# Sex-specific placental transcriptome alterations in late-onset preeclampsia reveal male-biased immune and metabolic dysregulation

## TL;DR

This study shows that late-onset preeclampsia affects placental gene expression differently depending on the baby's sex, with male placentas showing immune and metabolic changes.

## Contribution

The study reveals sex-specific placental transcriptome alterations in late-onset preeclampsia, highlighting male-specific immune and metabolic dysregulation.

## Key findings

- Male-bearing placentas showed 150 differentially expressed genes in late-onset preeclampsia, while female-bearing placentas did not.
- Increased CD14+ monocytes and CD8+ T cells were observed in male placentas, indicating immune activation.
- Gene modules in male placentas were enriched for RNA processing, immune regulation, and metabolism.

## Abstract

Preeclampsia is a hypertensive disorder of pregnancy with major maternal and fetal consequences. While the molecular basis of early-onset preeclampsia is well studied, the mechanisms underlying late-onset disease—and how they differ by fetal sex—remain poorly understood. Placental transcriptomic profiling at term can reveal persistent molecular alterations reflecting cumulative disease processes.

We conducted a cross-sectional observational analysis of placental gene expression using RNA sequencing in a subset of 58 term placentas (21 male-bearing and 37 female-bearing pregnancies) drawn from two large prospective birth cohorts. Pregnancies were classified based on a clinical diagnosis of late-onset preeclampsia (diagnosed ≥ 20 weeks’ gestation according to ISSHP criteria) or as uncomplicated pregnancies. We then assessed for differential gene expression. Cell type proportions were estimated using CIBERSORTx from a placenta-specific reference single-cell dataset. Weighted gene co-expression network analysis identified modules of co-expressed genes associated with late-onset preeclampsia and fetal sex.

Differential gene expression analysis identified 150 genes with altered expression in male-bearing placentas from pregnancies with late-onset preeclampsia compared to those from uncomplicated pregnancies. No differentially expressed genes were identified in female-bearing placentas. Cell type deconvolution revealed increased abundance of CD14 + monocytes and CD8 + activated T cells (log odds of 1.42 and 1.44 respectively) and reduced fetal GZMK natural killer cells (log odds of 0.60) in male-bearing placentas from affected pregnancies. In female-bearing placentas, late-onset preeclampsia was associated with increased fetal nucleated red blood cells and maternal plasma cells (log odds of 1.33 and 1.40 respectively). Male-specific co-expression analysis identified gene modules enriched for biological processes including RNA processing, immune regulation, and metabolism.

Placental transcription and cellular responses to late-onset preeclampsia differ by fetal sex. Evidence of altered immune cell composition and gene co-expression in male-bearing placentas suggests a sex-specific vulnerability. These findings highlight the importance of considering fetal sex in molecular investigation and clinical management of preeclampsia.

Preeclampsia is a common pregnancy complication marked by high blood pressure, but how it affects the placenta, especially in later pregnancy and depending on the baby’s sex, is not well understood. In this study, we analysed placental tissue from pregnancies with and without late-onset preeclampsia using RNA sequencing. By separating the data based on whether the neonate was male or female, we found striking differences in gene expression. Only placentas from male-bearing pregnancies showed significant changes in gene expression linked to preeclampsia. These changes involved genes related to immune response, metabolism and vascular function. We also used computational tools to estimate what types of cells were present in each placental sample. In male-bearing pregnancies affected by late-onset preeclampsia, there was a notable increase in certain immune cells, suggesting an altered immune response and increased inflammation. In contrast, female-bearing pregnancies affected by late-onset preeclampsia showed an increase in cell composition for two blood related cell types, but no significant gene expression differences. By grouping genes that worked together into networks, we identified several groups, especially in placentas from male-bearing pregnancies, that were strongly associated with biological processes known to be disrupted in preeclampsia, such as blood vessel formation, extracellular matrix remodelling, and hormone regulation. These findings emphasise the importance of considering fetal sex in pregnancy research and could help guide future sex-specific diagnostic or treatment strategies.

The online version contains supplementary material available at 10.1186/s13293-025-00781-w.

Sex-specific response: Significant placental gene expression changes between preeclamptic and uncomplicated pregnancies were found only in male-bearing pregnancies.

Immune involvement: Increased abundance of CD14 + monocytes and CD8 + T cells in placenta from male-bearing pregnancies suggests a heightened immune response.

ECM and vascular remodelling: Key gene modules in male-bearing placentas were enriched for extracellular matrix organisation and vascular function.

Transcriptomic network disruption: Co-expression analysis revealed distinct gene modules associated with preeclampsia in male-bearing pregnancies, reflecting changes in metabolism and gene signaling.

Female resilience hypothesis: Despite altered cell composition, female-bearing placentas showed no significant gene expression changes, suggesting possible adaptive resilience.

The online version contains supplementary material available at 10.1186/s13293-025-00781-w.