Postdoctoral Research Fellow, Karolinska Institute
Endocrine disrupting chemicals (EDCs) are widely prevalent in modern society, and are known to have a range of significant effects on human health. It is well-known that EDCs adversely affect the reproductive health of wildlife and human males, but there have been few studies examining their effects on human female reproductive biology, particularly ovarian health. This mainly due to the difficultly in studying human ovaries as internal organs, and ethical and logistical issues in ovarian tissue collection. Our research group has regular access to human ovarian tissue from consenting reproductive-aged women in Stockholm, Sweden. My research is endeavoring to design a novel ex vivo culture system, consisting of isolated human ovarian follicles containing the egg. Recapitulation of the complex ovarian endocrine environment is challenging, and so far no studies have been able to mature a human follicle from the beginning primordial phase to a mature follicle ready for ovulation. Once my culture system is able to support follicle growth for several weeks, the effects of EDCs as mixtures and single chemicals will be tested. Measures of follicular growth, health and function will be examined, and for the first time, we will be able to demonstrate the effects of EDCs on human ovarian health and female fertility.
Abstract: Does melamine have a toxic effect on oocyte development and fertility in vivo?Melamine had toxic effects on oocyte quality and fertility due to its effects on the oocyte cytoskeleton, apoptosis and autophagy induction, and epigenetic modifications in an in vivo mouse model.Melamine is a chemical compound that is widely used during the manufacture of amino resins and plastics. In 2008, melamine was reported to adulterate milk and infant formulas in China, which sparked food safety concerns worldwide. Ingesting melamine may result in reproductive damage, and bladder or kidney stones, which can lead to bladder cancer.Mice were randomly assigned to three groups and fed a diet that included melamine (0, 10 and 50 mg/kg/day) for 8 weeks. The in vivo effect of melamine on female reproduction was examined.We used immunofluorescent staining, western blotting and qRT-PCR to examine the effect of melamine on oocyte quality.Our results showed the following effects of this melamine-containing diet. (i) Ovary weights were reduced in melamine fed mice. Oocyte developmental competence was also reduced, as shown by reduced polar body extrusion rates. (ii) Melamine feeding resulted in abnormal oocyte cytoskeletons, as shown by increased rates of aberrant spindles and reduced actin microfilament expression. (iii) Melamine exposed oocytes had higher rates of abnormal mitochondrial distributions and early stage apoptosis/autophagy, which were shown by increased microtubule-associated protein 1 light chain 3 (LC3) protein expression level and caspase 9, autophagy-related protein 14 (atg14), and lc3 mRNA levels. (iv) Fluorescence intensity analysis showed that DNA methylation levels were reduced in the oocytes of melamine fed mice. Histone methylation levels were also altered, as Di-methyl-Histone H3 (Lys4) (H3K4me2) level was increased and Tri-methyl-Histone H3 (Lys9) (H3K9me3), Di-methyl-Histone H3 (Lys9) (H3K9me2), and Tri-methyl-Histone H3 (Lys27) (H3K27me3) levels were reduced in oocytes from melamine fed mice. (v) The litter sizes of melamine fed mice were significantly reduced when compared with those of controls.Although we examined the possible effects of melamine on oocyte quality and fertility, we did not determine the effect of melamine on offspring development.Our findings indicate that melamine plays a major role in oocyte quality and fertility. This information could contribute to a better understanding of melamine toxicity in female reproduction.This study was supported by the National Basic Research Program of China (2014CB138503) and the Natural Science Foundation of Jiangsu Province (BK20140030). The authors have no conflict of interest to disclose.
Pub.: 01 May '15, Pinned: 27 Sep '17
Abstract: Endocrine-disrupting chemicals (EDCs) are found abundantly in the environment, resulting in daily human exposure. This is of concern because many EDCs are known to target the female reproductive system and, more specifically, the ovary. In the female, the ovary is the key organ responsible for reproductive and endocrine functions. Exposure to EDCs is known to cause many reproductive health problems such as infertility, premature ovarian failure, and abnormal sex steroid hormone levels. Some EDCs and their effects on adult ovarian function have been studied extensively over the years, whereas the effects of others remain unclear. This review covers what is currently known about the effects of selected EDCs (bisphenol A, methoxychlor, 2,3,7,8-tetrachlorodibenzo-p-dioxin, phthalates, and genistein) on the adult ovary and the mechanisms by which they act upon the ovary, focusing primarily on their effects on folliculogenesis and steroidogenesis. Furthermore, this review discusses future directions needed to better understand the effects of EDCs, including the need to examine the effects of multiple and more consistent doses and to study different mechanisms of action.
