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  1. Article ; Online: Targeted genome-wide methylation and gene expression analyses reveal signaling pathways involved in ovarian dysfunction after developmental EDC exposure in rats.

    Zama, Aparna Mahakali / Uzumcu, Mehmet

    Biology of reproduction

    2013  Volume 88, Issue 2, Page(s) 52

    Abstract: Transient exposure to methoxychlor (MXC), an environmental endocrine-disrupting chemical, during fetal and neonatal stages causes ovarian dysfunction in pubertal, adult, and aging animals. Adult animals have reduced number of ovulations and abnormal ... ...

    Abstract Transient exposure to methoxychlor (MXC), an environmental endocrine-disrupting chemical, during fetal and neonatal stages causes ovarian dysfunction in pubertal, adult, and aging animals. Adult animals have reduced number of ovulations and abnormal follicular composition associated with altered gene expression and DNA methylation patterns. To test the hypothesis that the ovarian epigenomic changes induced by MXC are detectable following the exposure period, leading to altered gene expression by adulthood, we conducted a targeted genome-wide methylation study using Nimblegen 3x720K CpG Island Plus RefSeq Promoter Arrays. Control (vehicle), low-dose MXC (20 μg/kg/day), or high-dose MXC (100 mg/kg/day) treatments were administered between Embryonic Day 19 and Postnatal Day (PND) 7. Ovaries were collected at PND 7 immediately after exposure or at adulthood, PND 60. Array hybridizations were conducted with genomic DNA after methylated DNA immunoprecipitation and the array data were analyzed. DNA methylation events were functionally annotated, and candidate loci common to all the treatments or unique to some treatments were identified. Specific loci encoding signaling molecules such as the regulatory subunit p85 of phosphoinositide-3-kinase, insulin-like growth factor-1 receptor, Harvey rat sarcoma viral oncogene, insulin receptor, and forkhead box protein O3 were identified to be hypermethylated in MXC-treated ovaries at PND 7 and/or PND 60. Examination of gene expression changes with TaqMan low-density arrays revealed that nearly 25% of the genes that were assayed were downregulated. These data demonstrate that key molecules in specific signaling pathways such as PTEN signaling, IGF-1 signaling, or rapid estrogen signaling are epigenetically altered in MXC-exposed ovaries, which is associated with ovarian dysfunction and female infertility.
    MeSH term(s) Animals ; DNA Methylation/drug effects ; DNA Methylation/genetics ; Dose-Response Relationship, Drug ; Endocrine Disruptors/pharmacology ; Female ; Genome/drug effects ; Genome/genetics ; Infertility, Female ; Methoxychlor/pharmacology ; Models, Animal ; Ovarian Follicle/drug effects ; Ovarian Follicle/physiopathology ; Ovary/drug effects ; Ovary/embryology ; Ovary/physiopathology ; Ovulation/drug effects ; Ovulation/physiology ; Pregnancy ; Prenatal Exposure Delayed Effects/physiopathology ; Rats ; Rats, Inbred F344 ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Transcriptome/drug effects ; Transcriptome/genetics
    Chemical Substances Endocrine Disruptors ; Methoxychlor (RIA79UD69L)
    Language English
    Publishing date 2013-02-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1118-6
    ISSN 1529-7268 ; 0006-3363
    ISSN (online) 1529-7268
    ISSN 0006-3363
    DOI 10.1095/biolreprod.112.104802
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Epigenetic effects of endocrine-disrupting chemicals on female reproduction: an ovarian perspective.

    Zama, Aparna Mahakali / Uzumcu, Mehmet

    Frontiers in neuroendocrinology

    2010  Volume 31, Issue 4, Page(s) 420–439

    Abstract: The link between in utero and neonatal exposure to environmental toxicants, such as endocrine-disrupting chemicals (EDCs) and adult female reproductive disorders is well established in both epidemiological and animal studies. Recent studies examining the ...

