for transgenerational exposure and disease.
Matthew D. Anway - One of the best experts on this subject based on the ideXlab platform.
-
epigenetic transgenerational inheritance of Vinclozolin induced mouse adult onset disease and associated sperm epigenome biomarkers
Reproductive Toxicology, 2012Co-Authors: Carlos Guerrerobosagna, Matthew D. Anway, Eric E Nilsson, Trevor R Covert, Muksitul M Haque, Matthew L Settles, Michael K. SkinnerAbstract:The endocrine disruptor Vinclozolin has previously been shown to promote epigenetic transgenerational inheritance of adult onset disease in the rat. The current study was designed to investigate the transgenerational actions of Vinclozolin on the mouse. Transient exposure of the F0 generation gestating female during gonadal sex determination promoted transgenerational adult onset disease in F3 generation male and female mice, including spermatogenic cell defects, testicular abnormalities, prostate abnormalities, kidney abnormalities and polycystic ovarian disease. Pathology analysis demonstrated 75% of the Vinclozolin lineage animals developed disease with 34% having two or more different disease states. Interestingly, the Vinclozolin induced transgenerational disease was observed in the outbred CD-1 strain, but not the inbred 129 mouse strain. Analysis of the F3 generation sperm epigenome identified differential DNA methylation regions that can potentially be utilized as epigenetic biomarkers for transgenerational exposure and disease.
-
alterations in the developing testis transcriptome following embryonic Vinclozolin exposure
Reproductive Toxicology, 2010Co-Authors: Tracy M Clement, Matthew D. Anway, Matthew L Settles, Marina I Savenkova, Michael K. SkinnerAbstract:The current study investigates the direct effects of in utero Vinclozolin exposure on the developing F1 generation rat testis transcriptome. Previous studies have demonstrated that exposure to Vinclozolin during embryonic gonadal sex determination induces epigenetic modifications of the germ line and transgenerational adult onset disease states. Microarray analyses were performed to compare control and Vinclozolin treated testis transcriptomes at embryonic days 13, 14 and 16. A total of 576 differentially expressed genes were identified and the major cellular functions and pathways associated with these altered transcripts were examined. The sets of regulated genes at the different development periods were found to be transiently altered and distinct. Categorization by major known functions of altered genes was performed. Specific cellular process and pathway analyses suggest the involvement of Wnt and calcium signaling, vascular development and epigenetic mechanisms as potential mediators of the direct F1 generation actions of Vinclozolin.
-
comparative anti androgenic actions of Vinclozolin and flutamide on transgenerational adult onset disease and spermatogenesis
Reproductive Toxicology, 2008Co-Authors: Matthew D. Anway, Stephen S Rekow, Michael K. SkinnerAbstract:Abstract Exposure of gestating female rats to the anti-androgenic endocrine disruptor Vinclozolin has been shown to induce transgenerational adult onset disease phenotypes. The current study, was designed to compare the actions of Vinclozolin to the known anti-androgenic compound flutamide. The gestating female rats were exposed to intraperitoneal injections during embryonic day 8–14 (E8–E14) to 100 mg/kg/day Vinclozolin or flutamide at either 5 mg or 20 mg/kg/day. As previously observed, Vinclozolin induced a transgenerational testis phenotype of increased spermatogenic cell apoptosis and decreased epididymal sperm number. In contrast, the flutamide exposures resulted in a testis phenotype of increased spermatogenic cell apoptosis and decreased epididymal sperm numbers in the F1 generation only, and not the F2 and F3 generation adult males. Interestingly, some of the low dose (5 mg/kg) flutamide F2 generation offspring developed spinal agenesis and supernummery development (polymelia) of limbs. Although the actions of Vinclozolin and flutamide appear similar in the F1 generation males, the transgenerational effects of Vinclozolin do not appear to be acting through the same anti-androgenic mechanism as flutamide.