Pub.: 13 Jun '15, Pinned: 27 Sep '17
Abstract: Do dehydroepiandrosterone (DHEA)-treated rats with polycystic ovary syndrome (PCOS) demonstrate a high level of fibrosis in ovarian and uterine tissues?DHEA induces ovarian and uterine hyperfibrosis in rats, probably involving a transforming growth factor-β (TGF-β)-dependent mechanism.Chronic inflammation is the typical cause of fibrosis and is involved in the pathophysiological process of PCOS. Patients with PCOS are reported to have a higher serum level of TGF-β, a well-characterized key pro-fibrotic factor. Fibrillin-3, a protein capable of interacting with TGF-β, has been reported to be partially responsible for the fetal origin of PCOS.Female Sprague-Dawley rats were treated with a vehicle control or DHEA for 35 days, with subsequent analyses of changes in morphology and gene expression in ovarian and uterine tissues. Rescue groups treated with metformin or simvastatin and their corresponding controls were also analyzed. A total of 80 rats were included.The PCOS model was induced by daily administration of DHEA s.c. to 3-week-old female rats, and the rescue groups were injected daily with either metformin or simvastatin in addition to DHEA. Serum steroid hormone levels were measured by enzyme-linked immunosorbent assay. Samples were stained with hematoxylin and eosin for histological morphology, and Sirius Red and immunohistochemistry for revealing collagens. The expression of fibrosis-related genes was analyzed both at mRNA (real-time RT-PCR) and protein (western blot) levels.DHEA-induced rats with PCOS exhibited significantly higher levels of fibrosis (collagen IV) in both ovarian and uterine tissues. In ovarian tissue, the expression of connective tissue growth factor (CTGF) increased following DHEA treatment at both mRNA and protein levels (P < 0.05, P < 0.001 versus controls, respectively). Similar results versus controls were obtained at a protein level for TGF-β (P < 0.01) and mRNA level for fibronectin (P < 0.05) and angiotensin-II (P < 0.05). Likewise, in uterine tissue, the protein levels of both CTGF and TGF-β were higher than controls following DHEA treatment (P < 0.05). Treatment with either metformin or simvastatin attenuated the fibrosis progression induced by DHEA exposure, as evidenced by a reduction of TGF-β, plus CTGF or not, in both ovarian and uterine tissues.The particular mechanism involved in the DHEA-induced fibrosis was not fully revealed.Ovarian and uterine hyperfibrosis may occur in patients with PCOS and result in anovulation or other PCOS-related phenotypes. Anti-fibrotic therapy, for example metformin treatment, may be beneficial for patients with PCOS.This study was supported by the National Natural Science Foundation of China (81170541) and the Natural Basic Research Program of China (973 program 2010CB945103). The authors declare no conflicts of interest.
Pub.: 28 Aug '13, Pinned: 27 Sep '17
Abstract: Exposure to endocrine disrupting chemicals (EDCs) during development can have negative consequences later in life. In this study we investigated the effect of perinatal exposure to mixtures of human relevant EDCs on the female reproductive system. Rat dams were exposed to a mixture of phthalates, pesticides, UV-filters, bisphenol A, butyl-paraben, as well as paracetamol. The compounds were tested together (Totalmix) or in subgroups with anti-androgenic (AAmix) or estrogenic (Emix) potentials. Paracetamol was tested separately. In pre-pubertal rats, a significant reduction in primordial follicle numbers was seen in AAmix and PM groups, and reduced plasma levels of prolactin was seen in AAmix. In one-year-old animals, the incidence of irregular estrous cycles was higher after Totalmix-exposure and reduced ovary weights were seen in Totalmix, AAmix, and PM groups. These findings resemble premature ovarian insufficiency in humans, and raises concern regarding potential effects of mixtures of EDCs on female reproductive function.
Pub.: 02 Apr '16, Pinned: 27 Sep '17
Abstract: Endocrine disrupting chemicals (EDCs) comprise a group of chemical compounds that have been examined extensively due to the potential harmful effects in the health of human populations. During the past decades, particular focus has been given to the harmful effects of EDCs to the reproductive system. The estimation of human exposure to EDCs can be broadly categorized into occupational and environmental exposure, and has been a major challenge due to the structural diversity of the chemicals that are derived by many different sources at doses below the limit of detection used by conventional methodologies. Animal and in vitro studies have supported the conclusion that endocrine disrupting chemicals affect the hormone dependent pathways responsible for male and female gonadal development, either through direct interaction with hormone receptors or via epigenetic and cell-cycle regulatory modes of action. In human populations, the majority of the studies point towards an association between exposure to EDCs and male and/or female reproduction system disorders, such as infertility, endometriosis, breast cancer, testicular cancer, poor sperm quality and/or function. Despite promising discoveries, a causal relationship between the reproductive disorders and exposure to specific toxicants is yet to be established, due to the complexity of the clinical protocols used, the degree of occupational or environmental exposure, the determination of the variables measured and the sample size of the subjects examined. Future studies should focus on a uniform system of examining human populations with regard to the exposure to specific EDCs and the direct effect on the reproductive system.
Pub.: 16 Mar '17, Pinned: 27 Sep '17
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