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Michael K. Skinner - One of the best experts on this subject based on the ideXlab platform.

  • Pesticide Methoxychlor promotes the epigenetic transgenerational inheritance of adult-onset disease through the female germline
    2016
    Co-Authors: Mohan Manikkam, Muksitul M. Haque, Carlos Guerrero-bosagna, Eric E. Nilsson, Michael K. Skinner
    Abstract:

    Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide Methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to Methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and Methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the Methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the Methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be Methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide Methoxychlor has the potential t

  • Pesticide Methoxychlor promotes the epigenetic transgenerational inheritance of adult-onset disease through the female germline.
    PLoS ONE, 2014
    Co-Authors: Mohan Manikkam, Muksitul M. Haque, Carlos Guerrero-bosagna, Eric E. Nilsson, Michael K. Skinner
    Abstract:

    Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide Methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to Methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and Methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the Methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the Methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be Methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide Methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures.

  • actions of the endocrine disruptor Methoxychlor and its estrogenic metabolite on in vitro embryonic rat seminiferous cord formation and perinatal testis growth
    Reproductive Toxicology, 2001
    Co-Authors: Andrea S Cupp, Michael K. Skinner
    Abstract:

    Abstract The current study examines the actions of Methoxychlor and its estrogenic metabolite, 2, 2-bis-(p-hydroxyphenyl)-1, 1, 1-trichloroethane (HPTE), on seminiferous cord formation and growth of the developing rat testis. The developing testis in the embryonic and early postnatal period is likely more sensitive to hormonally active agents than at later stages of development. Embryonic day 13 (E13) testis organ cultures were treated with either 0.2, 2, or 20 μM Methoxychlor or 1, 3, 6, 15, 30, or 60 μM HPTE to examine effects on cord formation. No concentration of Methoxychlor completely inhibited cord formation. However, cord formation was abnormal with the presence of a reduced number of cords and appearance of “swollen” cords at the 2 and 20 μM concentrations of Methoxychlor. The swollen cords were due to an increase in the number of cells in a cord cross section and reduction of interstitial cell numbers between cords. Treatment of embryonic day 13 (E13) testes with HPTE caused abnormal cord formation at the 3 μM and 6 μM concentrations, and completely inhibited cord formation at the 15, 30, and 60 μM concentrations. In addition to the estrogenic metabolite HTPE, Methoxychlor can also be metabolized into anti-androgenic compounds. Therefore, to determine the spectrum of potential actions of Methoxychlor on testis development, different concentrations of estradiol, testosterone, and an anti-androgen (flutamide) were utilized to determine their effects on E13 testis organ culture morphology. Estradiol (1 μM) and flutamide (0.1μM) both inhibited seminiferous cord formation in E13 testis organ cultures. Therefore, Methoxychlor may be acting through the androgen and/or estrogen receptors to elicit its actions on seminiferous cord formation. Reverse transcription polymerase chain reaction (PCR) (RT-PCR) confirmed the presence of estrogen receptor alpha (ERα) mRNA from embryonic day 14 (E14) through postnatal day 5 (P5) while estrogen receptor beta (ERβ) mRNA did not appear until approximately E16 of testis development. Androgen receptor (AR) expression was present from E14 through P5 of testis development, but at apparently reduced levels at E14 and E16. Immunohistochemical analysis localized ERα to the cells of the seminiferous cords at E14 though P5 while ERβ was present in cells of the interstitium at E16 and P0. Androgen receptor was localized to germ and interstitial cells. The effects of Methoxychlor, HPTE, estradiol, and testosterone on cell growth of perinatal testes was determined with a thymidine incorporation assay in postnatal day zero (P0) testis cell cultures. Methoxychlor (0.002, 0.02, and 0.2 μM) and HPTE (2 and 20 μM) stimulated thymidine incorporation in P0 testis cell cultures in a similar manner to estradiol (0.01, 0.1, and 1 μM). In addition, testosterone (0.1 μM) also stimulated thymidine incorporation in P0 testis cultures. Observations suggest that Methoxychlor and its metabolite HPTE can alter normal embryonic testis development and growth. The actions of Methoxychlor and HPTE are likely mediated in part through the steroid receptors confirmed to be present in the developing testis.

