Lightning Talk + Poster ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Do phthalate interactions with activin A in fetal life influence testis development? (#412)

Junlan (Iris) Ma 1 2 , Penny Whiley 1 2 , Dagmar Wilhelm 3 , Kate Loveland 1 2 , Sarah Moody 1 2
  1. Department of Molecular and Translational Sciences, School of Clinical Sciences, Monash University, Clayton, VIC, Australia
  2. Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, VIC, Australia
  3. Department of Anatomy and Physiology, University of Melbourne, Parkville, Victoria, Australia

Phthalates are endocrine disrupting chemicals (EDCs) associated with male reproductive disorders. They can interact with TGFβ signalling pathways by activating SMADs, which in turn influence gene transcription. In fetal mice, exposure to either elevated activin A bioactivity (a feature of late pregnancy and pre-eclampsia in humans) or to phthalates generates similar testis phenotypes. We hypothesised that maternal di-2ethylhexyl phthalate (DEHP) exposure would exacerbate the adverse fetal testis phenotypes documented in InhaKO mice (lacking inhibin and exposed to elevated activin A). Pregnant females from HETxHET matings received either vehicle or 500mg/kg/day DEHP from embryonic day (E)12.5 to E14.5 or from E12.5 to E16.5, and testes collected at E15.5 and E17.5, respectively. At E15.5, DEHP exposure increased embryo resorption rate from 2.4% to 16.8%, indicating teratogenic effects, however levels of three known activin A-responsive transcripts, Ccl17, Hsd17b1, and Star, were unaffected in WT, HET and KO testes (n=4/genotype). Compared to WT, KO testes have smaller cord area, a trend towards lower gonocyte density and increased proportion of abnormal gonocytes (multinucleated and outside of cords). In the KO testes, DEHP did not affect cord area or gonocyte number but was associated with more abnormal gonocytes and greater variability compared to vehicle (SD from 1.33 to 8.4). Preliminary data revealed that KO testes have more CD45-positive immune cells compared to WT (3.3-fold increase), but DEHP exposure reduced immune cell numbers to WT levels (n=2-3/genotype). At E17.5, DEHP significantly increased levels of activin A target transcript, Ccl17 (1.36-fold) and decreased Sertoli cell transcript Amh (0.75-fold) in HET testes (n=5/genotype). These data suggest that DEHP affects fetal Sertoli cells and may interact with activin A signalling in these cells. This research will provide insights into how EDCs affect reproductive health in offspring of pregnant women with elevated activin A due to common pregnancy complications.