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Jodi Anne Flaws - One of the best experts on this subject based on the ideXlab platform.
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mono 2 ethylhexyl phthalate accelerates early Folliculogenesis and inhibits steroidogenesis in cultured mouse whole ovaries and antral follicles
Biology of Reproduction, 2015Co-Authors: Patrick R Hannon, Katherine E Brannick, Wei Wang, Jodi Anne FlawsAbstract:Humans are ubiquitously exposed to di(2-ethylhexyl) phthalate (DEHP), which is an environmental toxicant present in common consumer products. DEHP potentially targets the ovary through its metabolite mono(2-ethylhexyl) phthalate (MEHP). However, the direct effects of MEHP on ovarian Folliculogenesis and steroidogenesis, two processes essential for reproductive and nonreproductive health, are unknown. The present study tested the hypotheses that MEHP directly accelerates early Folliculogenesis via overactivation of phosphatidylinositol 3kinase (PI3K) signaling, a pathway that regulates primordial follicle quiescence and activation, and inhibits the synthesis of steroid hormones by decreasing steroidogenic enzyme levels. Neonatal ovaries from CD-1 mice were cultured for 6 days with vehicle control, DEHP, or MEHP (0.2–20 lg/ml) to assess the direct effects on Folliculogenesis and PI3K signaling. Further, antral follicles from adult CD-1 mice were cultured with vehicle control or MEHP (0.1–10 lg/ml) for 24–96 h to establish the temporal effects of MEHP on steroid hormones and steroidogenic enzymes. In the neonatal ovaries, MEHP, but not DEHP, decreased phosphatase and tensin homolog levels and increased phosphorylated protein kinase B levels, leading to a decrease in the percentage of germ cells and an increase in the percentage of primary follicles. In the antral follicles, MEHP decreased the mRNA levels of 17alpha-hydroxylase-17,20-desmolase, 17betahydroxysteroid dehydrogenase, and aromatase leading to a decrease in testosterone, estrone, and estradiol levels. Collectively, MEHP mediates the effect of DEHP on accelerated Folliculogenesis via overactivating PI3K signaling and inhibits steroidogenesis by decreasing steroidogenic enzyme levels. follicle, Folliculogenesis, mono(2-ethylhexyl) phthalate, ovary, phthalate, steroidogenesis
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daily exposure to di 2 ethylhexyl phthalate alters estrous cyclicity and accelerates primordial follicle recruitment potentially via dysregulation of the phosphatidylinositol 3 kinase signaling pathway in adult mice
Biology of Reproduction, 2014Co-Authors: Patrick R Hannon, Jackye Peretz, Jodi Anne FlawsAbstract:Humans are exposed daily to di(2-ethylhexyl) phthalate (DEHP), a plasticizer found in many consumer, medical, and building products containing polyvinyl chloride. Large doses of DEHP disrupt normal ovarian function; however, the effects of DEHP at environmentally relevant levels, the effects of DEHP on Folliculogenesis, and the mechanisms by which DEHP disrupts ovarian function are unclear. The present study tested the hypothesis that relatively low levels of DEHP disrupt estrous cyclicity as well as accelerate primordial follicle recruitment by dysregulating phosphatidylinositol 3-kinase (PI3K) signaling. Adult CD-1 mice were orally dosed with DEHP (20 μg/kg/day–750 mg/kg/day) daily for 10 and 30 days. Following dosing, the effects on estrous cyclicity were examined, and follicle numbers were histologically quantified. Further, the ovarian mRNA and protein levels of PI3K signaling factors that are associated with early Folliculogenesis were quantified. The data indicate that 10- and 30-day exposure to DEHP prolonged the duration of estrus and accelerated primordial follicle recruitment. Specifically, DEHP exposure decreased the percentage of primordial follicles and increased the percentage of primary follicles counted following 10-day exposure and increased the percentage of primary follicles counted following 30-day exposure. DEHP exposure, at doses that accelerate Folliculogenesis, increased the levels of 3-phosphoinositide-dependent protein kinase-1, mammalian target of rapamycin complex 1, and protein kinase B and decreased the levels of phosphatase and tensin homolog, potentially driving PI3K signaling. Collectively, relatively low levels of DEHP disrupt estrous cyclicity and accelerate primordial follicle recruitment potentially via a mechanism involving dysregulation of PI3K signaling.