Kiyoshi Sato - One of the best experts on this subject based on the ideXlab platform.

  • A Role of Bradyrhizobium elkanii and Closely Related Strains in the Degradation of Methoxychlor in Soil and Surface Water Environments
    Bioscience Biotechnology and Biochemistry, 2013
    Co-Authors: Koji Satsuma, Minoru Masuda, Kiyoshi Sato
    Abstract:

    We have reported that a leguminous bacterial strain, Bradyrhizobium sp. strain 17-4, isolated from river sediment, phylogenetically very close to Bradyrhizobium elkanii, degraded Methoxychlor through O-demethylation and oxidative dechlorination. In the present investigation, we found that B. elkanii (USDA94), a standard species deposited in the Culture Collection, degraded Methoxychlor. Furthermore, Bradyrhizobium sp. strain 4-1, also very close to B. elkanii, isolated from Japanese paddy field soil, degraded Methoxychlor. These B. elkanii and closely related strains degraded Methoxychlor through almost identical metabolic pathways, and cleaved the phenyl ring and mineralized. In contrast, another representative Bradyrhizobium species, B. japonicum (USDA110), did not degrade Methoxychlor at all. Based on these findings, B. elkanii and closely related strains are likely to play an important role not only in providing the readily biodegradable substrates but also in completely degrading (mineralizing) Methoxychlor by themselves in the soil and surface water environment.

  • o demethylation and successive oxidative dechlorination of Methoxychlor by bradyrhizobium sp strain 17 4 isolated from river sediment
    Applied and Environmental Microbiology, 2012
    Co-Authors: Koji Satsuma, Minoru Masuda, Kiyoshi Sato
    Abstract:

    ABSTRACT O-Demethylation of insecticide Methoxychlor is well known as a phase I metabolic reaction in various eukaryotic organisms. Regarding prokaryotic organisms, however, no individual species involved in such reaction have been specified and characterized so far. Here we successfully isolated a bacterium that mediates oxidative transformation of Methoxychlor, including O-demethylation and dechlorination, from river sediment. The isolate was found to be closely related to Bradyrhizobium elkanii at the 16S rRNA gene sequence level (100% identical). However, based on some differences in the physiological properties of this bacterium, we determined that it was actually a different species, Bradyrhizobium sp. strain 17-4. The isolate mediated O-demethylation of Methoxychlor to yield a monophenolic derivative [Mono-OH; 1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethane] as the primary degradation product. The chiral high-performance liquid chromatography (HPLC) analysis revealed that the isolate possesses high enantioselectivity favoring the formation of (S)-Mono-OH (nearly 100%). Accompanied by the sequential O-demethylation to form the bis-phenolic derivative Bis-OH [1,1,1-trichloro-2,2-bis(4-hydroxyphenyl)ethane], oxidative dechlorination of the side chain proceeded, and monophenolic carboxylic acid accumulated, followed by the formation of multiple unidentified polar degradation products. The breakdown proceeded more rapidly when reductively dechlorinated (dichloro-form) Methoxychlor was applied as the initial substrate. The resultant carboxylic acids and polar degradation products are likely further biodegraded by ubiquitous bacteria. The isolate possibly plays an important role for complete degradation (mineralization) of Methoxychlor by providing the readily biodegradable substrates.

Premendu P. Mathur - One of the best experts on this subject based on the ideXlab platform.

  • Methoxychlor induces apoptosis via mitochondria- and FasL-mediated pathways in adult rat testis.
    Chemico-Biological Interactions, 2010
    Co-Authors: S. Vaithinathan, B. Saradha, Premendu P. Mathur
    Abstract:

