Novel Approach to Screen Endocrine-Disrupting Chemicals via Endocrine-Enhanced Reduced Human Transcriptome

Endocrine-disrupting chemicals (EDCs) can interfere with multiple pathways and trigger different modes of action. Thus, the traditional EDC in vitro screening processes often require a battery of bioassays to cover multiple target pathways. Here we developed an endocrine-enhanced reduced human transcriptome (ERHT) focused on hormone receptor signaling induced by the EDCs regulating specific genes. ERHT was developed based on 1200 prioritized genes covering 110 endocrine-related biological pathways across eight potential adverse outcomes. The ability of this approach to identify EDCs was derived from machine learning of 1068 dose-dependent transcriptome profiles and enhanced by quantifying chemical-induced critical pathway responses, and thus, it demonstrated excellent classification performance (AUC = 0.84 ± 0.03) in internal cross-validation. We ultimately applied this approach to known EDCs and inactive substances to validate the reliability of this approach. Through external validation on 210 chemicals, the extrapolation accuracy exceeded 80%, demonstrating the outstanding practical performance of this approach. Meanwhile, the pathway responses induced by the same chemical were consistent with the experimental results reported by multiple sequencing platforms, highlighting the robustness of this approach. The above results demonstrate that this approach can provide novel insights for EDCs' high-throughput screening and comprehensive toxic mechanisms through biological pathways.