| 1. |
- Duque Björvang, Richelle
(författare)
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Fewer kids not always by choice : the link between endocrine-disrupting chemicals and female reproductive health
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fertility rates are declining from five children per woman in the 1950s to less than three children per woman in 2019. While this is partly due to women choosing to have fewer kids, there are growing evidence that endocrine-disrupting chemicals (EDCs) in the environment may play a role in this phenomenon. EDCs disrupt the endocrine system, which may affect reproductive health. The aim of this thesis is to study the link between EDCs and female reproductive health by combining epidemiological and experimental studies. The types of EDCs studied were organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and perfluoroalkyl substances (PFASs). Papers I-III investigated the associations of EDCs, both individually and as a mixture, with measures of reproductive health in women with different reproductive statuses (i.e. cesarean section patients (CS), pregnant women (SELMA) and infertile women undergoing assisted reproductive technologies (ART)). In the CS cohort, women with higher levels of OCPs and PCBs were associated with lower primordial, unilaminar, and healthy follicle densities, as well as higher odds for infertility. In the SELMA cohort, women with higher levels of PCBs were associated with longer time-to-pregnancy and higher odds for infertility, especially in women ≥ 29 years old who did not use combined oral contraceptives as their most recent pre-pregnancy contraceptive. In the ART cohort, women with higher levels of hexachlorobenzene, an OCP, was associated with lower ovarian reserve, and lower odds for clinical pregnancy and live birth. Women with higher levels of PCBs and PFASs were associated with higher ovarian reserve and ovarian response to gonadotropins but lower embryo quality. In summary, EDCs were associated with worse measures of female reproductive health. Papers III-V elucidated the transfer of chemicals from blood to target organs such as the follicular fluid (FF) in ovaries in the ART cohort as well as fetal tissues in women whose pregnancy was terminated or ended in stillbirth. EDCs passed the blood-follicle barrier, directly exposing the oocytes. They also crossed the placenta, depositing into the different fetal tissues such as adipose, liver, lung, heart and central nervous system (CNS composed of brain and spinal cord). The concentrations of EDCs were the highest in adipose and liver while the lowest in the CNS. Transfer efficiencies among groups of EDCs followed a trend: OCPs > PCBs > PFASs. Several biological factors such as woman’s age, gestational age, placental function and fetal sex affected the chemical transfer. In summary, blood may be used as proxy sample to estimate levels of EDCs in FF but may give a misleading picture for fetal tissues. Based on associations found and their tranfer to target organs in Papers I-V, five chemicals (HCB, p,p’-DDE, PCBs 156 and 180, and PFOS) were selected for 24-hour exposure studies in four ovarian cell cultures (COV434, KGN, PA1, primary ovarian cells). Using transcriptomics, seventeen genes were found to be common in all cell cultures exposed to these chemicals. Several of the mechanisms found were already recognized to be important for ovarian function such as mTOR, TGF-β, and IFN-α and IFN-γ signalling. This exhibited the potential of ovarian cell culture as a tool to screen and identify EDCs with reproductive effects. Overall, there was a link between EDCs and female reproductive health. By studying this, we unraveled mechanisms with clinically-relevant endpoints, which may be developed and tailored into assays that can be used to screen the thousands of chemicals in the market that have not been tested yet as well as new chemicals before they enter the market. This thesis advocates the need for better regulation of EDCs in order to achieve a chemically-safe environment where chemicals will not decide how many children you will have. That choice should only be made by you
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| 2. |
- Duque Björvang, Richelle, et al.