Patrick R Hannon - One of the best experts on this subject based on the ideXlab platform.
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mono 2 ethylhexyl phthalate accelerates early Folliculogenesis and inhibits steroidogenesis in cultured mouse whole ovaries and antral follicles
Biology of Reproduction, 2015Co-Authors: Patrick R Hannon, Katherine E Brannick, Wei Wang, Jodi Anne FlawsAbstract:Humans are ubiquitously exposed to di(2-ethylhexyl) phthalate (DEHP), which is an environmental toxicant present in common consumer products. DEHP potentially targets the ovary through its metabolite mono(2-ethylhexyl) phthalate (MEHP). However, the direct effects of MEHP on ovarian Folliculogenesis and steroidogenesis, two processes essential for reproductive and nonreproductive health, are unknown. The present study tested the hypotheses that MEHP directly accelerates early Folliculogenesis via overactivation of phosphatidylinositol 3kinase (PI3K) signaling, a pathway that regulates primordial follicle quiescence and activation, and inhibits the synthesis of steroid hormones by decreasing steroidogenic enzyme levels. Neonatal ovaries from CD-1 mice were cultured for 6 days with vehicle control, DEHP, or MEHP (0.2–20 lg/ml) to assess the direct effects on Folliculogenesis and PI3K signaling. Further, antral follicles from adult CD-1 mice were cultured with vehicle control or MEHP (0.1–10 lg/ml) for 24–96 h to establish the temporal effects of MEHP on steroid hormones and steroidogenic enzymes. In the neonatal ovaries, MEHP, but not DEHP, decreased phosphatase and tensin homolog levels and increased phosphorylated protein kinase B levels, leading to a decrease in the percentage of germ cells and an increase in the percentage of primary follicles. In the antral follicles, MEHP decreased the mRNA levels of 17alpha-hydroxylase-17,20-desmolase, 17betahydroxysteroid dehydrogenase, and aromatase leading to a decrease in testosterone, estrone, and estradiol levels. Collectively, MEHP mediates the effect of DEHP on accelerated Folliculogenesis via overactivating PI3K signaling and inhibits steroidogenesis by decreasing steroidogenic enzyme levels. follicle, Folliculogenesis, mono(2-ethylhexyl) phthalate, ovary, phthalate, steroidogenesis
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the effects of phthalates on the ovary
Frontiers in Endocrinology, 2015Co-Authors: Patrick R Hannon, Jodi A FlawsAbstract:Phthalates are commonly used as plasticizers in the manufacturing of flexible polyvinyl chloride products. Large production volumes of phthalates and their widespread use in common consumer, medical, building, and personal care products lead to ubiquitous human exposure via oral ingestion, inhalation, and dermal contact. Recently, several phthalates have been classified as reproductive toxicants and endocrine-disrupting chemicals based on their ability to interfere with normal reproductive function and hormone signaling. Therefore, exposure to phthalates represents a public health concern. Currently, the effects of phthalates on male reproduction are better understood than the effects on female reproduction. This is of concern because women are often exposed to higher levels of phthalates than men through their extensive use of personal care and cosmetic products. In the female, a primary regulator of reproductive and endocrine function is the ovary. Specifically, the ovary is responsible for Folliculogenesis, the proper maturation of gametes for fertilization, and steroidogenesis, and the synthesis of necessary sex steroid hormones. Any defect in the regulation of these processes can cause complications for reproductive and non-reproductive health. For instance, phthalate-induced defects in Folliculogenesis and steroidogenesis can cause infertility, premature ovarian failure, and non-reproductive disorders. Presently, there is a paucity of knowledge on the effects of phthalates on normal ovarian function; however, recent work has established the ovary as a target of phthalate toxicity. This review summarizes what is currently known about the effects of phthalates on the ovary and the mechanisms by which phthalates exert ovarian toxicity, with a particular focus on the effects on Folliculogenesis and steroidogenesis. Further, this review outlines future directions, including the necessity of examining the effects of phthalates at doses that mimic human exposure.
