The Interaction Between Iron Overload and Lead Exposure on Bone Metabolism

Osteoporosis (OP) is a common metabolic bone disease characterized by chronic bone loss and structural deterioration of bone tissue, and it is closely associated with environmental exposure to heavy metals. Although lead (Pb) and iron (Fe) are known to affect bone metabolism, the impact of iron overload under fixed lead exposure, along with the underlying metabolic mechanisms, remains unclear. This study aimed to investigate the effects of combined iron and lead exposure on bone mineral homeostasis and metabolic remodeling.

Male C57BL/6 mice were exposed for 8 weeks to lead acetate (50 mg/kg) in combination with either low-dose (100 mg/kg) or high-dose (300 mg/kg) iron dextran. Metal accumulation in femoral tissue was quantified using inductively coupled plasma mass spectrometer (ICP-MS). Bone microarchitecture was evaluated using microcomputed tomography (micro-CT). Bone-specific untargeted metabolomics and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to assess metabolic alterations.

Iron overload did not significantly affect lead accumulation but disrupted mineral balance in a dose-dependent manner, reducing levels of calcium, zinc, magnesium, and vanadium. Micro-CT analysis revealed significant alterations in bone microarchitecture. Metabolomic analysis identified 297 altered metabolites, primarily involved in amino acid, lipid, and nucleotide metabolism, as well as mineral absorption. KEGG pathway analysis revealed disturbances in amino acid biosynthesis, aminoacyl-tRNA biosynthesis, ATP-binding cassette (ABC) transporters, protein digestion and absorption, and mineral absorption, with distinct profiles observed between different iron doses.

Iron overload is associated with further alterations in bone metabolic homeostasis under fixed lead exposure, as evidenced by structural deterioration, disruption of trace element homeostasis, and extensive metabolic reprogramming in bone tissue.