Epidemiological studies have reported associations between environmental manganese (Mn) exposure and attention-based learning and motor function deficits in children and adolescents. These studies have raised concerns about the increased vulnerability of children to the neurotoxic effects of elevated Mn exposure and underscore the need for effective exposure biomarkers to improve exposure classification, and to better detect Mn-related impairments across the lifespan. Recent animal model studies have established that elevated developmental Mn exposure can cause executive function and motor impairments, including deficits in focused and selective attention, but the specific neurobiological alterations responsible for these impairments are not well understood. Further, the impact of long-term Mn exposure on tissue accumulation of Mn in blood, brain, and bone as exposure biomarkers, and its effects on the skeleton as a potential target organ, is similarly not well understood. To address these knowledge gaps, I used an established rodent model of early life or lifelong childhood oral Mn exposure in Chapter 2 to determine 1) the relationship between oral Mn exposure and blood, brain, and bone Mn levels over the lifespan, 2) whether Mn accumulates in bone with lifelong exposure, 3) whether elevated bone Mn altered the mineral structure or physical properties of bone, and 4) bone Mn levels in aged humans (age 41-91; female, n=30; male, n=19) living in regions impacted by historic ferromanganese alloy plant activity. In Chapter 3, I used this same rodent model of early life or lifelong oral Mn exposure to determine whether Mn causes 1) lasting disruption to the catecholaminergic system of the medial prefrontal cortex (mPFC), using quantitative protein immunohistochemistry of catecholaminergic proteins, 2) alterations to the evoked release of dopamine (DA) and norepinephrine (NE) in the PFC, and 3) whether changes in the mPFC catecholaminergic system were associated with heightened behavioral reactivity in an open field behavioral paradigm. In Chapter 2, I report that blood, brain, and bone Mn levels naturally decrease across the lifespan in the absence of elevated Mn exposure. In the presence of elevated oral exposure, bone Mn levels are strongly associated with blood and brain Mn, and that Mn did not accumulate with lifelong elevated exposure in any of the measured tissues. Additionally, elevated early life oral Mn exposures that produced high bone Mn levels up to 166 µg/g in young weanling animals caused some changes in bone mineral properties, including the local atomic structure of hydroxyapatite, and in young adult animals caused some physical changes in bone stiffness. In aged humans, bone Mn levels were universally very low (ranging from 0.014 – 0.17 µg/g), and decrease with age, but showed no relationship between gender or parity history in females. In Chapter 3, I report that postnatal Mn exposure caused heightened behavioral reactivity in the first 5-10 minutes of daily open field test sessions, consistent with deficits in arousal regulation. Mn exposure reduced the evoked release of NE, and caused lasting alteration in protein levels of tyrosine hydroxylase, DA and NE transporters, and DA D1 and D2 receptors. These findings show that Mn does not accumulate in bone over prolonged exposure, and that the skeleton may be a relatively minor target of elevated Mn exposure. However, bone Mn levels increased to a greater extent than blood with incremental increases in blood Mn, suggesting that the skeleton may be a more sensitive biomarker of recent ongoing Mn exposure than blood. They also indicate that early postnatal Mn exposure causes broad lasting hypofunctioning of the mPFC catecholaminergic systems, consistent with the deficits in arousal regulation and attentional function. These effects are also consistent with the DA/NE dysfunction that is proposed to underlie children diagnosed with ADHD, and with the attentional deficits associated with elevated Mn exposure in children. Collectively, these findings help move the field forward by demonstrating a causal relationship between early life Mn exposure and lasting disruptions in the catecholaminergic system of the PFC that plays an important role in mediating executive function and attention, providing a mechanistic basis for how elevated Mn exposure may produce deficits in those functions in children. They also advance our understanding of Mn exposure biomarkers and identify bone Mn levels as a potentially important and sensitive biomarker of recent ongoing, but not cumulative Mn exposure.