Bone Manganese is a Sensitive Biomarker of Ongoing Elevated Manganese Exposure, but Does Not Accumulate Across the Lifespan

Studies have established associations between environmental and occupational manganese (Mn) exposure and executive and motor function deficits in children, adolescents, and adults. These health risks from elevated Mn exposure underscore the need for effective exposure biomarkers to improve exposure classification and help detect/diagnose Mn-related impairments. Here, neonate rats were orally exposed to 0, 25, or 50 mg Mn/kg/day during early life (PND 1-21) or lifelong through ∼ PND 500 to determine the relationship between oral Mn exposure and blood, brain, and bone Mn levels over the lifespan, whether Mn accumulates in bone, and whether elevated bone Mn altered the local atomic and mineral structure of bone, or its biomechanical properties. Additionally, we assessed levels of bone Mn compared to bone lead (Pb) in aged humans (age 41-91) living in regions impacted by historic industrial ferromanganese activity. The animal studies show that blood, brain, and bone Mn levels naturally decrease across the lifespan without elevated Mn exposure. With elevated exposure, bone Mn levels were strongly associated with blood Mn levels, bone Mn was more sensitive to elevated exposures than blood or brain Mn, and Mn did not accumulate with lifelong elevated exposure. Elevated early life Mn exposure caused some changes in bone mineral properties, including altered local atomic structure of hydroxyapatite, along with some biomechanical changes in bone stiffness in weanlings or young adult animals. In aged humans, blood Mn ranged from 5.4 to 23.5 ng/mL; bone Mn was universally low, and decreased with age, but did not vary based on sex or female parity history. Unlike Pb, bone Mn showed no evidence of accumulation over the lifespan, and may not be a biomarker of cumulative long-term exposure. Thus, bone may be a useful biomarker of recent ongoing Mn exposure in humans, and may be a relatively minor target of elevated exposure.