(författare)
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Sexually Dimorphic Accumulation of Persistent Organic Pollutants in Fetuses
- 2022
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Ingår i: Frontiers in Toxicology. - : Frontiers Media S.A.. - 2673-3080. ; 4
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Forskningsöversikt (refereegranskat)abstract
- Living in an industrialized era, we are exposed to man-made chemicals including persistent organic pollutants (POPs). Previous studies have shown associations of POP exposure with adverse outcomes in humans, wildlife, and the environment, making it a global concern. Exposure during sensitive windows of susceptibility such as fetal development is of particular concern because of the potential increased risk of developing diseases in childhood and adulthood. However, there are limited studies on the sexual dimorphism of POP accumulation during the prenatal period. In this mini-review, we focus on differences in POP concentrations in the placenta and fetal tissues between males and females. We also show the sexually dimorphic adverse outcomes of prenatal exposure to POPs. Overall, our summary shows that males may accumulate higher concentrations of POPs in the placenta and fetal tissues compared to females, although studies are sparse and inconsistent. In addition, there are differences in adverse health outcomes associated to prenatal POP exposure according to sex. Hence, we highly urge researchers investigating the health effects of POP exposure to consider sexual dimorphism in their studies.
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| 3. |
- Hallberg, Ida, et al.
(författare)
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Associations between lifestyle factors and levels of per- and polyfluoroalkyl substances (PFASs), phthalates and parabens in follicular fluid in women undergoing fertility treatment
- 2023
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Ingår i: Journal of Exposure Science and Environmental Epidemiology. - : Springer Nature. - 1559-0631 .- 1559-064X. ; 33, s. 699-709
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Tidskriftsartikel (refereegranskat)abstract
- Background: Concerns have been raised whether exposure to endocrine-disrupting chemicals (EDCs) can alter reproductive functions and play a role in the aetiology of infertility in women. With increasing evidence of adverse effects, information on factors associated with exposure is necessary to form firm recommendations aiming at reducing exposure.Objective: Our aim was to identify associations between lifestyle factors including the home environment, use of personal care products (PCP), and dietary habits and concentrations of EDCs in ovarian follicular fluid.Methods: April-June 2016, 185 women undergoing ovum pick-up for in vitro fertilisation in Sweden were recruited. Correlation analyses were performed between self-reported lifestyle factors and concentration of EDCs analysed in follicular fluid. Habits related to cleaning, PCPs, and diet were assessed together with concentration of six per- and polyfluoroalkyl substances (PFASs) [PFHxS, PFOA, PFOS, PFNA, PFDA and PFUnDA], methyl paraben and eight phthalate metabolites [MECPP, MEHPP, MEOHP, MEHP, cxMinCH, cxMiNP, ohMiNP, MEP, MOHiBP]. Spearman's partial correlations were adjusted for age, parity and BMI.Results: Significant associations were discovered between multiple lifestyle factors and concentrations of EDCs in ovarian follicular fluid. After correcting p values for multiple testing, frequent use of perfume was associated with MEP (correlation rho = 0.41 (confidence interval 0.21-0.47), p < 0.001); hens' egg consumption was positively associated with PFOS (rho = 0.30 (0.15-0.43), p = 0.007) and PFUnDA (rho = 0.27 (0.12-0.40), p = 0.036). White fish consumption was positively associated with PFUnDA (rho = 0.34 (0.20-0.47), p < 0.001) and PFDA (rho = 0.27 (0.13-0.41), p = 0.028). More correlations were discovered when considering the raw uncorrected p values. Altogether, our results suggest that multiple lifestyle variables affect chemical contamination of follicular fluid.Impact statement: This study shows how lifestyle factors correlate with the level of contamination in the ovary by both persistent and semi-persistent chemicals in women of reproductive age. Subsequently, these data can be used to form recommendations regarding lifestyle to mitigate possible negative health outcomes and fertility problems associated with chemical exposure, and to inform chemical policy decision making. Our study can also help form the basis for the design of larger observational and intervention studies to examine possible effects of lifestyle changes on exposure levels, and to unravel the complex interactions between biological factors, lifestyle and chemical exposures in more detail.
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| 4. |
- Li, Tianyi, et al.
