Nadja Visser: Effects of Endocrine Disrupting Chemicals on endometrial cells: Life in plastic is not fantastic

Abstract

Endocrine Disrupting Chemicals (EDCs) are compounds that interfere with normal hormone balances. Reproductive functions rely on precise endocrine regulation involving hormones produced in the brain and ovaries. Several epidemiological studies have shown associations with EDC exposure and adverse fertility outcomes. However, effects of EDCs on the endometrium are still not well investigated. Therefore, this PhD thesis aimed to unravel the effects of EDCs, especially phthalates, on endometrial cell function. 

Study I showed the effects of several EDCs on decidualisation, a key process for a successful pregnancy. Protein kinases involved in the decidualisation process, as well as PRL and IGFBP1 excretion, were reduced by different EDCs. To continue our search for candidate genes and pathways affected by EDCs, we exposed different endometrial primary cells and cell lines to phthalate mixtures in study II. Phthalate mixtures were based on urine samples from the Midlife Women’s Health study cohort. All mixtures affected endometrial cells, with MEHHP being the main actor in the phthalate mixtures. Many genes and pathways found with RNA sequencing were involved with the cytoskeleton and mitochondria. 

Therefore, we conducted study III, where we investigated the effect of MEHHP on mitochondrial metabolism and structure in the endometrial stromal cell line T-HESC. While mitochondrial metabolism was not significantly affected overall, a significant concentration-response effect was observed in spare respiratory capacity. Mitochondrial structure was significantly altered by MEHHP exposure, resulting in decreased branching and volume, but increased sphericity. 

In conclusion, EDCs affected endometrial cells by disrupting decidualisation; phthalates specifically affected genes related to mitochondria and the cytoskeleton. MEHHP had the most substantial effect on gene expression, significantly affecting spare respiratory capacity and mitochondrial structure. Future studies should investigate the effects of phthalates on the cytoskeleton and other mitochondrial parameters, with implications for embryo implantation.