Dynamic dose-time proteomic profiling of cadmium exposure in rat prefrontal cortex

Area of Science:

• Neuroscience
• Proteomics
• Toxicology

Background:

• Cadmium (Cd) is a neurotoxic metal with cumulative effects on the central nervous system.
• Understanding how dose and time influence brain proteome changes, especially under low-dose exposure, remains unclear.
• Time-resolved proteomics requires methods to separate dose-time effects from biological variability.

Purpose of the Study:

• To map dynamic brain proteome responses to cadmium exposure.
• To identify early molecular events under low-dose, short-duration cadmium exposure.
• To develop a method for deconvolving dose-time interactions in proteomic data.

Main Methods:

• Oral exposure of rats to cadmium chloride (CdCl2) at varying doses (30μg/kg/day, 1mg/kg/day) and durations (2, 4, 8 weeks).
• Deep quantitative proteomics (diaPASEF) of the prefrontal cortex.
• Integrative analysis using Mfuzz, STEM, and linear mixed-effects modeling (LMM) to deconvolve Dose×Time interactions.

Main Results:

• Quantified 8,209 proteins; identified significant Dose (173), Time (476), and Dose×Time interaction effects (356 proteins).
• Dose×Time interactions substantially shaped cadmium-responsive proteome variation.
• Identified Itpr1 and Pde5a as early-response proteins, down-regulated at 2 weeks/30μg/kg, linked to altered Ca²⁺ handling and glutamatergic signaling.

Conclusions:

• Explicitly deconvolving dose, time, and interaction effects revealed dynamic proteome responses in the prefrontal cortex.
• An early Itpr1/Pde5a-centered calcium-cGMP-glutamatergic signature is detectable even under low-dose, short-duration cadmium exposure.
• The DIA dataset and workflow serve as a resource for neurotoxicant research and candidate biomarker discovery.