P1 – Steroid alteration and male fertility

The potential contribution of environmental chemicals to endocrine modulation in exposed humans and the subsequent impairment of fertility is one of the most intensely, and controversially, discussed questions in contemporary human toxicology research. This project aims to support regulatory authorities by developing scientific expertise which will contribute to national and international efforts in addressing underlying mechanisms leading to adverse effects on male fertility.

The prevalence of low semen quality and the incidence of testicular cancer have been steadily increasing over the past decades in different parts of the world. In Switzerland, as in many other countries, semen quality in young adult men is not optimal and additionally Switzerland has one of the highest testicular cancer rates in Europe.

Many compounds have been proposed to affect a men’s reproductive health by disrupting endocrine functions – including phthalates, organoplatinum compounds, organotins, heavy metals, vinclozolin, and other pesticides. However, the underlying mechanisms leading to effects on the male reproductive system are largely unknown and need further characterisation. Establishing mechanisms of action and discovering potential human biomarkers will aid human risk assessment.

This project aims to establish new measurable human biomarkers of exposure and effect, and thus contribute to human risk assessment and early identification of new male reproductive toxicants. Through association studies, the potential impact of lifestyle or environmental factors such as endocrine disrupting chemicals (EDCs), cannabis and mobile phone on semen quality and male hormones in the Swiss general population will be evaluated.

P2 – Swiss workers occupationally exposed to endocrine disruptors

There is an increasing concern that endocrine disrupting chemicals (EDCs) may impact the health of human populations. Some EDCs are indeed suspected to affect sex-steroids levels, sperm quality, epigenetic status of the gametes, and may even trigger transmissible reproductive and metabolic disorders. Of particular concern are occupational exposures to phthalates, which may reach 4 to 1000 folds higher levels compared to the general population.

An occupational cohort of plastic industry workers that use or produce phthalates will be established. Workers’ exposures will be measured and endocrine clinical consequences evaluated regarding steroids, sperm qualities, sperm epigenomes, and metabolic disease symptoms. The data collected will be used to develop a physiologically based toxicokinetic model (PBTK), to establish the no-observed-adverse-effect level (NOAEL) for phthalate exposures on semen, and may result in the constitution of a quantitative Adverse Outcome Pathways (AOP).

P3 – Xenobiotics disrupting the corticosteroid-androgen balance

Increasing evidence indicates that, besides genetic predisposition, the exposure to xenobiotics (environmental pollutants, industrial and occupationally relevant chemicals, body care products, food additives, supplements, recreational drugs, pharmaceuticals) can contribute to the development and progression of major diseases. Despite the key role of corticosteroids and the corticosteroid–androgen balance, the impact of xenobiotics disrupting their function represents a neglected topic. Indeed, the research on endocrine disrupting chemicals (EDC) focused largely on estrogen receptors and reproductive toxicity. Thus, there is a need to identify hazardous substances and key events for early detection of xenobiotics-induced disturbances of corticosteroid and androgen homeostasis.

This project focusses on generating experimental data that can serve as a basis to improve regulatory test systems for the characterisation of EDCs affecting corticosteroid and androgen homeostasis. Current regulatory tests for EDCs focus on effects on oestrogen, androgen, and thyroid receptor signalling and on sex steroid production, but do not adequately assess mineralocorticoids, glucocorticoids, and adrenal androgens.

The project aims to investigate the early and converging key events leading to effects on metabolism and immune system or to effects on the reproductive system. Furthermore, mechanistic aspects of endocrine disruption will be examined through a broad range of methods, computer-based models, biological testing systems and using targeted and untargeted steroid profiling. Identifying markers of disturbed corticosteroid and androgen homeostasis will facilitate the investigation of potential EDCs disturbing this balance and should ultimately allow testing for correlation between a given compound, a steroid marker and a physiologic, respectively a disease read-out.

Regulatory authorities are participating in large-scale projects on chemical safety focusing on substances that disrupt endocrine functions. However, the currently available methods and potential targets under investigation are still highly limited and additional testing strategies are required. The tools that will be developed in this project should help in the identification of potentially hazardous chemicals, and the steroidomic profiling should facilitate the investigation of their modes of action and subsequently their potential hazard to humans.