Virtual Presentation SRB Virtual Awards 2020

RA signalling is critical for healthy testis development and a site of vulnerability to environmental chemicals (#21)

Cassy Spiller 1 , Monica Kam Draskau 2 , Chun-Wei Allen Feng 1 , Terje Svingen 2 , Josephine Bowles 1
  1. School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia
  2. Division of Diet, Disease Prevention and Toxicology, National Food Institute, Technical University of Denmark, Kongens Lyngby, Denmark

Disorders of human male reproductive health include cryptorchidism, hypospadias, infertility/subfertility, testicular germ cell cancer and primary hypogonadism. The ‘testis dysgenesis syndrome’ hypothesis proposes that ALL of these problems have a shared origin during fetal life: if testis development is perturbed during a critical window of time whilst in the womb, reproductive health and function is affected, with life-long ramifications. These disorders are escalating at such high rates that it is presumed that environmental causes, rather than genetic changes, are to blame and the key suspect is our increasing exposure to ‘endocrine disrupting chemicals’ (EDCs), particularly during fetal life. We have previously shown that the presence of retinoic acid (RA, a signalling molecule with many functions during development) is detrimental to development of all three cell types of the mouse fetal testis – germ cells, Sertoli cells and fetal Leydig cells. Normally, a P450 enzyme, CYP26B1, degrades RA during fetal development, but if CYP26B1 does not function, ectopic RA causes germ cells to aberrantly enter meiosis, the testis is partially feminized, and the development of secondary sexual structures is abnormal. By combining classic developmental biology and mouse transgenic expertise with reproductive toxicology, we have developed a novel ex-vivo testis culture system as a read-out for RA-Cyp26b1 signalling perturbation to environmental chemical load. This system will allow us to contribute novel understanding of how RA disruption is involved in human disorders, demonstrating causality rather than just association, and have future translational importance for the refinement of current chemical screening methodologies.