    Abstract The link between in utero and neonatal exposure to environmental toxicants, such as endocrine-disrupting chemicals (EDCs) and adult female reproductive disorders is well established in both epidemiological and animal studies. Recent studies examining the epigenetic mechanisms involved in mediating the effects of EDCs on female reproduction are gathering momentum. In this review, we describe the developmental processes that are susceptible to EDC exposures in female reproductive system, with a special emphasis on the ovary. We discuss studies with select EDCs that have been shown to have physiological and correlated epigenetic effects in the ovary, neuroendocrine system, and uterus. Importantly, EDCs that can directly target the ovary can alter epigenetic mechanisms in the oocyte, leading to transgenerational epigenetic effects. The potential mechanisms involved in such effects are also discussed.
    MeSH term(s) Animals ; Endocrine Disruptors/toxicity ; Environmental Pollutants/toxicity ; Epigenomics ; Female ; Gene Expression Profiling ; Genitalia, Female/drug effects ; Genitalia, Female/growth & development ; Humans ; Infertility, Female/chemically induced ; Infertility, Female/genetics ; Male ; Mice ; Neurosecretory Systems/drug effects ; Neurosecretory Systems/growth & development ; Ovary/drug effects ; Ovary/growth & development ; Receptors, Androgen/analysis ; Receptors, Estrogen/analysis ; Uterus/drug effects ; Uterus/growth & development
    Chemical Substances Endocrine Disruptors ; Environmental Pollutants ; Receptors, Androgen ; Receptors, Estrogen
    Language English
    Publishing date 2010-07-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 390985-2
    ISSN 1095-6808 ; 0532-7466 ; 0091-3022
    ISSN (online) 1095-6808
    ISSN 0532-7466 ; 0091-3022
    DOI 10.1016/j.yfrne.2010.06.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Fetal and neonatal exposure to the endocrine disruptor methoxychlor causes epigenetic alterations in adult ovarian genes.

    Zama, Aparna Mahakali / Uzumcu, Mehmet

    Endocrinology

    2009  Volume 150, Issue 10, Page(s) 4681–4691

    Abstract: Exposure to endocrine-disrupting chemicals during development could alter the epigenetic programming of the genome and result in adult-onset disease. Methoxychlor (MXC) and its metabolites possess estrogenic, antiestrogenic, and antiandrogenic activities. ...

    Abstract Exposure to endocrine-disrupting chemicals during development could alter the epigenetic programming of the genome and result in adult-onset disease. Methoxychlor (MXC) and its metabolites possess estrogenic, antiestrogenic, and antiandrogenic activities. Previous studies showed that fetal/neonatal exposure to MXC caused adult ovarian dysfunction due to altered expression of key ovarian genes including estrogen receptor (ER)-beta, which was down-regulated, whereas ERalpha was unaffected. The objective of the current study was to evaluate changes in global and gene-specific methylation patterns in adult ovaries associated with the observed defects. Rats were exposed to MXC (20 microg/kgxd or 100 mg/kg.d) between embryonic d 19 and postnatal d 7. We performed DNA methylation analysis of the known promoters of ERalpha and ERbeta genes in postnatal d 50-60 ovaries using bisulfite sequencing and methylation-specific PCRs. Developmental exposure to MXC led to significant hypermethylation in the ERbeta promoter regions (P < 0.05), whereas the ERalpha promoter was unaffected. We assessed global DNA methylation changes using methylation-sensitive arbitrarily primed PCR and identified 10 genes that were hypermethylated in ovaries from exposed rats. To determine whether the MXC-induced methylation changes were associated with increased DNA methyltransferase (DNMT) levels, we measured the expression levels of Dnmt3a, Dnmt3b, and Dnmt3l using semiquantitative RT-PCR. Whereas Dnmt3a and Dnmt3l were unchanged, Dnmt3b expression was stimulated in ovaries of the 100 mg/kg MXC group (P < 0.05), suggesting that increased DNMT3B may cause DNA hypermethylation in the ovary. Overall, these data suggest that transient exposure to MXC during fetal and neonatal development affects adult ovarian function via altered methylation patterns.
    MeSH term(s) Animals ; Animals, Newborn ; DNA Methylation/drug effects ; DNA Modification Methylases/metabolism ; Down-Regulation ; Epigenesis, Genetic/drug effects ; Estrogen Receptor alpha/metabolism ; Estrogen Receptor beta/metabolism ; Female ; Methoxychlor/toxicity ; Ovary/drug effects ; Ovary/metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects ; Promoter Regions, Genetic ; Rats ; Rats, Inbred F344 ; Up-Regulation
    Chemical Substances Estrogen Receptor alpha ; Estrogen Receptor beta ; DNA Modification Methylases (EC 2.1.1.-) ; Methoxychlor (RIA79UD69L)
    Language English
    Publishing date 2009-07-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/en.2009-0499
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Regulation of arcuate genes by developmental exposures to endocrine-disrupting compounds in female rats.

