Sexual dimorphisms in brain gene expression in the growth-restricted guinea pig can be modulated with intra-placental therapy

Abstract

BACKGROUND: Fetal responses to adverse pregnancy environments are sex-specific. In fetal guinea pigs (GPs), we assessed morphology and messenger RNA (mRNA) expression in fetal growth-restricted (FGR) tissues at midpregnancy. METHODS: Female GPs were assigned either an ad libitum diet (C) or 30% restricted diet (R) prior to pregnancy to midpregnancy. At midpregnancy, a subset of R females underwent ultrasound-guided nanoparticle (NP) injection to enhance placental function. Five days later, fetuses were sampled. Fetal brain, heart, and liver were assessed for morphology (hematoxylin and eosin), proliferation (Ki67), and vascularization (CD31), as well as expression of inflammatory markers. RESULTS: R fetuses were 19% lighter with reduced organ weights and evidence of brain sparing compared to controls. No increased necrosis, proliferation, or vascularization was found between C and R nor male or female fetal organs. Sexual dimorphism in mRNA expression of Tgfβ and Ctgf was observed in R but not C fetal brains: increased expression in females. NP treatment increased fetal brain mRNA expression of Tgfβ and Ctgf in R males, abolishing the significant difference observed in untreated R fetuses. CONCLUSIONS: Sex-specific differences in mRNA expression in the fetal brain with FGR could impart a potential survival bias and may be useful for the development of treatments for obstetric diseases.

Placental treatment with insulin-like growth factor 1 via nanoparticle differentially impacts vascular remodeling factors in guinea pig sub-placenta/decidua

“…At GD30-33, females underwent a nanoparticle injection of plasmid containing hIGF-1 (Control + hIGF-1 n = 4 or MNR + hIGF-1 n = 7), or PBS sham injection (Control n = 7 or MNR n = 5), and were then sacrificed five days after injection (GD35-38). At time of sacrifice, major maternal and fetal organs were collected and weighed; fetal sex was also determined by visual inspection and confirmed using PCR as previously described (Depreux, Czech et al 2018, Wilson, Stephens et al 2021. Placentas were halved and either fixed 4% w/v paraformaldehyde (PFA) or the labyrinth and sub-placenta/decidua tissue separated, and snap-frozen in liquid nitrogen and stored at -80ºC.…”

Nanoparticle-mediated transgene expression of insulin-like growth factor 1 in the growth restricted guinea pig placenta increases placenta nutrient transporter expression and fetal glucose concentrations

“…Tissue collection was performed as previously described however, tissue placenta in PFA fixed was processed and paraffin embedded following standard protocols. Fetal sex was determined by examination of the gonads and confirmed using PCR as previously published [26].…”

Working towards precision medicine in developmental programming

“…Of most interest, despite only directly affecting the placenta, nanoparticle treatment resulted in changes in fetal brain mRNA expression of the inflammatory markers Tgfβ and Ctgf, so that the expression was similar between male and female fetuses in the nutrientrestricted groups. 10 Combined, therefore, the observations in the study of Wilson et al 10 provide a good example of working towards precision medicine in the field of developmental programming not only by using targeted therapy but also by doing so using an experimental design that includes the sex of the fetus and of its placenta as biological variables. Only by adopting such approaches will real advances be made to expedite translational discoveries and isolate optimal therapy to improve the health of pregnant women and their children.…”

“…The authors suggest that differences in gene expression between males and females may confer a selective advantage or disadvantage during adverse intrauterine conditions. 10 Their studies also show that treatment of the placenta with a nanoparticle known to increase insulin-like growth factor 1 expression can not only protect fetal growth by increasing nutrient transporter expression and placental angiogenesis in adverse pregnancy but that it can also affect mRNA expression in the brain of the offspring in a sex-specific manner. Of most interest, despite only directly affecting the placenta, nanoparticle treatment resulted in changes in fetal brain mRNA expression of the inflammatory markers Tgfβ and Ctgf, so that the expression was similar between male and female fetuses in the nutrientrestricted groups.…”

“…In this issue of Pediatric Research, Wilson et al, 10 in an elegant study, report sexual dimorphism in the gene expression of the brain in a model of fetal growth restriction by maternal nutrient restriction in the guinea pig. In a pregnancy complicated by fetal growth restriction, inflammatory marker messenger RNA (mRNA) expression in the fetal brain was significantly higher in females compared to males.…”