Cellular and molecular mechanisms mediating the effect of polychlorinated biphenyls on oocyte in vitro maturation.
ABSTRACT Cellular and molecular mechanisms mediating the effect of polychlorinated biphenyls on oocyte in vitro maturation: Polychlorinated biphenyls (PCBs) are stable, lipophilic compounds that accumulate in the environment and in the food chain. Recent studies provide evidence that exposure to PCBs can cause reproductive problems. PCBs have been identified in the ovarian follicle of women and other mammals and many data in the literature clearly indicate that both follicles and oocytes are particularly susceptible to these pollutants. In the present review we describe the multifaceted effects of PCBs on mammalian oocyte maturation in detail. Published studies clearly indicate that PCB congeners, both singly or as complex mixtures, disrupt mammalian oocyte maturation and subsequent embryo development. Specifically, data point out to the ability of PCBs to interfere with the organization of the microtubules cytoplasmic network resulting in an altered compartmentalization of the ooplasm. Furthermore, a critical role of cumulus cells in mediating PCB ovotoxicity has been observed, most likely related to a disregulation in intracellular communication between the germinal and the somatic compartment. Finally, since coplanar PCBs, induce gene expression via a ligand-dependent transactivating factor, the aryl hydrocarbon receptor, this signalling pathway is also reviewed with respect to understanding the toxic mechanisms of these compounds.
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ABSTRACT: The transcriptional regulators aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) modulate the transcription of genes involved in cellular differentiation and proliferation. In this study, we investigated the expression of these transcriptional regulators in the female reproductive tract. AHR and ARNT mRNA transcripts were readily detected by a ribonuclease protection assay in all reproductive tissues examined. The expression of these factors in the endometrium and myometrium did not vary during the menstrual cycle, and was not different in pre- versus post-menopausal women. However, post-menopausal women on continuous hormone replacement therapy had greater expression of AHR but not of ARNT in the endometrium and myometrium when compared with women not taking hormones. Leiomyomas expressed significantly less AHR and ARNT mRNA compared with normal myometrium. The ovaries expressed both AHR and ARNT mRNA, and expression was unaffected by age. Endometriotic ovarian cysts expressed more AHR but not more ARNT mRNA compared with healthy ovarian tissue. However, there were no changes in the expression of AHR or ARNT mRNA in ovarian cancer. In conclusion, the female reproductive tract expresses mRNA for the transcription factors AHR and ARNT, and changes in their expression at select target sites in specific pathological conditions such as endometriosis and uterine leiomyomas suggest a potential role for these factors in the pathogenesis of these conditions.Molecular Human Reproduction 02/2002; 8(1):75-80. · 4.54 Impact Factor
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ABSTRACT: The aryl hydrocarbon receptor (AhR), so-designated based on the ability of the protein to bind with and be activated by polycyclic aromatic hydrocarbons (PAH) and related halogenated hydrocarbons, is part of an emerging family of ligand-activated transcriptional regulators that are distinct from the steroid-thyroid hormone receptor superfamily. Once bound by ligand, the AhR interacts with the AhR nuclear translocator (ARNT) protein to form the aryl hydrocarbon receptor complex (AHRC). Both subunits of the AHRC contain sequences corresponding to basic helix-loop-helix domains, a motif that is shared by a number of other dimeric transcription factors. Although the natural ligand(s) for the AhR remains to be elucidated, to date over fifteen genes, including enzymes, growth factors and other transcription factors, have been identified as potential targets for transcriptional regulation by the chemically-activated AHRC. In the ovary, PAH exposure is known to cause destruction of oocytes within immature follicles, implying that one function of the AhR is to mediate cell death signaling in the female germ line. To assess this possibility, we explored AhR expression patterns in the murine ovary, and then determined the impact of AhR-deficiency (gene knockout) on female germ cell dynamics. Immunohistochemical analysis of ovaries of wild-type female mice indicated that AhR protein was abundantly and exclusively expressed in oocytes and granulosa cells of follicles at all stages of development. Histomorphometric analysis of serial ovarian sections revealed a two-fold higher number of primordial follicles in Ahr-null versus wild-type females at day 4 postpartum. This phenotype likely results from a cell-intrinsic death defect in the developing germ line since AhR-deficiency attenuated the magnitude of oocyte apoptosis in fetal ovaries cultured without hormonal support for 72 h. We propose that the AhR, activated by an as yet unknown endogenous ligand(s), serves to regulate the size of the oocyte reserve endowed at birth by affecting germ cell death during female gametogenesis.Endocrinology 01/2000; 141(1):450-3. · 4.72 Impact Factor
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ABSTRACT: Adult male non-human primates, Macaca nemestrina, were orally-exposed to corn oil or corn oil containing either Aroclor 1016 or 1260 at doses of 0.8, 1.6 or 3.2 mg/(kg.day) for 20 weeks. Brain concentrations of biogenic amines and individual PCB congeners were determined following exposure. Aroclor 1016 significantly decreased concentrations of dopamine and its metabolites in the caudate, putamen, substantia nigra and hypothalamus but did not alter neurotransmitter or metabolite concentrations in the globus pallidus and hippocampus. Total PCB concentrations ranged from 1 to 5 ppm with only three congeners detected (2,4,4'; 2,4,2',4' and 2,5,2',5') making up, on average, 72%, 18% and 7% respectively of the total residue in brain. There were no discernible differences in the congener make-up between brain regions. Aroclor 1260 reduced dopamine concentrations in the caudate, putamen and hypothalamus but produced no effects in the substantia nigra, globus pallidus or hippocampus. Aroclor 1260 concentrations ranged from 18 to 28 ppm with the highest levels found in the hippocampus. Of the congeners that made up more than 5% of the total residue in brain, all were hexa- and heptachlorinated di-ortho-substituted congeners. There were no discernible differences in congener make-up between brain regions. We conclude that: (1) ortho-substituted non-planar congeners are responsible for the observed changes in neurochemical function; (2) both Aroclor 1016 and Aroclor 1260 decrease dopamine concentrations by similar mechanisms; and (3) based on differences in brain concentrations of Aroclor 1260 congeners compared to Aroclor 1016 congeners, lightly-chlorinated congeners are more effective in reducing central dopamine concentrations than are the more highly chlorinated congeners.Toxicology 03/1991; 66(2):145-63. · 4.02 Impact Factor