Vickeline NambaBisfenol A, bisfenol F e DEHP remodel the transcriptome of a human 3D placenta model

Microplastics are recognized as important vectors of endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), bisphenol F (BPF), and di(2-ethylhexyl) phthalate (DEHP). Their recent detection in human placentas has raised substantial concern. However, the precise molecular mechanisms by which these compounds disrupt the placental barrier remain incompletely understood.

To investigate the effects of microplastic-associated EDCs on the transcriptome of a human 3D placental model.

A human 3D placental model composed of JEG-3 trophoblast spheroids was exposed for 24 h to low concentrations of BPA (1 nM), BPF (1 nM), or DEHP (4 μM). Global transcriptome sequencing was performed using the Illumina NextSeq 2000 platform (paired-end, 2 × 100 bp). Transcript quantification and differential expression analyses were performed using Salmon and DESeq2 (|log2FoldChange| ≥ 1 and FDR < 0.05), respectively. We conducted functional enrichment analysis using clusterProfiler. Oxidative stress markers, including malondialdehyde (MDA) and protein carbonylation, were assessed biochemically.

BPA altered the expression of 117 differentially expressed genes (DEGs; 87 upregulated and 30 downregulated), BPF altered 16 DEGs (6 upregulated and 10 downregulated), and DEHP altered 497 DEGs (353 upregulated and 144 downregulated). Both BPA and DEHP increased HSPA1B expression, a key mediator of the proteotoxic stress response, whereas BPF and DEHP downregulated EHMT2, which encodes G9a, a histone methyltransferase involved in chromatin compaction. GO enrichment analysis revealed alterations in processes related to nuclear speckles, RNA splicing, cell adhesion, and syncytialization. Biochemically, descriptive measurements showed higher protein carbonylation levels in BPA- and DEHP-exposed spheroids compared with the vehicle-treated condition.

Even at low concentrations, BPA, BPF, and DEHP alter the transcriptome of a human 3D placental model, affecting genes and pathways related to proteostasis, RNA processing, and epigenetic regulation. These findings reveal potential molecular mechanisms of placental toxicity associated with exposure to endocrine-disrupting chemicals, with possible implications in the context of the Developmental Origins of Health and Disease (DOHaD).