Disruption of steroidogenesis: Cell models for mechanistic investigations and as screening tools

Abstract

In the modern world, humans are exposed during their whole life to a large number of synthetic chemicals. Some of these chemicals have the potential to disrupt endocrine functions and contribute to the development and/or progression of major diseases. Every year approximately 1000 novel chemicals, used in industrial production, agriculture, consumer products or as pharmaceuticals, are reaching the market, often with limited safety assessment regarding potential endocrine activities. Steroids are essential endocrine hormones, and the importance of the steroidogenesis pathway as a target for endocrine disrupting chemicals (EDCs) has been recognized by leading scientists and authorities. Cell lines have a prominent role in the initial stages of toxicity assessment, i.e. for mechanistic investigations and for the medium to high throughput analysis of chemicals for potential steroidogenesis disrupting activities. Nevertheless, the users have to be aware of the limitations of the existing cell models in order to apply them properly, and there is a great demand for improved cell-based testing systems and protocols. This review intends to provide an overview of the available cell lines for studying effects of chemicals on gonadal and adrenal steroidogenesis, their use and limitations, as well as the need for future improvements of cell-based testing systems and protocols.

Monocrotophos pesticide affects synthesis and conversion of sex steroids through multiple targets in male goldfish (Carassius auratus)

“…Studies on endocrine disruption of exogenous compounds, particularly regarding steroidogenesis, have focused mainly on gene expression and activity of steroidogenesis enzymes 24, 25 , especially aromatase 26, 27 , although multiple factors could be involved in steroidogenesis. In this research, we demonstrated that MCP pesticide acted on many target sites, affecting the transport of cholesterol and gene expression of steroidogenesis enzymes, leading to abnormal levels of sex hormone synthesis intermediates and effectual hormones, and thus resulting in a proportional imbalance of sex hormones in male goldfish.…”

Deoxynivalenol as potential modulator of human steroidogenesis

“…This process is initiated by the transfer of a hydrophobic molecule of cholesterol from the outer to the inner membrane of the mitochondria, which enables StAR protein, a part of the StAR‐related lipid transfer domain family (Rathor et al, ). Cholesterol might be produced directly in cells from acetyl‐coenzyme A or come from dietary products (Odermatt, Strajhar, & Engeli, ). Then, cholesterol is converted to pregnenolone, a precursor of all steroids, by CYP cholesterol side chain cleavage enzyme (CYP11A1), finally to produce tissue‐specific hormones: androgens, estrogens, glucocorticoids as well as mineralocorticoids (Doghman‐Bouguerra & Lalli, ).…”

“…Then, cholesterol is converted to pregnenolone, a precursor of all steroids, by CYP cholesterol side chain cleavage enzyme (CYP11A1), finally to produce tissue‐specific hormones: androgens, estrogens, glucocorticoids as well as mineralocorticoids (Doghman‐Bouguerra & Lalli, ). Steroids are produced in the adrenal glands, gonads (testis and ovaries) as well as in the placenta during pregnancy (Odermatt et al, ). Steroidogenesis is also present in other organs expressing steroidogenic enzymes such as the brain, intestinal tract and skin, although its action is mainly restricted to local tissue (Odermatt et al, ).…”

“…In the ovaries, steroidogenesis takes place in theca and granulosa cells and needs an exchange of the products between cells (Figure ). Granulosa cells synthetize pregnenolone from cholesterol, which is then converted by theca cells to DHEA and androstenedione, which is back transported to granulosa cells and converted by 17β‐HSD1 to estradiol (Odermatt et al, ). Ovarian steroidogenesis is controlled by luteinizing hormone and follicle‐stimulating hormone levels, which enhance the expression of CYP11A1, 3β‐HSD2 and 17β‐HSD1, respectively, which consequently regulates the expression of progesterone and estradiol during the menstrual cycle (Jamnongjit & Hammes, ).…”

“…Cholesterol might be produced directly in cells from acetyl-coenzyme A or come from dietary products (Odermatt, Strajhar, & Engeli, 2016).…”