Ressler, M. | Search bioRxiv

bioRxiv2025

Maternal smoking in early pregnancy disrupts placental function through syncytiotrophoblast and macrophage dysregulation.

Smoking in pregnancy is the leading avoidable cause of gestational morbidity and mortality, causally linked to fetal growth restriction (FGR). The placenta, functional interface between mother and fetus is essential for healthy fetal development. For the first time, we studied cell type-resolved smoking effects on placental development at high molecular resolution using single-nucleus RNA sequencing and deep visual proteomics of matched tissues. We validated our findings through an independent cohort and in-vitro cigarette smoke exposure to primary human trophoblast cells. Our results show placental macrophages (Hofbauer cells; HBC) and the syncytiotrophoblast (STB) barrier are most affected by smoking, with dysregulation of cell-cell adhesion, extracellular matrix organization, and stress phenotype. STBs show moderate compositional increases in smokers and in-silico trophoblast differentiation modelling indicates a preferential shift towards the STB lineage in this group. The trophoblast displays a large upregulation of pro-angiogenic effectors, increases in xenobiotic detoxification, reduced mitochondrial function, and vastly altered transmembrane transport. These molecular changes affect placental development with important consequences for fetal growth. We provide insight into placental dysfunction contributing to FGR early in pregnancy, before clinical symptoms appear. We anticipate this data to advance diagnostics and therapies to improve FGR outcomes.

systems biology↗

bioRxiv2020

A causal role for estradiol in human reinforcement learning

The sex hormone estrogen is hypothesized to play a key role in human cognition via its interactions with the dopaminergic system. Work in rodents has shown that estrogens most potent form, estradiol, impacts striatal dopamine functioning predominately via increased D1-receptor signalling, while human work has suggested that high estradiol levels are associated with altered reward sensitivity. Here, we addressed two fundamental questions: 1) whether estradiol causally alters reward sensitivity in men, and 2) whether this effect of estradiol is moderated by individual variation in polymorphisms of dopaminergic genes. To test this, we performed a double-blind placebo-controlled administration study in which hundred men received either a single dose of estradiol (2 mg) or placebo. We found that estradiol administration increased reward sensitivity, which was moderated by baseline dopamine. This was observed in choice behaviour and increased learning rates. These results confirm a causal role of estradiol in reinforcement learning in men that is moderated by the striatal dopaminergic pathway.

neuroscience↗