    Roepke, Troy A / Yang, Jennifer A / Yasrebi, Ali / Mamounis, Kyle J / Oruc, Elif / Zama, Aparna Mahakali / Uzumcu, Mehmet

    Reproductive toxicology (Elmsford, N.Y.)

    2016  Volume 62, Page(s) 18–26

    Abstract: Developmental exposure to endocrine-disrupting compounds (EDCs) alters reproduction and energy homeostasis, both of which are regulated by the arcuate nucleus (ARC). Little is known about the effects of EDC on ARC gene expression. In Experiment #1, ... ...

    Abstract Developmental exposure to endocrine-disrupting compounds (EDCs) alters reproduction and energy homeostasis, both of which are regulated by the arcuate nucleus (ARC). Little is known about the effects of EDC on ARC gene expression. In Experiment #1, pregnant dams were treated with either two doses of bisphenol A (BPA) or oil from embryonic day (E)18-21. Neonates were injected from postnatal day (PND)0-7. Vaginal opening, body weights, and ARC gene expression were measured. Chrm3 (muscarinic receptor 3) and Adipor1 (adiponectin receptor 1) were decreased by BPA. Bdnf (brain-derived neurotropic factor), Igf1 (insulin-like growth factor 1), Htr2c (5-hydroxytryptamine receptor), and Cck2r (cholescystokinin 2 receptor) were impacted. In Experiment #2, females were exposed to BPA, diethylstilbestrol (DES), di(2-ethylhexyl)phthalate, or methoxychlor (MXC) during E11-PND7. MXC and DES advanced the age of vaginal opening and ARC gene expression was impacted. These data indicate that EDCs alter ARC genes involved in reproduction and energy homeostasis in females.
    Language English
    Publishing date 2016-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 639342-1
    ISSN 1873-1708 ; 0890-6238
    ISSN (online) 1873-1708
    ISSN 0890-6238
    DOI 10.1016/j.reprotox.2016.04.014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Genetic analysis of Kit ligand functions during mouse spermatogenesis.

    Bedell, Mary A / Mahakali Zama, Aparna

    Journal of andrology

    2003  Volume 25, Issue 2, Page(s) 188–199

    MeSH term(s) Animals ; Mice ; Mutation ; Oncogene Proteins/physiology ; Proto-Oncogene Proteins c-kit ; Signal Transduction/physiology ; Spermatogenesis/physiology ; Stem Cell Factor/genetics
    Chemical Substances Oncogene Proteins ; Stem Cell Factor ; Proto-Oncogene Proteins c-kit (EC 2.7.10.1)
    Language English
    Publishing date 2003-10-09
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
    ZDB-ID 604624-1
    ISSN 1939-4640 ; 0196-3635
    ISSN (online) 1939-4640
    ISSN 0196-3635
    DOI 10.1002/j.1939-4640.2004.tb02779.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Analysis of hypomorphic KitlSl mutants suggests different requirements for KITL in proliferation and migration of mouse primordial germ cells.

    Mahakali Zama, Aparna / Hudson, F Parker / Bedell, Mary A

    Biology of reproduction

    2005  Volume 73, Issue 4, Page(s) 639–647

    Abstract: Germ cell development in mice is initiated when a small number of primordial germ cells (PGCs) are set aside from somatic cells during gastrulation. In the subsequent 4 to 5 days, PGCs enter the hindgut, undergo a directed migration away from the hindgut ...