-
transgenerational epigenetic effects of the endocrine disruptor Vinclozolin on pregnancies and female adult onset disease
Reproduction, 2008Co-Authors: Eric E Nilsson, Matthew D. Anway, Jacob StanfieldAbstract:Endocrine disruptor exposure during gonadal sex determination was previously found to induce male rat adult onset transgenerational disease (F1-F4 generation), and this was associated with an alteration in the epigenetic (i.e., DNA methylation) programming of the male germ line. The current study was designed to characterize the transgenerational disease phenotypes of the female adult offspring. Pregnant rats (F0 generation) were treated transiently with Vinclozolin (i.e., fungicide with anti-androgenic activity) on embryonic (E) days E8-E14 of gestation. F1 control and Vinclozolin generation offspring from different litters were mated to produce F2 offspring, and similarly F2 generation animals produced F3 generation offspring. Observations demonstrated that 9 out of 105 pregnant rats (8.6%) from the Vinclozolin F1-F3 generations exhibited uterine hemorrhage and/or anemia late in pregnancy. None (0 out of 82) of the control F1-F3 generation females had similar pregnancy problems. Complete blood cell counts and serum chemistry profiles demonstrated that selected Vinclozolin generation animals, but not controls, exhibited marked regenerative anemia in late pregnancy. Examination of kidney histology revealed moderate or severe glomerular abnormalities in 67% of the Vinclozolin F2 and F3 generation adult females compared with 18% of the controls. Adult female Vinclozolin generation animals also developed various types of tumors in 6.5% of the animals (11 out of 170), while 2% of control-line animals (3 out of 151) developed mammary tumors. Observations demonstrate that Vinclozolin exposure during gonadal sex determination promotes a transgenerational increase in pregnancy abnormalities and female adult onset disease states.
-
Transgenerational effects of the endocrine disruptor Vinclozolin on the prostate transcriptome and adult onset disease.
The Prostate, 2008Co-Authors: Matthew D. AnwayAbstract:PURPOSE The ability of an endocrine disruptor exposure during gonadal sex determination to promote a transgenerational prostate disease phenotype was investigated in the current study. METHODS Exposure of an F0 gestating female rat to the endocrine disruptor Vinclozolin during F1 embryo gonadal sex determination promoted a transgenerational adult onset prostate disease phenotype. The prostate disease phenotype and physiological parameters were determined for males from F1 to F4 generations and the prostate transcriptome was assessed in the F3 generation. RESULTS Although the prostate in prepubertal animals develops normally, abnormalities involving epithelial cell atrophy, glandular dysgenesis, prostatitis, and hyperplasia of the ventral prostate develop in older animals. The ventral prostate phenotype was transmitted for four generations (F1–F4). Analysis of the ventral prostate transcriptome demonstrated 954 genes had significantly altered expression between control and Vinclozolin F3 generation animals. Analysis of isolated ventral prostate epithelial cells identified 259 genes with significantly altered expression between control and Vinclozolin F3 generation animals. Characterization of regulated genes demonstrated several cellular pathways were influenced, including calcium and WNT. A number of genes identified have been shown to be associated with prostate disease and cancer, including beta-microseminoprotein (Msp) and tumor necrosis factor receptor superfamily 6 (Fadd). CONCLUSIONS The ability of an endocrine disruptor to promote transgenerational prostate abnormalities appears to involve an epigenetic transgenerational alteration in the prostate transcriptome and male germ-line. Potential epigenetic transgenerational alteration of prostate gene expression by environmental compounds may be important to consider in the etiology of adult onset prostate disease. Prostate 68: 517–529, 2008. © 2008 Wiley-Liss, Inc.
Mehmet Uzumcu - One of the best experts on this subject based on the ideXlab platform.
