Fetal Zone Steroids and Estrogen Show Sex Specific Effects on Oligodendrocyte Precursor Cells in Response to Oxidative Damage

Abstract

Oxygen causes white matter damage in preterm infants and male sex is a major risk factor for poor neurological outcome, which speculates the role of steroid hormones in sex-based differences. Preterm birth is accompanied by a drop in 17β-estradiol (E2) and progesterone along with increased levels of fetal zone steroids (FZS). We performed a sex-based analysis on the FZS concentration differences in urine samples collected from preterm and term infants. We show that, in preterm urine samples, the total concentration of FZS, and in particular the 16α-OH-DHEA concentration, is significantly higher in ill female infants as compared to males. Since we previously identified Nup133 as a novel target protein affected by hyperoxia, here we studied the effect of FZS, allopregnanolone (Allo) and E2 on differentiation and Nup133 signaling using mouse-derived primary oligodendrocyte progenitor cells (OPCs). We show that the steroids could reverse the effect of hyperoxia-mediated downregulation of Nup133 in cultured male OPCs. The addition of FZS and E2 protected cells from oxidative stress. However, E2, in presence of 16α-OH-DHEA, showed a negative effect on male cells. These results assert the importance of sex-based differences and their potential implications in preterm stress response.

Fetal Zone Steroids Show Discrete Effects on Hyperoxia-Induced Attenuation of Migration in Cultured Oligodendrocyte Progenitor Cells

“…These studies, however, did not consider the continuing postnatal synthesis of fetal zone steroids by the adrenal of the preterm infant. Our current and previous findings [ 7 , 19 ] have elaborated the neuroprotective effects of FZS and either no or even harmful effects when FZS are combined with estradiol. Therefore, here, we add new insights to clarify the question whether maintaining the placental hormone level after preterm birth is a promising therapeutic strategy, and our approach considers the unique hormonal milieu of the preterm infant with high postnatal production of FZS.…”

“…Placenta is the main source of estrogen during pregnancy [ 6 ], and the fetus provides 90% of the androgenic precursors required for the synthesis of estrogen. The active steroidogenic specialized compartment of the fetal adrenal cortex is called the fetal zone, which together with the placenta forms an effective steroid exchange channel, and this functional association is termed as the “fetoplacental unit” [ 7 ]. The fetus is constantly exposed to the changing hormone levels during its crucial stages of development.…”

“…Studies have reported that even though the high DHEAS levels during the 1st week of life may reflect the sudden discontinuation of the placental metabolism of circulating DHEAS into estrogens at birth, it might also partly represent a stress response [ 16 ]. Since preterm birth is accompanied by a drop in estrogen level and an increase in the levels of these precursor molecules, the precise role of these precursor molecules in brain development needs to be addressed [ 7 ]. Experimental models of steroids and the brain in preterm infants have yet to consider this unique hormone milieu [ 17 ].…”

“…We have also demonstrated sex-based differences in the response of OPCs towards oxidative stress and have uncovered the underlying molecular mechanism [ 20 ]. Based on this mechanism involving the nucleoporin protein Nup133, nuclear respiratory factor 1 (Nrf1), and the classical estrogen receptor alpha (ER α ), we have also shown how the FZS have differential effects on the maturation of male- and female-derived OPCs and how these observed differences correlate to concentration differences of these steroids observed in urine samples collected from preterm infants [ 7 ].…”

Mechanistic advances of hyperoxia-induced immature brain injury

“…For the study of BPD with brain injury, the period of hyperoxic exposure can be up to 14 days ( Table 1 ). Sex differences in adverse neurological outcomes have been identified in clinical studies and experimentally [ [15] , [16] , [17] , [18] , [19] ], with females having a superior prognosis to males [ 20 ]. A study by Donna et al showed that stronger regulation of estrogen receptor alpha in female cells allowed them to better cope with oxidative stress [ 19 ].…”