Diverse effects of endocrine-disruptive chemicals on Leydig and adrenocortical cell steroidogenesis in rodents and humans

Abstract: We are living in a man-made world and often exposed to different chemicals known as endocrine disrupting chemicals (EDCs) that negatively influence our hormonal system. These compounds have the potential to interrupt a normal steroidogenesis and result in harmful effects on the reproductive health of humans and among other organisms. Several studies have demonstrated a considerable decrease in fertility biomarkers such as sperm counts, and increase in malformations and undermasculinization of the male reproductive tract of mammals including humans. Increasing incidence of cryptorchidism, hypospadias and micropenis in male babies may be a consequence of the detrimental effect of environmental chemicals on male fetuses due to disruption of the steroidogenic machinery in the adrenal glands and gonads. The general aim of this thesis was to examine the impact of selected EDCs on hormonal function of steroidogenic cells from mice and human. In papers 1 and 2 we made use of primary cultures of immature mouse Leydig cells (LCs) to probe their response to bisphenol A and mono-phthalates. The cells were incubated with or without human chorionic gonadotropin (hCG) and a selection of chemicals ranging in concentrations over a certain period of time. It was uncovered that immature mouse LCs with varying abilities to produce testosterone were unaffected by estrogenic stimuli. Moreover, they exhibited a similar response to mono-phthalates. Our study showed that bisphenol A is able to stimulate testosterone production in the hCG pre-treated immature mouse LCs. However, among three mono-phthalates, only MEHP significantly increased basal androgen production via upregulation of StAR expression. In addition, mono-phthalates disturb a normal mitochondrial function, by attenuating ATP generation and increasing super oxide synthesis. In papers 3 and 4 we had possibility to obtain human abortion material from terminated pregnancies at gestational week 9-12. In study 3, we used a primary culture of human adrenocortical cells, stimulated with or without adrenocorticotropic hormone (ACTH) with resveratrol treatment, whereas in paper 4, the whole tissue of the human fetal adrenal gland (HFA) was taken for analysis. We observed that resveratrol had a suppressive effect on the synthesis of androstenedione, dehydroepiandrosterone (DHEA) and cortisol by the primary culture of human fetal adrenocortical cells through inhibition of lyase activity of cytochrome Cyp17 and Cyp21 expression in these cells. With the help of GC-MS/MS expertize was detected that the HFA is limited to produce androgens to testosterone and androsterone at the first trimester of pregnancy. This finding correlates with an observation of fully activated CYP17A1-POR-CYB5 complex and the concurrent upregulation of transcription factors (SF1, GATA-6) and downregulation of HSD3B2. Altogether, our results indicated that environmental endocrine disruptive chemicals have diverse effect on androgen production in steroidogenic cells in rodents and humans. Bisphenol A and MEHP should be taken into consideration as possible causes of premature maturation in boys. In contrast, pregnant women at an early gestational stage should try to avoid taking resveratrol due its ability to suppress steroidogenesis in the human fetal adrenals.