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daily exposure to di 2 ethylhexyl phthalate alters estrous cyclicity and accelerates primordial follicle recruitment potentially via dysregulation of the phosphatidylinositol 3 kinase signaling pathway in adult mice
Biology of Reproduction, 2014Co-Authors: Patrick R Hannon, Jackye Peretz, Jodi Anne FlawsAbstract:Humans are exposed daily to di(2-ethylhexyl) phthalate (DEHP), a plasticizer found in many consumer, medical, and building products containing polyvinyl chloride. Large doses of DEHP disrupt normal ovarian function; however, the effects of DEHP at environmentally relevant levels, the effects of DEHP on Folliculogenesis, and the mechanisms by which DEHP disrupts ovarian function are unclear. The present study tested the hypothesis that relatively low levels of DEHP disrupt estrous cyclicity as well as accelerate primordial follicle recruitment by dysregulating phosphatidylinositol 3-kinase (PI3K) signaling. Adult CD-1 mice were orally dosed with DEHP (20 μg/kg/day–750 mg/kg/day) daily for 10 and 30 days. Following dosing, the effects on estrous cyclicity were examined, and follicle numbers were histologically quantified. Further, the ovarian mRNA and protein levels of PI3K signaling factors that are associated with early Folliculogenesis were quantified. The data indicate that 10- and 30-day exposure to DEHP prolonged the duration of estrus and accelerated primordial follicle recruitment. Specifically, DEHP exposure decreased the percentage of primordial follicles and increased the percentage of primary follicles counted following 10-day exposure and increased the percentage of primary follicles counted following 30-day exposure. DEHP exposure, at doses that accelerate Folliculogenesis, increased the levels of 3-phosphoinositide-dependent protein kinase-1, mammalian target of rapamycin complex 1, and protein kinase B and decreased the levels of phosphatase and tensin homolog, potentially driving PI3K signaling. Collectively, relatively low levels of DEHP disrupt estrous cyclicity and accelerate primordial follicle recruitment potentially via a mechanism involving dysregulation of PI3K signaling.
Jennifer L Dube - One of the best experts on this subject based on the ideXlab platform.
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synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function
Molecular Endocrinology, 2001Co-Authors: Changning Yan, Pei Wang, Janet L Demayo, Francesco J Demayo, Julia A Elvin, Cecilia Carino, Sarvamangala V Prasad, Sheri S Skinner, Bonnie S Dunbar, Jennifer L DubeAbstract:Knockout mouse technology has been used over the last decade to define the essential roles of ovarian-expressed genes and uncover genetic interactions. In particular, we have used this technology to study the function of multiple members of the transforming growth factor-beta superfamily including inhibins, activins, and growth differentiation factor 9 (GDF-9 or Gdf9). Knockout mice lacking GDF-9 are infertile due to a block in Folliculogenesis at the primary follicle stage. In addition, recombinant GDF-9 regulates multiple cumulus granulosa cell functions in the periovulatory period including hyaluronic acid synthesis and cumulus expansion. We have also cloned an oocyte-specific homolog of GDF-9 from mice and humans, which is termed bone morphogenetic protein 15 (BMP-15 or Bmp15). To define the function of BMP-15 in mice, we generated embryonic stem cells and knockout mice, which have a null mutation in this X-linked gene. Male chimeric and Bmp15 null mice are normal and fertile. In contrast to Bmp15 null males and Gdf9 knockout females, Bmp15 null females (Bmp15(-/-)) are subfertile and usually have minimal ovarian histopathological defects, but demonstrate decreased ovulation and fertilization rates. To further decipher possible direct or indirect genetic interactions between GDF-9 and BMP-15, we have generated double mutant mice lacking one or both alleles of these related homologs. Double homozygote females (Bmp15(-/-)Gdf9(-/-)) display oocyte loss and cysts and resemble Gdf9(-/-) mutants. In contrast, Bmp15(-/-)Gdf9(+/-) female mice have more severe fertility defects than Bmp15(-/-) females, which appear to be due to abnormalities in ovarian Folliculogenesis, cumulus cell physiology, and fertilization. Thus, the dosage of intact Bmp15 and Gdf9 alleles directly influences the destiny of the oocyte during Folliculogenesis and in the periovulatory period. These studies have important implications for human fertility control and the maintenance of fertility and normal ovarian physiology.