-
transgenerational effect of the endocrine disruptor Vinclozolin on male spermatogenesis
Journal of Andrology, 2006Co-Authors: Matthew D. Anway, Mushtaq A Memon, Mehmet UzumcuAbstract:ABSTRACT: The current study was designed to examine the actions of a model endocrine disruptor on embryonic testis development and male fertility. Pregnant rats (F0) that received a transient embryonic exposure to an environmental endocrine disruptor, Vinclozolin, had male offspring (F1) with reduced spermatogenic capacity. The reduced spermatogenetic capacity observed in the F1 male offspring was transmitted to the subsequent generations (F2-F4). The administration of Vinclozolin, an androgen receptor antagonist, at 100 mg/kg/day from embryonic day 8–14 (E8-E14) of pregnancy to only the F0 dam resulted in a transgenerational phenotype in the subsequent male offspring in the F1-F4 generations. The litter size and male/female sex ratios were similar in controls and the Vinclozolin generations. The average testes/body weight index of the postnatal day 60 (P60) males was not significantly different in the Vinclozolin-treated generations compared to the controls. However, the testicular spermatid number, as well as the epididymal sperm number and motility, were significantly reduced in the Vinclozolin generations compared to the control animals. Postnatal day 20 (P20) testis from the Vinclozolin F2 generation had no morphological abnormalities, but did have an increase in spermatogenic cell apoptosis. Although the P60 testis morphology was predominantly normal, the germ cell apoptosis was significantly increased in the testes cross sections of animals from the Vinclozolin generations. The increase in apoptosis was stage-specific in the testis, with tubules at stages IX—XIV having the highest increase in apoptotic germ cells. The tubules at stages I—V also had an increase in apoptotic germ cells compared to the control samples, but tubules at stages VI—VIII had no increase in apoptotic germ cells. An outcross of a Vinclozolin generation male with a wild-type female demonstrated that the reduced spermatogenic cell phenotype was transmitted through the male germ line. An outcross with a Vinclozolin generation female with a wild-type male had no phenotype. A similar phenotype was observed in outbred Sprague Dawley and inbred Fisher rat strains. Observations demonstrate that a transient exposure at the time of male sex determination to the antiandrogenic endocrine disruptor Vinclozolin can induce an apparent epigenetic transgenerational phenotype with reduced spermatogenic capacity.
-
effect of the anti androgenic endocrine disruptor Vinclozolin on embryonic testis cord formation and postnatal testis development and function
Reproductive Toxicology, 2004Co-Authors: Mehmet Uzumcu, Hiroetsu Suzuki, Michael K. SkinnerAbstract:Abstract Vinclozolin is a systemic dicarboximide fungicide that is used on fruits, vegetables, ornamental plants, and turf grass. Vinclozolin and its metabolites are known to be endocrine disruptors and act as androgen receptor antagonists. The hypothesis tested in the current study is that transient embryonic exposure to an anti-androgenic endocrine disruptor at the time of testis determination alters testis development and subsequently influences adult spermatogenic capacity and male reproduction. The effects of Vinclozolin on embryonic testicular cord formation in vitro were examined, as well as the effects of transient in utero Vinclozolin exposure on postnatal testis development and function. Embryonic day 13 (E13, sperm-positive vaginal smear day = E0) gonads were cultured in the absence or presence of Vinclozolin (50–500 μM). Vinclozolin treated gonads had significantly fewer cords (P
-
effect of the anti androgenic endocrine disruptor Vinclozolin on embryonic testis cord formation and postnatal testis development and function
Reproductive Toxicology, 2004Co-Authors: Mehmet Uzumcu, Hiroetsu Suzuki, Michael K. SkinnerAbstract:Vinclozolin is a systemic dicarboximide fungicide that is used on fruits, vegetables, ornamental plants, and turf grass. Vinclozolin and its metabolites are known to be endocrine disruptors and act as androgen receptor antagonists. The hypothesis tested in the current study is that transient embryonic exposure to an anti-androgenic endocrine disruptor at the time of testis determination alters testis development and subsequently influences adult spermatogenic capacity and male reproduction. The effects of Vinclozolin on embryonic testicular cord formation in vitro were examined, as well as the effects of transient in utero Vinclozolin exposure on postnatal testis development and function. Embryonic day 13 (E13, sperm-positive vaginal smear day = E0) gonads were cultured in the absence or presence of Vinclozolin (50-500microM). Vinclozolin treated gonads had significantly fewer cords (P < 0.05) and the histology of the cords that formed were abnormal as compared to vehicle-treated organs. Pregnant rats were exposed to Vinclozolin (100 mg/kg/day) between embryonic days 8 and 14 (E8-E14) of development. Testis morphology and function were analyzed from postnatal day (P) 0, pubertal P20, and adult P60. No significant effect of Vinclozolin on testis histology or germ cell viability was observed in P0 testis. The pubertal P20 testis from Vinclozolin exposed animals had significantly higher numbers of apoptotic germ cells (P < 0.01), but testis weight was not affected. The adult P60 sperm motility was significantly lower in Vinclozolin exposed males (P < 0.01). In addition, apoptotic germ cell number in testis of Vinclozolin exposed animals was higher in adult P60 animals. Observations demonstrate that Vinclozolin can effect embryonic testicular cord formation in vitro and that transient in utero exposure to Vinclozolin increases apoptotic germ cell numbers in the testis of pubertal and adult animals. This correlated to reduced sperm motility in the adult. In conclusion, transient exposure to Vinclozolin during the time of testis differentiation (i.e. cord formation) alters testis development and function. Observations indicate that transient exposure to an anti-androgenic endocrine disruptor during embryonic development causes delayed effects later in adult life on spermatogenic capacity.
