Objectives

Fetal origin of male reproductive disorders

Many of the male reproductive health issues (low sperm count, testicular cancer, low production of male hormone), which a large portion of the male population in the Western countries face today are thought to arises because of mal-development and malfunction of the fetal testis. These reproductive disorders are thus thought to comprise a testicular dysgenesis syndrome (TDS).

 

Several pieces of evidence suggest that common environmental chemicals, probably acting together in mixtures or in combination with other factors (genetic, lifestyle) could contribute causally to TDS. However, there are numerous obstacles to proving this scientifically, such as the long latency (up to 40 years) between cause (in fetal life) and health consequence, coupled with inherent difficulties in evaluating human fetal exposure to complex chemical mixtures; assessing interactions between chemical exposures and other factors adds greater complexity.

 

The DEER strategy

In order to circumvent the above-mentioned obstacles we will in DEER take advantage of existing human birth cohorts/samples with their associated chemical exposure analyses. Established animal and in vitro models will be used to improve our understanding of fetal testis development and function and its relationship to male reproductive development. The complexity of real-life chemical exposures will be tackled by new bioinformatics approaches for assessing associations between real-life exposure scenarios and effects in humans. More specifically:

 

· Longitudinal follow-up of established birth cohorts as they approach and enter puberty will allow us to relate early occurrence of TDS disorders as well as hormone levels, testis size, and chemical exposures at birth to reproductive health in adolescence.

 

· Effects of earlier maternal chemical exposures (in pregnancy) as well as current lifestyle and exposures will be scrutinized in cohorts of young men and related to their reproductive health

 

· Associations between exposures, lifestyle, and health outcomes observed in the human studies will be explored mechanistically in animal and in vitro models and, conversely, new findings in these models will be used to direct and focus the human studies

 

· Metabolomics and associated chemical mixtures analysis will provide new insights into “real-life” human exposures and interaction with the endocrine systems

 

· Systems biology and bioinformatic analytical approaches, using data obtained from human studies, will be used for assessing exposure-outcome associations based on a real-life exposure scenario.

DEER

Developmental Effects of Environment on Reproduction

Left: Adult rat testis showing normal production of sperm (green colour)

Right: Adult rat testis after fetal exposure to a phthalate showing lack of sperm production (absence of green colour)

Follow-up  of birth cohorts includes physical and biochemical examinations

Bioinformatic approaches will be used to analyse for chemical-protein associations related to TDS