During the first trimester of pregnancy, the human placenta undergoes a major transition: the partial pressure of oxygen in the intervillous space rises from 2–3% at around 8–10 weeks of gestation to more than 6% after the twelfth week. This increase, triggered by the remodeling of maternal spiral arteries under the action of invasive extravillous trophoblasts, meets the placenta's high oxygen demand. Far from trivial, it represents a pivotal period: an excess, a deficiency, or an abnormality in this process can lead to pregnancy disorders such as spontaneous abortion, prematurity, or preeclampsia, whose mechanisms remain poorly understood. Previous work has moreover suggested the existence of sex-differentiated responses, with the male placenta proving particularly more vulnerable to certain mitochondrial disturbances under hypoxic conditions.
To map the processes active during this physiological rise in oxygen, the authors compared the transcriptomes of human placentas collected at two time windows, 8–10 weeks and 12–14 weeks of gestation. Twenty samples were collected and distributed into four groups balanced according to sex and gestational age. Villous cytotrophoblasts were isolated by Percoll gradient, fetal sex was determined by PCR on sex chromosome-linked genes, and messenger RNA was then sequenced by RNAseq. The identification of key genes relied on two complementary approaches: DESeq2 differential analysis and weighted gene co-expression network analysis (WGCNA). To link expression profiles to oxygen variations, the team additionally assembled a local database of known or predicted targets of hypoxia-inducible factors (HIF), bringing together the alpha and beta subunits. Enrichment patterns, within each group and between groups, were analyzed using Gene Ontology annotations and KEGG pathways.
This work provides an overview of the biological processes mobilized in trophoblasts during the physiological increase in oxygen, distinguishing time-related and sex-related variations, as well as those associated with HIF targets. The authors nevertheless point out several limitations. The samples did not cluster into two clearly distinct temporal groups, which may have weakened the precision of key gene filtering. As the study was intended to be descriptive, no functional manipulation experiments were carried out to validate the role of the selected genes, even though the expression profiles of certain critical genes were examined individually. Finally, the choice of preparation kit directed the analysis toward messenger RNAs alone, which the authors acknowledge as a bias. Overall, this characterization should contribute to the identification of genes or pathways that may constitute therapeutic targets in the human placenta.