    Abstract In the past few years, there has been much concern about the adverse health effects of environmental contaminants in general and organochlorine in particular. Studies have shown the repro-toxic effects of long-term exposure to Methoxychlor, a member of the organochlorine family. However, the insight into the mechanisms of gonadal toxicity induced by Methoxychlor is not well known. In the present study we sought to elucidate the mechanism(s) underpinning the gonadal effects within hours of exposure to Methoxychlor. Experimental rats were divided into six groups of four each. Animals were orally administered with a single dose of Methoxychlor (50 mg/kg body weight) and killed at 0, 3, 6, 12, 24, and 72 h post-treatment. The levels and time-course of induction of apoptosis-related proteins like cytochorome C, caspase 3 and procaspase 9, Fas–FasL and NF-κB were determined to assess sequential induction of apoptosis in the rat testis. DNA damage was assessed by TUNEL assay and flowcytometry. Administration of Methoxychlor resulted in a significant increase in the levels of cytosolic cytochrome c and procaspase 9 as early as 6 h following exposure. Time-dependent elevations in the levels of Fas, FasL, pro- and cleaved caspase 3 were observed. The DNA damage was measured and showed time-dependent increase in the TUNEL positive cells, and also by flowcytometry of testicular cells. The study demonstrates induction of testicular apoptosis in adult rats following exposure to a single dose of Methoxychlor.

  • Methoxychlor-induced alteration in the levels of HSP70 and clusterin is accompanied with oxidative stress in adult rat testis.
    Journal of Biochemical and Molecular Toxicology, 2009
    Co-Authors: S. Vaithinathan, B. Saradha, Premendu P. Mathur
    Abstract:

    Methoxychlor, an organochlorine pesticide, has been reported to induce abnormalities in male reproductive tract. However, the insight into the mechanisms of gonadal toxicity induced by Methoxychlor is not well known. We investigated whether treatment with Methoxychlor would alter the levels of stress proteins, heat shock proteins (HSP), and clusterin (CLU), and oxidative stress-related parameters in the testis of adult male rats. Animals were exposed to a single dose of Methoxychlor (50 mg/kg body weight) orally and were terminated at various time points (0, 3, 6, 12, 24, and 72 h) using anesthetic ether. The levels of HSP70, CLU, and the activities of superoxide dismutase (SOD), catalase, and lipid peroxidation levels were evaluated in a 10% testis homogenate. A sequential reduction in the activities of catalase and SOD with concomitant increase in the levels of thiobarbituric acid reactive substance (TBARS) was observed. These changes elicited by Methoxychlor were very significant between 6–12 h of posttreatment. Immunoblot analysis of HSP revealed the expression of HSP72, an inducible form of HSP, at certain time points (3–24 h) following exposure to Methoxychlor. Similarly, the levels of secretory CLU (sCLU) were also found to be elevated between 3–24 h of treatment. The present data demonstrate Methoxychlor-elicited increase in the levels of inducible HSP72 and sCLU, which could be a part of protective mechanism mounted to reduce cellular oxidative damage. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:29–35, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20262

  • Transient inhibitory effect of Methoxychlor on testicular steroidogenesis in rat: an in vivo study.
    Archives of Toxicology, 2008
    Co-Authors: S. Vaithinathan, B. Saradha, Premendu P. Mathur
    Abstract:

    Methoxychlor, an organochlorine pesticide, has been reported to induce reproductive abnormalities in male reproductive tract. To get more insight into the mechanism(s) of gonadal toxicity provoked by Methoxychlor, we investigated whether treatment with Methoxychlor at low observed adverse effect level (LOAEL) would alter the activities of steroidogenic enzymes such as Δ53β-hydroxysteroid dehydrogenase (3β-HSD) and Δ517β-hydroxysteroid dehydrogenase (17β-HSD), the expression levels of steroidogenic acute regulatory (StAR) protein and androgen binding protein (ABP) in the testis of adult male rats. The experimental rats were exposed to a single dose of Methoxychlor (50 mg/kg body weight) orally. The rats were killed at 0, 3, 6, 12, 24 and 72 h following treatment using anesthetic ether and testes were collected, processed and used to measure the activities of 3β-HSD, 17β-HSD, levels of hydrogen peroxide produced and the expression levels of StAR protein, and ABP. Methoxychlor administration resulted in a sequential reduction in the expression of StAR protein and activities of 3β-HSD, 17β-HSD with concomitant increase in the levels of hydrogen peroxide in the testis. These changes were significant between 6–12 h following treatment. The levels of ABP declined at 6–12 h following exposure to Methoxychlor. The present study demonstrates transient effect of Methoxychlor at LOAEL on testicular steroidogenesis and the possible role of hydrogen peroxide in mediating these effects.

