Early Postnatal Manganese Exposure Reduces Rat Cortical and Striatal Biogenic Amine Activity in Adulthood

Abstract

Growing evidence from studies with children and animal models suggests that elevated levels of manganese during early development lead to lasting cognitive and fine motor deficits. This study was performed to assess presynaptic biogenic amine function in forebrain of adult Long-Evans rats exposed orally to 0, 25, or 50 mg Mn/kg/day over postnatal day 1–21 or continuously from birth to the end of the study (approximately postnatal day 500). Intracerebral microdialysis in awake rats quantified evoked outflow of biogenic amines in the right medial prefrontal cortex and left striatum. Results indicated that brain manganese levels in the early life exposed groups (postnatal day 24) largely returned to control levels by postnatal day 66, whereas levels in the lifelong exposed groups remained elevated 10%–20% compared with controls at the same ages. Manganese exposure restricted to the early postnatal period caused lasting reductions in cortical potassium-stimulated extracellular norepinephrine, dopamine, and serotonin, and reductions in striatal extracellular dopamine. Lifelong manganese exposure produced similar effects with the addition of significant decreases in cortical dopamine that were not evident in the early postnatal exposed groups. These results indicate that early postnatal manganese exposure produces persistent deficits in cortical and striatal biogenic amine function. Given that these same animals exhibited lasting impairments in attention and fine motor function, these findings suggest that reductions in catecholaminergic activity are a primary factor underlying the behavioral effects caused by manganese, and indicate that children exposed to elevated levels of manganese during early development are at the greatest risk for neuronal deficiencies that persist into adulthood.

Early postnatal manganese exposure causes arousal dysregulation and lasting hypofunctioning of the prefrontal cortex catecholaminergic systems

“…In those studies the increased mPFC D2 levels persisted into adulthood (PND 107), while the reduced DAT and D1 levels were normalized to control levels in adults. Together, these changes are consistent with our prior results showing reduced evoked release of DA and NE in the mPFC of adult rats following lifelong Mn exposure (Beaudin et al, ; Lasley et al, ). Others have reported similar, albeit more limited, effects of early life Mn exposure on brain catecholaminergic systems.…”

“…The Mn effect on the mPFC catecholaminergic systems, while broad in scope, was also somewhat specific, as there was no measurable effect of Mn on α 2A receptor protein levels (Figures c and ). Finally, these catecholaminergic protein changes, most notably the reduction in TH (Figures a and ), are consistent with the lasting reductions in the evoked release of NE in young weanling (Figure a, b) and adult (Beaudin et al, ; Lasley et al, ) animals exposed to the same oral Mn doses.…”

“…Blood and brain Mn concentrations were determined in littermates of the immunostaining study animals that were retained specifically for tissue Mn analyses (PND 24 and PND 66) or that were sacrificed following behavioral testing and evoked neurotransmitter measurement by microdialysis (~PND 590; n = 6–12/treatment group and time point, 104 animals total), as reported previously (Beaudin, Strupp, Strawderman, et al, ; Beaudin et al, ; Beaudin et al, and Lasley et al, ). Animals were heavily anesthetized with sodium pentobarbital overdose (75 mg/kg intraperitoneal injection), and whole blood (2–3 ml) was collected from the left ventricle of the surgically‐exposed heart and stored in ethylenediaminetetraacetic acid vacutainers at −20°C for analyses.…”

“…Limited available evidence has shown that developmental Mn exposure increases D2 receptor levels in the mPFC of weanling rodents that may last into adulthood (Kern & Smith, ; Kern et al, ). Our recent studies have revealed lasting reductions in evoked DA and norepinephrine (NE) release in the mPFC in adulthood in animals exposed only during early postnatal development (Beaudin et al, ; Lasley et al, ), with lasting changes in PFC DA D2 protein levels in adults (Kern & Smith, ). However, the extent to which developmental and lifelong Mn exposure impacts the mPFC catecholaminergic systems in adulthood is not well known.…”

Estimating daily intakes of manganese due to breast milk, infant formulas, or young child nutritional beverages in the United States and France: Comparison to sufficiency and toxicity thresholds

“…In adults, Mn is excreted by the biliary system; however, the biliary excretion mechanism is not yet mature in neonates, leading to higher Mn retention at the youngest ages [10,11,89]. In experimental animal studies, neonatal rats fed supplemental Mn showed increased brain dopamine levels and changes in behavior consistent with neurodevelopmental damage [101,102].…”