BioProject

Estradiol (E2) is a well-known modulator of fetal neuroendocrine activity, and has been proposed as a critical endocrine signal readying the fetus for birth and postnatal life. To investigate the modulatory role of E2 on fetal stress responsiveness and the response of the fetal brain to asphyxic stress, we subjected chronically catheterized fetal sheep to a transient (10 min) brachiocephalic occlusion or sham occlusion. Half of the fetuses received subcutaneous pellets that released E2 (5 days@~250 μg/day, increasing plasma E2 from 62±6 to 102±12 pg/mL). Hypothalamic mRNA was analyzed using the Agilent 8x15k ovine array (019921), processed and annotated as previously reported by our laboratory. Analysis of the data by ANOVA revealed that E2 differentially regulated (DR) 561 genes, and BCO DR 894 genes compared to control and estradiol+BCO DR 1153 genes compared to BCO alone (all p<0.05). E2 upregulated epigenetic pathways and downregulated local steroid biosynthesis, but did not significantly involve genes known to directly respond to the estrogen receptor (ie., contain ERE sequences). BCO upregulated kinase pathways as well as genes associated with lymphocyte infiltration into the brain, and downregulated neuropeptide synthesis. E2 upregulated immune- and apopotosis- related pathways after BCO, and reduced kinase and epigenetic pathway responses to the BCO. We conclude that array results are consistent with the results of more limited hypotheses previously published from these experiments. Overall design: Chronically catheterized fetal sheep; 4 groups: control (no treatment); estradiol treatment (250 ug/day x 5 days); brachiocephalic occlusion of fetal sheep (BCO, 10 min, no other treatment); BCO plus estradiol (combination of estradiol treatment and BCO). All fetuses had blood drawn from chronically implanted catheters at 0, 5, 10, and 30 min after start of BCO or sham-BCO period. Fetal sheep 124-128 days gestation (term=147 days) at the time of study. Fetuses euthanized and fetal hypothalami collected for gene array studies 1 hour after first blood sample drawn (and start of BCO or sham-BCO period).