  • Induction of oxidative stress in the rat testis after short-term exposure to the organochlorine pesticide Methoxychlor
    Archives of Toxicology, 2002
    Co-Authors: C Latchoumycandane, Premendu P. Mathur
    Abstract:

    Methoxychlor is one of the environmental contaminants that has been shown to induce reproductive abnormalities in male rats. The mechanism of action of Methoxychlor on the male reproductive system remains unclear. In the present study we have sought to investigate whether short-term administration of Methoxychlor induces oxidative stress in the testis of adult rats. Methoxychlor (50, 100, or 200 mg/kg body weight per day) was administered orally for 1, 4, or 7 days. The animals were killed using anesthetic ether on the day following the last dosing. The weights of epididymides, seminal vesicles, and ventral prostate decreased after 50, 100, or 200 mg/kg per day for 7 days but remained unchanged after 1 and 4 days of treatment. The production of superoxide anion and hydrogen peroxide increased in the animals that received Methoxychlor for 4 and 7 days. The activities of the antioxidant enzymes superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase decreased, while the level of lipid peroxidation increased in the testis after 4 or 7 days of treatment. The results indicated that short-term exposure to Methoxychlor induces oxidative stress in the testis by decreasing antioxidant enzymes and increasing lipid peroxidation, possibly by inducing reactive oxygen species. In conclusion, the adverse effect of Methoxychlor on the male reproduction could be due to induction of oxidative stress in testis.

  • The effect of Methoxychlor on the epididymal antioxidant system of adult rats.
    Reproductive Toxicology, 2002
    Co-Authors: C Latchoumycandane, Premendu P. Mathur
    Abstract:

    Abstract Methoxychlor is widely used as a pesticide in many countries and has been shown to induce reproductive abnormalities in male rats, causing reduced fertility. The mechanism of action of Methoxychlor on the male reproductive system is not clear. In the present study we investigated whether administration of Methoxychlor induces oxidative stress in the epididymis and epididymal sperm of adult rats. Methoxychlor (50, 100, or 200 mg/kg body weight/day) was administered orally for 1, 4, or 7 days. The animals were killed using anesthetic ether 24 h after of the last treatment. Epididymal sperm were collected by cutting the epididymis into small pieces in Ham’s F-12 medium at 35°C. The body weight and weights of the testis, liver, and kidney did not show any significant changes in the Methoxychlor-treated rats. The weight of the epididymis, seminal vesicles, and ventral prostate as well as epididymal sperm counts decreased after 50, 100, or 200 mg/kg/day for 7 days but remained unchanged after shorter courses of treatment. Epididymal sperm motility was decreased in a dose-dependent manner in the animals treated with Methoxychlor for 4 or 7 days. The activities of the antioxidant enzymes superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase were decreased while the levels of hydrogen peroxide and lipid peroxidation were increased in the epididymal sperm as well as in the caput, corpus, and cauda epididymis after 4 or 7 days of treatment. The activities of superoxide dismutase decreased while the levels of lipid peroxidation increased in the liver but not in the kidney in all groups. Co-administration of the antioxidant vitamin E (20 mg/kg body weight/ day) to the 200 mg/kg/d Methoxychlor-treated rats for 7 days prevented significant changes in the antioxidant systems in the epididymis and epididymal sperm and prevented alterations in sperm counts and motility. The results indicated that Methoxychlor induces oxidative stress in the epididymis and epididymal sperm by decreasing antioxidant enzymes, possibly by inducing reactive oxygen species. In conclusion the adverse effect of Methoxychlor on the male reproduction could be due to induction of oxidative stress.

Tai L Guo - One of the best experts on this subject based on the ideXlab platform.