Bennard Van Ravenzwaay - One of the best experts on this subject based on the ideXlab platform.
-
Vinclozolin a case study on the identification of endocrine active substances in the past and a future perspective
Toxicology Letters, 2013Co-Authors: Bennard Van Ravenzwaay, Susanne N Kolle, Tzutzuy Ramirez, Hennicke KampAbstract:Abstract In the late 1980s Vinclozolin was tested for prenatal developmental toxicity in rats for registration purposes in USA. At 1000 mg/kg bw, 95% of all fetuses were female upon visual inspection (ano-genital distance determination). Anti-androgenic effects (AA) were also noted in a subsequent 2-generation study. These findings triggered mechanistic investigations at BASF and at US-EPA. Results published by the latter were the starting point of the endocrine disruption (ED) discussion in the 1990s. AA effects of Vinclozolin are mediated by two metabolites, which have an antagonistic effect on the androgen receptor. Currently, determination of ED has become a major end-point in toxicology testing and the US-EPA has set up an elaborated testing paradigm to fulfill this requirement. Future screening for ED can be improved making use of new technologies. ED modes of action can be determined by three alternative (3R) methods. Steroid synthesis in H295R cells (1), androgen-receptor binding in modified yeast (2) and metabolomics (3). Using Vinclozolin as a case study, results indicate: (1) an effect on steroid synthesis in vitro, (2) an antagonistic effect on the androgen receptor and (3) that the metabolome profile of Vinclozolin is similar to that of other receptor mediated anti-androgens (e.g. flutamide).
-
Vinclozolin no transgenerational inheritance of anti androgenic effects after maternal exposure during organogenesis via the intraperitoneal route
Reproductive Toxicology, 2013Co-Authors: Steffen Schneider, Roland Buesen, Heike Marxfeld, Sibylle Groters, Bennard Van RavenzwaayAbstract:Abstract The goal of this study was to examine the potential transgenerational inheritance of anti-androgenic effects induced by Vinclozolin administered intraperitoneally to pregnant Wistar rats (Crl:WI[Han]). Dams were dosed with Vinclozolin at 0, 4 or 100 mg/kg bw/d on gestation days 6–15. Male offspring of F1–F3 generations were bred with untreated females to yield F2–F4 offspring. No evident anti-androgenic effects were observed at 4 mg/kg bw/d, but a case of hypospadias as well as delayed sexual maturation in F1 male offspring was observed as a sign of anti-androgenicity at 100 mg/kg bw/d. However, F1–F3 males developed normally to sexual maturity and were able to mate and to generate healthy progeny. Sperm count, morphology and motility were not affected in F1–F4 generation male offspring. In conclusion, transgenerational inheritance of Vinclozolin's anti-androgenic effects was not evident in outbred Wistar rats.
