Biotransformation of Atmospheric-Aged Metal-Sulfide Nanosheets in Respiratory Tract Fluids Potentiates Ferroptosis toward Alveolar Macrophages

The widespread application and unavoidable atmospheric
release
of transitional metal dichalcogenides (TMDCs) pose significant inhalation-related
health risks. During respiration, atmospheric aging of nanoparticles
occurs first; nonetheless, the hazard of air-aged TMDCs and the effect
of postbiotransformation in the microenvironment following inhalation
remain unclear. By mimicking atmospheric conditions and respiratory
media, we discovered that air-aged molybdenum disulfide (A-MoS2) and tungsten disulfide (A-WS2) underwent biotransformation
in artificial nasal fluids and Gamble’s solution, increasing
the hydrophobicity and roughness of the nanosheets. The oxidized products
(31.7% in A-MoS2 and 44.5% in A-WS2) were partially
converted to sulfidation-state species via thiol-mediated reduction.
Both biotransformed and air-aged TMDCs were localized to macrophage
lysosomes at approximate concentrations, whereas the lysosomal membrane
damage and ferrous ion (Fe2+) release were more significant
for biotransformed forms. Transcriptome and lipidomics analyses indicated
that ferroprotein degradation and ferroportin1 inhibition also facilitated
Fe2+ overload, along with glutathione peroxidase 4 inhibition,
lipid acylation, and phospholipid biosynthesis activation, worsening
lipid peroxidation (154.3–225.6%). Shapley Additive Explanations
substantiated the reduction of oxidized species, 1T-phase stabilization,
and increased hydrophobicity as major contributors to ferroptosis
aggravation of biotransformed TMDCs. Our findings highlight the necessity
of incorporating biotransformation into risk assessment, rather than
merely relying on the versions of nanomaterials following environmental
processes as the testing endpoints.