Fewer kids not always by choice : the link between endocrine-disrupting chemicals and female reproductive health

• 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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