Deciphering the trace metal-inflammation axis in the pathophysiology of recurrent pregnancy loss

Recurrent Pregnancy Loss (RPL) is a multifactorial reproductive disorder influenced by genetic, immunological, and metabolic disturbances. Altered trace element and heavy metal levels increasingly contribute to oxidative stress, inflammation, and impaired methylation, potentially affecting pregnancy outcomes.

A case-control study was conducted including RPL patients (n = 48) and healthy controls (n = 48). Serum levels of Cu, Zn, Pb, Fe, Cr, Se, Cd, As, and Mg were assessed using Atomic Absorption Spectrophotometry. Inflammatory and metabolic biomarkers MMP-2, TNF-α, Vitamin B12, Folate, and Homocysteine measured using ELISA. Molecular docking analyses (Auto Dock Vina) performed to determine the binding affinities of the trace metals with TNF-α, Vitamin B12, and Homocysteine.

Cu, Cr, Mg, and Pb levels were significantly elevated in RPL patients (p < 0.01), whereas Zn and Fe were markedly lower (p < 0.0001). No significant differences were observed for Se, Cd, and As. RPL patients exhibited higher MMP-2 and TNF-α levels (p = 0.0001 each) and reduced Vitamin B12 (p = 0.0364), while homocysteine levels were unexpectedly decreased (p = 0.006). Docking analysis revealed strong Pb²⁺ affinity for TNF-α (-12.58 kcal/mol), suggesting pro-inflammatory stabilization, while Cu²⁺ demonstrated high affinity for Vitamin B12 (-8.5 kcal/mol).

The study findings indicate that dysregulated trace element patterns specifically elevated Pb²⁺, Cu²⁺, and Cr³⁺ with reduced Zn²⁺ and Fe²⁺ may disrupt inflammatory, metabolic, and methylation pathways in RPL. High-affinity metal-protein interactions further support their potential diagnostic and therapeutic relevance.