Ralf Butzow - One of the best experts on this subject based on the ideXlab platform.
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human growth differentiation factor 9 gdf 9 and its novel homolog gdf 9b are expressed in oocytes during early Folliculogenesis
The Journal of Clinical Endocrinology and Metabolism, 1999Co-Authors: Johanna Aaltonen, Mika Laitinen, Kaisa Vuojolainen, Risto Jaatinen, Nina Horellikuitunen, Laura Seppa, Henna Louhio, Timo Tuuri, Jari Sjoberg, Ralf ButzowAbstract:Growth differentiation factor 9 (GDF-9) is a transforming growth factor-beta family member that is required for normal Folliculogenesis in female mice, but its role as a regulator of human fertility is still unclear. We determined here by in situ hybridization and immunohistochemical analyses the localization of the GDF-9 messenger ribonucleic acid (mRNA) and protein during human Folliculogenesis. The GDF-9 transcripts were not detected in primordial follicles, but they are abundantly expressed in primary follicles in frozen sections of ovarian cortical tissue material obtained at laparoscopic surgery. We raised antipeptide antibodies against GDF-9 and showed by immunohistochemical studies on paraffin sections of whole human ovaries that the GDF-9 protein is most abundantly expressed in primary follicles. We recently demonstrated that a novel GDF-9-related factor, GDF-9B, is coexpressed with GDF-9 during murine Folliculogenesis. We now isolated human GDF-9B complementary DNA and genomic clones and report the unusually restricted expression pattern of human GDF-9B. The human GDF-9B transcript can be detected only in the gonads by RT-PCR analysis, and in situ hybridization studies indicate that it is not expressed in small primary follicles but, rather, in the oocytes of late primary follicles. Functional studies using the Xenopus laeuis embryo model indicate that unlike the transforming growth factor-beta family members activin and bone morphogenetic protein-4, neither GDF-9 nor GDF-9B affects mesoderm induction, suggesting that they may use signaling pathways distinct from those well defined for activin and bone morphogenetic protein-4. We conclude that 1) both GDF-9 mRNA and protein are abundantly expressed in oocytes of primary follicles in human ovary, suggesting that the GDF-9 transcript is translated at this early stage of Folliculogenesis; 2) human GDF-9B is specifically expressed in gonads at low levels; and 3) the expression of GDF-9 mRNA begins slightly earlier than that of GDF-9B in the human oocytes during follicular development. Our results are consistent with the suggestion that GDF-9 and GDF-9B may regulate human Folliculogenesis in a manner specific to the ovary.
Hitomi Suzuki - One of the best experts on this subject based on the ideXlab platform.
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lhx8 regulates primordial follicle activation and postnatal Folliculogenesis
BMC Biology, 2015Co-Authors: Hitomi Suzuki, Krishna Jagarlamudi, Kayla Golnoski, Megan M Mcguire, Rita Lopes, Vassilis Pachnis, Aleksandar RajkovicAbstract:Background The early stages of ovarian follicle formation—beginning with the breakdown of germ cell cysts and continuing with the formation of primordial follicles and transition to primary and secondary follicles—are critical in determining reproductive life span and fertility. Previously, we discovered that global knockouts of germ cell-specific transcriptional co-regulators Sohlh1, Sohlh2, Lhx8, and Nobox, cause rapid oocyte loss and ovarian failure. Also factors such as Nobox and Sohlh1 are associated with human premature ovarian failure. In this study, we developed a conditional knockout of Lhx8 to study oocyte-specific pathways in postnatal Folliculogenesis.