Age-related Accumulation of Non-heme Ferric and Ferrous Iron in Mouse Ovarian Stroma Visualized by Sensitive Non-heme Iron Histochemistry

Asano, Yoshiya

doi:10.1369/0022155411431734

Cited by 45 publications

(53 citation statements)

References 48 publications

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“…A similar population of enlarged macrophage cells was observed previously in the ovarian stroma of aged C57B/6J mice, thereby corroborating our findings in CB6F1 and CD1 mice (Asano 2012). These enlarged macrophages were also characterized by a frothy cytoplasm with polymorphic inclusion bodies and lysosomes, multiple nuclei, and intense autofluorescence (Asano 2012).…”

Section: Discussionsupporting

confidence: 92%

“…This observation is consistent with the well-documented role of macrophages in numerous ovarian processes including folliculogenesis, ovulation, and corpus luteum formation and regression (Wu, et al 2004). These macrophages had varying morphologies, including small spindle-shaped macrophages and ovoid macrophages, suggesting sub-populations with differing functions (Asano 2012) (Figures 7B, D). …”

Section: Resultsmentioning

confidence: 99%

“…These enlarged macrophages were also characterized by a frothy cytoplasm with polymorphic inclusion bodies and lysosomes, multiple nuclei, and intense autofluorescence (Asano 2012). It was also noted that there was a reproductive age-associated accumulation of non-heme iron in the ovarian stroma and that the subpopulation of enlarged macrophages had particularly high levels of nonheme ferric iron (NHF[III]), non-heme ferrous iron (NHF[II]), and oxidative stress (Asano 2012). This non-heme iron accumulation in the ovary with age may result from heme oxygenase-1-mediated heme degradation during follicular atresia and luteal regression (Asano 2012).…”

Section: Discussionmentioning

confidence: 99%

“…It was also noted that there was a reproductive age-associated accumulation of non-heme iron in the ovarian stroma and that the subpopulation of enlarged macrophages had particularly high levels of nonheme ferric iron (NHF[III]), non-heme ferrous iron (NHF[II]), and oxidative stress (Asano 2012). This non-heme iron accumulation in the ovary with age may result from heme oxygenase-1-mediated heme degradation during follicular atresia and luteal regression (Asano 2012). Disruption of iron homeostasis in several organs, including the liver, heart, and pancreas, leads to organ fibrosis (Ramm and Ruddell 2010).…”

Section: Discussionmentioning

confidence: 99%

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Reproductive age-associated fibrosis in the stroma of the mammalian ovary

et al. 2016

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Under normal physiological conditions, tissue remodeling in response to injury leads to tissue regeneration without permanent damage. However, if homeostasis between synthesis and degradation of extracellular matrix (ECM) components is altered, fibrosis – or the excess accumulation of ECM – can disrupt tissue architecture and function. Several organs, including the heart, lung, and kidney, exhibit age-associated fibrosis. Here we investigated whether fibrosis underlies aging in the ovary - an organ that ages chronologically before other organs. We used Picrosirius Red (PSR), a connective tissue stain specific for collagen I and III fibers, to evaluate ovarian fibrosis. Using brightfield, epifluorescence, confocal, and polarized light microscopy, we validated the specific staining of highly ordered PSR-stained fibers in the ovary. We next examined ovarian PSR staining in two mouse strains (CD1 and CB6F1) across an aging continuum and found that PSR staining was minimal in ovaries from reproductively young adult animals, increased in distinct foci in animals of mid-to-advanced reproductive age, and was prominent throughout the stroma of the oldest animals. Consistent with fibrosis, there was a reproductive aged-associated increase in ovarian hydroxyproline content. We also observed a unique population of multinucleated macrophage giant cells, which are associated with chronic inflammation, within the ovarian stroma exclusively in reproductively old mice. In fact, several genes central to inflammation had significantly higher levels of expression in ovaries from reproductively old mice relative to young. These results establish fibrosis as an early hallmark of the aging ovarian stroma, and this altered microenvironment may contribute to the age-associated decline in gamete quality.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Reproductive age-associated fibrosis in the stroma of the mammalian ovary

et al. 2016

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“…Meanwhile, it has been suggested that OS modulates the age-related decline in fertility [20]. Additionally, a recent study indicated that nonheme iron accumulation on ovarian stromal tissue may be related to aging of the ovary due to increasing OS [38]. The age-related decline in fertility due to OS has a special impact in our group of patients, because of their increased age average due to significant improvements in chelation treatment modalities.…”

Section: Iron and Pathophysiology Of Btm Infertilitymentioning

confidence: 99%

Beta-Thalassemia Major and Female Fertility: The Role of Iron and Iron-Induced Oxidative Stress

Roussou

Tsagarakis

Kountouras

et al. 2013

Anemia

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Endocrine complications due to haemosiderosis are present in a significant number of patients with beta-thalassemia major (BTM) worldwide and often become barriers in their desire for parenthood. Thus, although spontaneous fertility can occur, the majority of females with BTM is infertile due to hypogonadotropic hypogonadism (HH) and need assisted reproductive techniques. Infertility in these women seems to be attributed to iron deposition and iron-induced oxidative stress (OS) in various endocrine organs, such as hypothalamus, pituitary, and female reproductive system, but also through the iron effect on other organs, such as liver and pancreas, contributing to the impaired metabolism of hormones and serum antioxidants. Nevertheless, the gonadal function of these patients is usually intact and fertility is usually retrievable. Meanwhile, a significant prooxidants/antioxidants imbalance with subsequent increased (OS) exists in patients with BTM, which is mainly caused by tissue injury due to overproduction of free radicals by secondary iron overload, but also due to alteration in serum trace elements and antioxidant enzymes. Not only using the appropriate antioxidants, essential trace elements, and minerals, but also regulating the advanced glycation end products, could probably reduce the extent of oxidative damage and related complications and retrieve BTM women's infertility.

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Therapeutic applications of chelating drugs in iron metabolic disorders of the brain and retina

Shahandeh

Bui

Finkelstein

et al. 2020

J of Neuroscience Research

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Iron is essential for normal cellular function, however, excessive accumulation of iron in neural tissue has been implicated in both cortical and retinal diseases. The exact role of iron in the pathogenesis of neurodegenerative disorders remains incompletely understood. However, iron‐induced damage to the brain and retina is often attributed to the redox ability of iron to generate dangerous free radicals, which exacerbates local oxidative stress and neuronal damage. Iron chelators are compounds designed to scavenge labile iron, aiding to regulate iron bioavailability. Recently there has been growing interest in the application of chelating agents for treatment of diseases including neurodegenerative conditions, characterized by increased oxidative stress. This article reviews both clinical and preclinical evidence relating to the effectiveness of iron chelation therapy in conditions of iron dyshomeostasis linked to neurodegeneration in the brain and retina. The limitations as well as future opportunities iron chelation therapy are discussed.

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Age-related Accumulation of Non-heme Ferric and Ferrous Iron in Mouse Ovarian Stroma Visualized by Sensitive Non-heme Iron Histochemistry

Cited by 45 publications

References 48 publications

Reproductive age-associated fibrosis in the stroma of the mammalian ovary

Reproductive age-associated fibrosis in the stroma of the mammalian ovary

Beta-Thalassemia Major and Female Fertility: The Role of Iron and Iron-Induced Oxidative Stress

Therapeutic applications of chelating drugs in iron metabolic disorders of the brain and retina

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