TY - JOUR

T1 - Overcoming barriers to non-animal risk assessments for anti-androgenic effects in humans

AU - Dent, M.

AU - Carmichael, P.

AU - Vantangoli, M.

AU - Boekelheide, K.

AU - Martin, Francis Luke

PY - 2016/9/16

Y1 - 2016/9/16

N2 - Toxicology testing is undergoing a transformation from a system based on high-dose studies in animals to one founded primarily on in vitro methods that evaluate changes in normal cellular signalling pathways using human-relevant cells or tissues. This is a challenge for anti-androgenic effects in humans, since some parts of the hypothalamus-pituitary-testicular axis are not well represented by accepted in vitro methods. These include key events relating to gonadotropin releasing hormone (GnRH) signalling which could be affected at the level of the hypothalamus and pituitary. In vitro tools are needed to characterize either specific effects (such as GnRH receptor antagonism) or non-specific effects (such as general toxicity causing a reduction in gonadotropin release) before an integrated model of the HPT axis can be described. We have been evaluating how this could be achieved using human non-pituitary cells that express GnRH receptors and synthesize gonadotropins. Furthermore, tools to characterize a tipping point between endocrine activity and adversity need to be developed to allow an assessment that is more representative of the underlying biological response to endocrine active chemicals. To this end we have been developing and characterizing human derived scaffold-free prostate microtissues to provide morphological and molecular readouts to identify exposures that lead to adverse responses. Our ambition is to use these tools in an exposure-led safety assessment to enable robust safety decision making for endocrine active chemicals without use of animals ( Dent et al., 2015).

AB - Toxicology testing is undergoing a transformation from a system based on high-dose studies in animals to one founded primarily on in vitro methods that evaluate changes in normal cellular signalling pathways using human-relevant cells or tissues. This is a challenge for anti-androgenic effects in humans, since some parts of the hypothalamus-pituitary-testicular axis are not well represented by accepted in vitro methods. These include key events relating to gonadotropin releasing hormone (GnRH) signalling which could be affected at the level of the hypothalamus and pituitary. In vitro tools are needed to characterize either specific effects (such as GnRH receptor antagonism) or non-specific effects (such as general toxicity causing a reduction in gonadotropin release) before an integrated model of the HPT axis can be described. We have been evaluating how this could be achieved using human non-pituitary cells that express GnRH receptors and synthesize gonadotropins. Furthermore, tools to characterize a tipping point between endocrine activity and adversity need to be developed to allow an assessment that is more representative of the underlying biological response to endocrine active chemicals. To this end we have been developing and characterizing human derived scaffold-free prostate microtissues to provide morphological and molecular readouts to identify exposures that lead to adverse responses. Our ambition is to use these tools in an exposure-led safety assessment to enable robust safety decision making for endocrine active chemicals without use of animals ( Dent et al., 2015).

U2 - 10.1016/j.toxlet.2016.06.1592

DO - 10.1016/j.toxlet.2016.06.1592

M3 - Meeting abstract

VL - 258

SP - S155

JO - Toxicology Letters

JF - Toxicology Letters

SN - 1879-3169

IS - Suppl.

ER -