Human Lactoferrin is a Novel PFAS Target: Implications for Neo-natal Immune Function and Protein Stability
Per-and polyfluoroalkyl substances (PFAS) constitute a diverse class of persistent synthetic chemicals utilized across industrial, medical, and consumer sectors that are pervasive global pollutants. Exposure to PFAS is linked to adverse impacts on both innate and adaptive immune systems. Human lactoferrin (hLF) is a key antimicrobial component of the developing innate immune system present in…
Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals that are widely used across various industries and have become pervasive environmental pollutants. Exposure to these chemicals has been associated with negative effects on both the innate and adaptive immune systems. One component of the innate immune system that is particularly important in newborns is human lactoferrin (hLF), which is found in colostrum and breast milk and acts as an antimicrobial agent.
The researchers hypothesized that hLF could potentially bind to PFAS and contribute to the immunotoxicity caused by these chemicals. To test this hypothesis, they conducted experiments to investigate the effects of various PFAS on the structure of hLF. The results showed that all 11 tested PFAS bind to and destabilize the structure of hLF.
Some of the most damaging PFAS included PFBA, PFOS, HFPO-DA, and 6:2 FTSA, which decreased the melting temperature of apo-hLF (the free form of hLF) from 64°C to as low as 37°C, indicating that these PFAS can destabilize hLF protein structure under normal physiological conditions.
The strength of the binding between PFAS and hLF was determined by calculating the relative binding affinities (Kd) for each chemical, which ranged from 0.2 to 11 mM. Molecular docking experiments were used to confirm the experimental binding affinities and identify the molecular interactions involved in this binding process. The calculations revealed that the Gibbs Free Energies of binding for PFAS ranged from -4.4 to -8.8 kcal/mol, indicating that the binding of PFAS to hLF is comparable to the binding of other PFAS binding proteins, such as human serum albumin.
These findings provide strong evidence that PFAS can bind to and destabilize hLF protein structure under conditions that are relevant to the human body. This suggests that PFAS exposures may have significant implications for neonatal immune function and overall health.
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