PANDA - Persistent health effects caused by widely used pesticides with antiandrogenic activity

Background:
More and more epidemiological and animal studies indicate that pesticide exposure can contribute to disturbance in the development of the male reproductive system. The effects include malformed genitalia, impaired sperm quality, as well as testicular- and prostate cancer. The development of the male phenotype is fully dependent on the influence of androgens formed in the unborn fetus.
Animal studies have shown that several pesticides are able to interfere with the androgenic action in the male fetus, either by blocking the androgen receptor or by reducing androgen production. We have, using an in-house developed computer model, predicted that 8% of all existing chemicals have the ability to block the androgen receptor, indicating that we have only seen the tip of the iceberg. In addition, we have using cell experiments recently found that a number of new pesticides are able to effectively block the androgen receptor. These pesticides are commonly used, and among those with the highest risk of human exposure.
In this project a new approach, including cell-based studies addressing anti-androgenic mechanisms, and computer modeling of physiologically-based kinetics (PBK), will be applied of selecting 3 out of 11 pesticides for further study of adverse effects on the male reproductive system. For this a rat model based on in utero exposure and subsequent studies of the male offspring for various defects, hormonal and epigenetic changes, and precursors of prostate cancer will be used. The goal of the project is to provide new knowledge on the potential effects of commonly used pesticides on the unborn fetus, leading to permanent health effects.
Two overall purposes will be fulfilled with this project: 1) To generate new knowledge for human risk assessment of specific pesticides which may form the basis for new risk management initiatives by the authorities and 2) To generate knowledge about the applicability of alternative test methods such as in vitro studies and PBK modeling that may form the basis for suggesting new testing strategies and requirements for pesticides.
The following specific hypotheses will be addressed:
1.A generic PBK model which includes the fetal compartment is capable of covering the ‘chemical space’ of anti-androgens
2.Our PBK model screening tool will be valuable for prioritizing antiandrogenic agents for in vivo testing, when only in vitro assay data are available
3.Pesticides identified as having potent anti-androgenic effects in vitro and evaluated as being able to reach the fetus will display anti-androgenic activities in vivo
4.Persistent epigenetic effects in terms of DNA methylation will be induced in adult rat offspring after perinatal exposure to a male developmental toxicant
5.Perinatal programming by exposure to anti-androgenic pesticides can induce persistent changes in the prostate, thus predisposing the gland to elevated cancer risks.