-
assessment of combinations of antiandrogenic compounds Vinclozolin and flutamide in a yeast based reporter assay
Regulatory Toxicology and Pharmacology, 2011Co-Authors: Susanne N Kolle, Stephanie Melchingkollmuss, G Krennrich, Robert Landsiedel, Bennard Van RavenzwaayAbstract:Abstract Humans are exposed to a combination of various substances such as cosmetic ingredients, drugs, biocides, pesticides and natural-occurring substances in food. The combined toxicological effects of two or more substances can simply be additive on the basis of response-addition, or it can be greater (synergistic) or smaller (antagonistic) than this. The need to assess combined effects of compounds with endocrine activity is currently discussed for regulatory risk assessment. We have used a well described yeast based androgen receptor transactivation assay YAS to assess the combinatorial effects of Vinclozolin and flutamide; both mediating antiandrogenicity via the androgen receptor. Both Vinclozolin and flutamide were antiandrogens of similar potency in the YAS assay. In the concentration range tested the two antiandrogens Vinclozolin and flutamide did not act synergistically. Concentration additivity was observed in the linear, non-receptor-saturated concentration range. At high concentrations of one of the two substances tested the contribution of the second at lower concentration levels was less than additive. The combined response of both compounds at high concentration levels was also less than additive (saturation effect). At concentration levels which did not elicit a response of the individual compounds, the combination of these compounds also did not elicit a response.
-
Vinclozolin the lack of a transgenerational effect after oral maternal exposure during organogenesis
Reproductive Toxicology, 2008Co-Authors: Steffen Schneider, Wolfgang Kaufmann, Roland Buesen, Bennard Van RavenzwaayAbstract:Abstract The purpose of the study was to investigate a possible transgenerational effect of the fungicide Vinclozolin on the male reproductive system following oral exposure since this effect was reported by Anway et al. [Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 2005;308(5727 (June 3)):1466–9] after intraperitoneal administration. Pregnant Wistar rats were dosed by oral gavage with Vinclozolin 0, 4 or 100 mg/(kg bw day) on days 6–15 post coitum (p.c.). F1 male offspring was mated with untreated females to produce F2, which were then similarly mated to produce F3 offspring. F0 maternal treatment had no effect on mating and fertility indices or male offspring sexual development, mean sperm parameters, or histopathology of the sexual organs in F1, F2 or F3 males (at age 127–134 days). Apoptotic germ cell counts were statistically significantly lower in F1, F2 and F3 generations, however, control values showed a pronounced variance over time. Also, as anti-androgenic compounds are more likely to induce the opposite effect (increased apoptosis), this observation is not considered to be treatment related. Consequently, spermatogenesis was not affected by Vinclozolin exposure in utero. As Vinclozolin has been shown to induce clear anti-androgenic effects in offspring following treatment with 100 mg/(kg bw day) during entire gestation, the lack of effects in this study indicates that the window of sensitivity for anti-androgenic effects is from days 16–20 p.c. No transgenerational effect on the male reproductive system was found. The NOAEL was >100 mg/(kg bw day) for fertility and reproductive performance, for systemic parental and developmental toxicity in F1, F2 and F3 males.
Frank David - One of the best experts on this subject based on the ideXlab platform.
-
Stir bar sorptive extraction applied to the determination of dicarboximide fungicides in wine
Journal of Chromatography A, 2001Co-Authors: Pat Sandra, Bart Tienpont, Joeri Vercammen, Andreas G. J. Tredoux, Tom Sandra, Frank DavidAbstract:Abstract The dicarboximide fungicides Vinclozolin, iprodione and procymidone were analyzed in white wines using stir bar sorptive extraction (SBSE) in combination with thermal desorption–capillary GC–MS analysis (TD–cGC–MS). The method was optimized using spiked water samples in a concentration range between 0.5 and 100 μg/l. Iprodione was measured as its degradation product 3,5-dichlorophenyl hydantoin. Limits of quantification in the full scan MS mode are 0.5 μg/l for Vinclozolin and procymidone and 5 μg/l for iprodione. In the ion monitoring mode, concentrations 100 times lower can be dosed. Because of wine matrix effects on the recoveries, quantification of the target fungicides in wine had to be carried out by standard addition. For the thermolabile iprodione, the accuracy of SBSE–TD–cGC–MS was verified using SBSE followed by liquid desorption and analysis by liquid chromatography–atmospheric pressure chemical ionization mass spectroscopy. Procymidone and iprodione were detected in wines in concentrations up to 65 μg/l while the highest concentration of Vinclozolin detected was smaller than 3 μg/l.