(författare)
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Persistent organic pollutants dysregulate energy homeostasis in human ovaries in vitro
- 2024
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 187
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to persistent organic pollutants (POPs), such as dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs), has historically been linked to population collapses in wildlife. Despite international regulations, these legacy chemicals are still currently detected in women of reproductive age, and their levels correlate with reduced ovarian reserve, longer time -to -pregnancy, and higher risk of infertility. However, the specific modes of action underlying these associations remain unclear. Here, we examined the effects of five commonly occurring POPs - hexachlorobenzene (HCB), p,p '-dichlorodiphenyldichloroethylene (DDE), 2,3,3 ' ,4,4 ' ,5-hexachlorobiphenyl (PCB156), 2,2 ' ,3,4,4 ' ,5,5 ' -heptachlorobiphenyl (PCB180), perfluorooctane sulfonate (PFOS) - and their mixture on human ovaries in vitro . We exposed human ovarian cancer cell lines COV434, KGN, and PA1 as well as primary ovarian cells for 24 h, and ovarian tissue containing unilaminar follicles for 6 days. RNA -sequencing of samples exposed to concentrations covering epidemiologically relevant levels revealed significant gene expression changes related to central energy metabolism in the exposed cells, indicating glycolysis, oxidative phosphorylation, fatty acid metabolism, and reactive oxygen species as potential shared targets of POP exposures in ovarian cells. Alpha-enolase ( ENO1 ), lactate dehydrogenase A ( LDHA ), cytochrome C oxidase subunit 4I1 ( COX4I1 ), ATP synthase F1 subunit alpha ( ATP5A ), and glutathione peroxidase 4 ( GPX4 ) were validated as targets through qPCR in additional cell culture experiments in KGN. In ovarian tissue cultures, we observed significant effects of exposure on follicle growth and atresia as well as protein expression. All POP exposures, except PCB180, decreased unilaminar follicle proportion and increased follicle atresia. Immunostaining confirmed altered expression of LDHA, ATP5A, and GPX4 in the exposed tissues. Moreover, POP exposures modified ATP production in KGN and tissue culture. In conclusion, our results demonstrate the disruption of cellular energy metabolism as a novel mode of action underlying POP -mediated interference of follicle growth in human ovaries.
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| 5. |
- Tarvainen, Ilari, et al.
(författare)
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Identification of phthalate mixture exposure targets in the human and mouse ovary in vitro
- 2023
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Ingår i: Reproductive Toxicology. - : Elsevier. - 0890-6238 .- 1873-1708. ; 119
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Tidskriftsartikel (refereegranskat)abstract
- Chemical health risk assessment is based on single chemicals, but humans and wildlife are exposed to extensive mixtures of industrial substances and pharmaceuticals. Such exposures are life-long and correlate with multiple morbidities, including infertility. How combinatorial effects of chemicals should be handled in hazard charac-terization and risk assessment are open questions. Further, test systems are missing for several relevant health outcomes including reproductive health and fertility in women. Here, our aim was to screen multiple ovarian cell models for phthalate induced effects to identify biomarkers of exposure. We used an epidemiological cohort study to define different phthalate mixtures for in vitro testing. The mixtures were then tested in five cell models representing ovarian granulosa or stromal cells, namely COV434, KGN, primary human granulosa cells, primary mouse granulosa cells, and primary human ovarian stromal cells. Exposures at epidemiologically relevant levels did not markedly elicit cytotoxicity or affect steroidogenesis in short 24-hour exposure. However, significant effects on gene expression were identified by RNA-sequencing. Altogether, the exposures changed the expression of 124 genes on the average (9-479 genes per exposure) in human cell models, without obvious concentration or mixture-dependent effects on gene numbers. The mixtures stimulated distinct changes in different cell models. Despite differences, our analyses suggest commonalities in responses towards phthalates, which forms a starting point for follow-up studies on identification and validation of candidate biomarkers that could be developed to novel assays for regulatory testing or even into clinical tests.
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