Transcriptomic effects of lead on the differentiation of human embryonic stem cells into ectoderm: implication for adverse pregnancy outcomes and neurodevelopmental disorders.

Epidemiological studies revealed associations between maternal lead (Pb) exposure and adverse pregnancy and birth outcomes as well as neurodevelopmental disorders. However, the underlying mechanisms remained unclear, and thus was investigated at the transcriptional level in this study using human embryonic stem cells (hESCs). Differentiation of hESCs to ectoderm was induced for 7 days using STEMdiff™ Trilineage Differentiation Kit containing 0 (water), 6.2 (geometric mean concentration of Pb in human maternal blood), or 118 µg Pb2+/L, in the form of lead chloride (PbCl2), followed by bulk RNA sequencing. Both doses of PbCl2 altered gene expression related to protein metabolism and trafficking, while also causing changes in genes involved in gastrulation, proliferation, DNA repair, stress response, and immune-cell development. PbCl2 at the low dose induced gene changes predicting decreased cell proliferation and increased sensory loss. Cells exposed to the high dose of PbCl2 had a distinct global gene expression profile from that of control cells with specific changes predicting increased neurodegeneration. The differences in expression of ectoderm lineage marker genes (ELMG) between control and PbCl2 treated cells did not reach statistical significance. However, expression of some genes downstream of ELMG differed markedly between control and PbCl2 treated cells. Multiple adverse outcome pathways involving WNT, IGF-1, RHO-PKN, CDK5, MAP kinase, and Ca2+ signaling, cell cycle control, protein metabolism and trafficking, DNA double strand break and repair, and immune response were detected in PbCl2 treated cells. Overall, the findings suggest that Pb exposure disrupted early ectodermal development by prioritizing genome preservation over fate execution.