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  • Regulation of Gja involves a member

    2021-10-22

    Regulation of Gja4 involves a member of the wingless-type MMTV integration site family, WNT4. Mice deficient in Wnt4 had reduced (30%) expression of GJA1 compared to WT mice [40]. It is thought that WNT signaling regulates GJA1 expression and GJIC in granulosa Fmoc-Trp-OH sale by modulating beta-catenin stability and localization. Furthermore, knockdown of the beta-catenin gene altered FSH-mediated mobilization of GJA1 into GJ’s [41]. Thus, WNT signaling is likely involved in control of GJA1 function, but whether other GJ proteins are regulated similarly remains unclear. In addition to Gja4 and Gja1, knockout of Gjc1 and Gjb2 in mice has been accomplished but leads to embryonic death with cardiovascular defects and insufficient embryonic development, respectively [[42], [43], [44], [45]]. mice have no ovarian defects although they do have deficiencies in the visual system and mice remain fertile [46,47]. Ovarian findings for these genetic mice models lacking Gja4 and Gja1 support that ovarian CX proteins have important roles in relation to follicle and oocyte survivability, quality, and growth. In conjunction with the developmental functions of GJ in the ovary, they are also targets for reproductive toxicants and may represent conduits for toxicants to reach the oocyte. Exposure to chemicals during development or in adulthood can have serious implications for female fertility via disruption of normal ovarian function (Fig. 2). Ovotoxicants can selectively affect a follicle population in the ovary, resulting in either temporary or permanent infertility [48]. The breakdown of GJIC due to ovotoxicant exposure is a potential etiology underlying ovarian dysfunction. In this review, we describe the studies that have investigated the impacts of ovarian toxicants on ovarian GJ and we identify gaps in our understanding of this area of reproductive biology including the dearth of information on the underlying mechanisms that impair GJIC.
    Ovotoxicants that impact gap junctions Endocrine disrupting chemicals (EDC) are exogenous substances or mixtures (natural or synthetic) that disrupt normal actions of endogenous hormones such as their synthesis, secretion, transport, metabolism, binding, and elimination in various organ systems [49]. In the ovary, EDC’s have been shown to affect fertility through impacting follicle growth [[50], [51], [52], [53], [54]], alteration of ovarian steroidogenesis [[50], [51], [52]], mimicry of receptor signaling [55,56], and impaired oocyte competence [[57], [58], [59], [60], [61]]. The potential sources of exposure to EDC’s include plasticizers, anti-estrogenic and/or anti-androgenic drugs, pesticides, and solvents. While the effects of EDC’s on the female reproductive system have been recently investigated, relatively few studies have focused specifically on their effects on ovarian GJIC.
    Future directions for research and conclusion The rising rates of obesity as well as an aging population may also contribute to the severity of ovotoxic effects, so further studies considering these dynamics would also be beneficial in reducing the reproductive risks of chemical exposures. Taking what is learned from in vivo and in vitro animal models and identifying which CX proteins play a similar role(s) in the human ovary could aid in treatment of reproductive dysfunction. Additionally, greater insight in determining the compounds that are shuttled through ovarian GJ and whether chemicals can directly interact with ovarian cells through these communication portals is worthwhile, as well as determining the basal physiological components that regulate CX protein expression are areas for future study. Translation of data generated through in vitro and in vivo laboratory models to better understand the impacts of altered GJIC on human reproductive health as well as any relevance to chemical exposure limits represents a gap in our knowledge in this area. For many ovotoxicants, human exposure remains ill-defined and will be altered by physiological and developmental status of the exposed individual and this is a major gap in our appreciation of ovotoxicant risk. While toxicant exposures that are higher than those to which humans are exposed have relevance to working out potential mechanisms of action of a chemical, performing studies that are within the range and via the routes of realistic exposures are critical to this field. It is also important to acknowledge that while some studies may present statistically significant effects from chemical exposures, they do not necessarily reflect all adverse effects that may result, especially when many studies do not look at long term exposures and latency of effects. In addition, whether a statistically-significant finding is biologically-significant is not always clear and potential impact of mammalian developmental status is also an important consideration.