  • dietary Methoxychlor exposure modulates splenic natural killer cell activity antibody forming cell response and phenotypic marker expression in f0 and f1 generations of sprague dawley rats
    Toxicology, 2005
    Co-Authors: Kimber L White, Dori R Germolec, C D Booker, D M Hernendez, J A Mccay, K B Delclos, R R Newbold, C Weis, Tai L Guo
    Abstract:

    Abstract Methoxychlor, a chlorinated hydrocarbon pesticide, is a persistent environmental contaminant that has been identified in human reproductive tissues. Methoxychlor has been shown to be estrogenic in both in vivo and in vitro studies. As an endocrine disrupter, it may have the potential to adversely affect endocrine, reproductive, and immune systems in animals. The present study evaluated Methoxychlor's immunotoxic potential in F 0 (dams) and F 1 generations of Sprague Dawley rats exposed to an isoflavone-free diet containing Methoxychlor at concentrations of 10, 100, and 1000 ppm. In dams, exposure to Methoxychlor from gestation day 7 to postpartum day 51 (65 days total exposure) produced a significant increase in the NK activity (1000 ppm) and the percentages of T cells (1000 ppm), helper T cells (1000 ppm) and macrophages (100 and 1000 ppm). In contrast, a decrease in the numbers of splenocytes and B cells was observed at the 100 and 1000 ppm concentrations. In F 1 males, exposure to Methoxychlor gestationally, lactationally and through feed from postnatal day 22–64 (78 days total exposure) produced an increase in the spleen IgM antibody-forming cell response to sheep red blood cells (100 and 1000 ppm) and the activity of NK cells (1000 ppm). However, there was a decrease in the terminal body weight (1000 ppm), spleen weight (1000 ppm), thymus weight (100 and 1000 ppm), and the numbers of splenocytes (1000 ppm), B cells (100 and 1000 ppm), cytotoxic T cells (1000 ppm) and NK cells (100 and 1000 ppm). In F 1 females, exposure to Methoxychlor produced a decrease in the terminal body weight (1000 ppm) and the percentages of cytotoxic T cells (10, 100 and 1000 ppm). These results demonstrate that developmental and adult dietary exposure to Methoxychlor modulates immune responses in Sprague Dawley rats. Immunological changes were more pronounced in the F 1 generation male rats that were exposed during gestation and postpartum, when compared to the F 0 and F 1 generation females. Increases in antibody-forming cell response and NK cell activity, and altered spleen cell subpopulation numbers were observed in the F 1 generation male rats, without similar changes to the F 1 generation females.

Ian D Morris - One of the best experts on this subject based on the ideXlab platform.

  • effects of endocrine disrupting contaminants on amphibian oogenesis Methoxychlor inhibits progesterone induced maturation of xenopus laevis oocytes in vitro
    Environmental Health Perspectives, 1999
    Co-Authors: Daniel B Pickford, Ian D Morris
    Abstract:

    There is currently little evidence of pollution-induced endocrine dysfunction in amphibia, in spite of widespread concern over global declines in this ecologically diverse group. Data regarding the potential effects of endocrine-disrupting contaminants (EDCs) on reproductive function in amphibia are particularly lacking. We hypothesized that estrogenic EDCs may disrupt progesterone-induced oocyte maturation in the adult amphibian ovary, and tested this with an in vitro germinal vesicle breakdown assay using defolliculated oocytes from the African clawed frog, Xenopus laevis. While a variety of natural and synthetic estrogens and xenoestrogens were inactive in this system, the proestrogenic pesticide Methoxychlor was a surprisingly potent inhibitor of progesterone-induced oocyte maturation (median inhibitive concentration, 72 nM). This inhibitory activity was specific to Methoxychlor, rather than to its estrogenic contaminants or metabolites, and was not antagonized by the estrogen receptor antagonist ICI 182,780, suggesting that this activity is not estrogenic per se. The inhibitory activity of Methoxychlor was dose dependent, reversible, and early acting. However, washout was unable to reverse the effect of short Methoxychlor exposure, and Methoxychlor did not competitively displace [3H]progesterone from a specific binding site in the oocyte plasma membrane. Therefore, Methoxychlor may exert its action not directly at the site of progesterone action, but downstream on early events in maturational signaling, although the precise mechanism of action is unclear. The activity of Methoxychlor in this system indicates that xenobiotics may exert endocrine-disrupting effects through interference with progestin-regulated processes and through mechanisms other than receptor antagonism.