    Abstract Germ cell development in mice is initiated when a small number of primordial germ cells (PGCs) are set aside from somatic cells during gastrulation. In the subsequent 4 to 5 days, PGCs enter the hindgut, undergo a directed migration away from the hindgut into the developing gonads, and undergo a massive increase in cell number. It is well established that Kit ligand (KITL, also known as stem cell factor and mast cell growth factor) is required for the survival and proliferation of PGCs. However, there is little information on a direct role for KITL in PGC migration. By comparing the effects of multiple Kitl mutations, including two N-ethyl-N-nitrosourea-induced hypomorphic mutations, we were able to distinguish stages of PGC development that are preferentially affected by certain mutations. We provide evidence that the requirements for KITL in proliferation are different in PGCs before and after they start migrating, and different levels of KITL function are required to support PGC proliferation and migration. This study illustrates the usefulness of an allelic series of mutations to dissect developmental processes and suggests that these mutants may be useful for further studies of molecular mechanisms of KITL functions in gametogenesis.
    MeSH term(s) Animals ; Cell Count ; Cell Movement/genetics ; Cell Proliferation ; Ethylnitrosourea/toxicity ; Female ; Male ; Mice ; Mice, Mutant Strains ; Mutation ; Ovary/cytology ; Ovary/embryology ; Ovum/cytology ; Ovum/metabolism ; Spermatozoa/cytology ; Spermatozoa/metabolism ; Stem Cell Factor/drug effects ; Stem Cell Factor/genetics ; Stem Cell Factor/metabolism ; Testis/cytology ; Testis/embryology
    Chemical Substances Stem Cell Factor ; Ethylnitrosourea (P8M1T4190R)
    Language English
    Publishing date 2005-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 1118-6
    ISSN 1529-7268 ; 0006-3363
    ISSN (online) 1529-7268
    ISSN 0006-3363
    DOI 10.1095/biolreprod.105.042846
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Developmental methoxychlor exposure affects multiple reproductive parameters and ovarian folliculogenesis and gene expression in adult rats.

    Armenti, AnnMarie E / Zama, Aparna Mahakali / Passantino, Lisa / Uzumcu, Mehmet

    Toxicology and applied pharmacology

    2008  Volume 233, Issue 2, Page(s) 286–296

    Abstract: Methoxychlor (MXC) is an organochlorine pesticide with estrogenic, anti-estrogenic, and anti-androgenic properties. To investigate whether transient developmental exposure to MXC could cause adult ovarian dysfunction, we exposed Fischer rats to 20 microg/ ...

    Abstract Methoxychlor (MXC) is an organochlorine pesticide with estrogenic, anti-estrogenic, and anti-androgenic properties. To investigate whether transient developmental exposure to MXC could cause adult ovarian dysfunction, we exposed Fischer rats to 20 microg/kg/day (low dose; environmentally relevant dose) or 100 mg/kg/day (high dose) MXC between 19 days post coitum and postnatal day 7. Multiple reproductive parameters, serum hormone levels, and ovarian morphology and molecular markers were examined from prepubertal through adult stages. High dose MXC accelerated pubertal onset and first estrus, reduced litter size, and increased irregular cyclicity (P<0.05). MXC reduced superovulatory response to exogenous gonadotropins in prepubertal females (P<0.05). Rats exposed to high dose MXC had increasing irregular estrous cyclicity beginning at 4 months of age, with all animals showing abnormal cycles by 6 months. High dose MXC reduced serum progesterone, but increased luteinizing hormone (LH). Follicular composition analysis revealed an increase in the percentage of preantral and early antral follicles and a reduction in the percentage of corpora lutea in high dose MXC-treated ovaries (P<0.05). Immunohistochemical staining and quantification of the staining intensity showed that estrogen receptor beta was reduced by high dose MXC while anti-Mullerian hormone was upregulated by both low- and high dose MXC in preantral and early antral follicles (P<0.05). High dose MXC significantly reduced LH receptor expression in large antral follicles (P<0.01), and down-regulated cytochrome P450 side-chain cleavage. These results demonstrated that developmental MXC exposure results in reduced ovulation and fertility and premature aging, possibly by altering ovarian gene expression and folliculogenesis.
    MeSH term(s) Animals ; Anti-Mullerian Hormone/metabolism ; Cholesterol Side-Chain Cleavage Enzyme/drug effects ; Cholesterol Side-Chain Cleavage Enzyme/metabolism ; Dose-Response Relationship, Drug ; Estrogen Receptor beta/drug effects ; Estrogen Receptor beta/metabolism ; Estrous Cycle/drug effects ; Female ; Fertility/drug effects ; Gene Expression Regulation/drug effects ; Immunohistochemistry ; Insecticides/administration & dosage ; Insecticides/toxicity ; Litter Size/drug effects ; Luteinizing Hormone/drug effects ; Luteinizing Hormone/metabolism ; Methoxychlor/administration & dosage ; Methoxychlor/toxicity ; Ovarian Follicle/drug effects ; Ovarian Follicle/pathology ; Ovulation/drug effects ; Pregnancy ; Progesterone/metabolism ; Rats ; Rats, Inbred F344 ; Sexual Maturation/drug effects
    Chemical Substances Estrogen Receptor beta ; Insecticides ; Progesterone (4G7DS2Q64Y) ; Anti-Mullerian Hormone (80497-65-0) ; Luteinizing Hormone (9002-67-9) ; Cholesterol Side-Chain Cleavage Enzyme (EC 1.14.15.6) ; Methoxychlor (RIA79UD69L)
    Language English
    Publishing date 2008-12-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 204477-8
    ISSN 1096-0333 ; 0041-008X
    ISSN (online) 1096-0333
    ISSN 0041-008X
    DOI 10.1016/j.taap.2008.09.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Orthotopic transplantation of neonatal GFP rat ovary as experimental model to study ovarian development and toxicology.

    Marano, Jason E / Sun, Dongming / Zama, Aparna Mahakali / Young, Wise / Uzumcu, Mehmet

    Reproductive toxicology (Elmsford, N.Y.)

    2008  Volume 26, Issue 3-4, Page(s) 191–196

    Abstract: The rat is one of the most commonly used experimental animal species in biomedical research. The availability of new research tools in rats could therefore provide considerable advances in the areas where this mammal is extensively used. We report the ... ...

    Abstract The rat is one of the most commonly used experimental animal species in biomedical research. The availability of new research tools in rats could therefore provide considerable advances in the areas where this mammal is extensively used. We report the development of a new green fluorescent protein (GFP) rat strain suitable for organ transplantation and the birth of GFP rats following orthotopic transplantation of neonatal ovaries from this newly developed GFP rat strain to a wild-type Fischer 344 (F344) strain. A new GFP rat strain was developed by backcrossing eGFP Sprague-Dawley (SD-Tg(CAG-EGFP)Cz-004Osb) to wild-type F344 for eight generations. Whole ovaries from postnatal day (PND) 8 or PND 21 GFP rats were transplanted orthotopically to bilaterally ovariectomized wild-type adult females (n=6). All recipients were mated, and three of the five resulting litters contained GFP pups. In the PND 8 group, all recipients cycled regularly and the ovarian morphology appeared normal when collected at 9 months post-transplantation. In the PND 21 group, 60% of the recipients displayed regular estrous cycles at 9 months post-transplantation, but showed reduced ovarian size. This new strain and neonatal orthotopic transplantation could be useful for many biomedical fields including transplantation, development, and reproductive toxicology.
    MeSH term(s) Animals ; Animals, Newborn ; Female ; Fertility ; Green Fluorescent Proteins ; Ovary/drug effects ; Ovary/growth & development ; Ovary/transplantation ; Rats ; Rats, Inbred F344
    Chemical Substances Green Fluorescent Proteins (147336-22-9)
    Language English
    Publishing date 2008-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 639342-1
    ISSN 1873-1708 ; 0890-6238
    ISSN (online) 1873-1708
    ISSN 0890-6238
    DOI 10.1016/j.reprotox.2008.09.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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