Manganese in Development Leaves Lasting Genomic Scars in Flies, While Quercetin Shields Them

What happens early in life does not always stay in early life. A new study in fruit flies suggests that a brief developmental encounter with a common environmental metal can quietly rewrite the chemistry of adulthood, leaving behind elevated oxidative stress, fragmented DNA, and damaged proteins long after the exposure has ended. And in a striking twist, the same developmental window spent under the influence of a dietary antioxidant appears to do the opposite: priming the animals’ defenses and preserving genomic integrity. The work, published in the journal Discover Toxicology, offers some of the clearest evidence yet that the developing nervous system can be chemically programmed toward vulnerability or resilience by what it consumes.

The research team, led by Tolulope T. Arogundade of Redeemer’s University in Nigeria together with colleagues in Nigeria and Poland, chose the fruit fly Drosophila melanogaster for a reason. The insect’s antioxidant pathways are well conserved with those of mammals, its generation time allows entire life-course experiments to be completed in weeks, and its larval crawling and feeding behaviors provide quantifiable readouts of neurological function. Crucially, the fly allows researchers to isolate the developmental period with precision: larvae were reared from their first instar through pupation and eclosion on food containing the test compounds, after which the treatment ceased entirely. Any differences seen in adulthood therefore represent latent programming effects rather than ongoing toxicity.

The toxicant in question was manganese, an element with a double identity. It is essential for life, serving as a cofactor for manganese superoxide dismutase and a suite of other enzymes, yet at elevated levels it is a recognized neurotoxicant. Human epidemiological studies have linked early-life manganese exposure, whether from contaminated drinking water or occupational settings, to cognitive deficits, motor impairments, and neuropsychiatric symptoms that often emerge insidiously years later. In the experiment, larvae were exposed to manganese chloride at two concentrations, 0.5 and 3.0 millimolar, doses selected and validated through pilot survival assays to represent a sub-clinical level and a biologically active but non-lethal level. Against this, the researchers tested quercetin, a flavonoid abundant in onions and apples, at 0.25 and 1.0 millimolar.

The behavioral results painted a nuanced picture. Larvae raised on high-dose manganese crawled dramatically shorter distances than controls, covering just 1.8 centimeters in one minute compared with 2.6 centimeters for untreated animals, a dose-dependent impairment that was statistically significant. Their feeding was also disturbed, with mouth-hook contractions running roughly fifteen percent faster than controls, a hyperactive pattern that suggests the sensory-motor circuitry governing feeding had been perturbed. Yet when those same larvae eclosed into adults and were tested five days later in the rapid iterative negative geotaxis assay, which measures climbing ability, the deficits had largely vanished. Adult climbing performance was indistinguishable from controls across all treatment groups. The molecular damage, however, told a very different story.

Biochemical assays of young adult flies revealed that the manganese-exposed animals carried a persistent oxidizing burden. Hydrogen peroxide, a central reactive oxygen species, accumulated to 3.8 nanomoles per milligram of protein in the high-dose manganese group, more than double the 1.8 nanomoles measured in controls, a difference that was highly significant. This accumulation occurred despite the fact that the activities of the classic antioxidant enzymes superoxide dismutase and catalase were largely preserved, suggesting that manganese disrupts redox balance not by crippling the enzyme defenses but by overwhelming the system at its source. The authors point to manganese’s established capacity to interfere with mitochondrial electron transport, particularly at complex II, and to drive Fenton-like chemistry that generates hydroxyl radicals from hydrogen peroxide.

The genomic consequences were the study’s most dramatic finding. Using a diphenylamine colorimetric assay to quantify the DNA fragmentation index, the researchers found that high-dose manganese pushed fragmentation to approximately 54 percent, compared with 29 percent in controls, an increase of roughly 85 percent. In other words, adult flies that had never touched manganese since emerging from their pupal cases carried genomes riddled with damage seeded during their larval feeding. The mechanism is likely multipronged: hydroxyl radicals derived from elevated hydrogen peroxide attack DNA to produce lesions such as 8-oxoguanine, and manganese ions can directly inhibit OGG1, the glycosylase enzyme that initiates repair of that very lesion, by displacing the magnesium ion in its active site. Damage production and damage repair are compromised simultaneously.

A parallel story unfolded in the realm of protein damage. Advanced glycation end-products, or AGEs, irreversible protein modifications produced when lipid peroxidation byproducts such as malondialdehyde react with amino acid residues, accumulated 57 percent above control levels in the high-dose manganese group, reaching 58 nanograms per milligram of protein versus 37 in controls. AGEs are more than passive markers of wear. When they modify components of the MRE11-RAD50-NBS1 complex, the cellular machinery that senses and initiates repair of DNA double-strand breaks, they can blunt the DNA damage response itself. The correlation between elevated DNA fragmentation and elevated glycation in the manganese-exposed flies suggests a self-amplifying cycle in which oxidative and glycative stress each feed the other, degrading both genome and proteome together.

Quercetin told the opposite tale. Flies developmentally exposed to the lower dose of the flavonoid showed enhanced catalase activity, roughly 28 percent above control levels, while maintaining basal hydrogen peroxide concentrations and showing no behavioral deficits at any stage. Their DNA fragmentation index trended downward, with the 0.25 millimolar group averaging around 14 percent, roughly half the control value, although this reduction fell just short of statistical significance. AGE levels in this group were 32 percent below controls, a significant decrease. The selective boost to catalase aligns with quercetin’s known ability to activate the Keap1-Nrf2 antioxidant signaling axis, whose fly ortholog, CncC, directly regulates catalase transcription under oxidative challenge. Notably, the higher quercetin dose failed to produce further benefits, echoing the biphasic behavior of flavonoids, which at high concentrations can undergo autoxidation and paradoxically generate reactive species.

Why did the manganese-exposed adults climb normally while their larval selves had crawled poorly, and while their molecules told a story of damage? The authors propose several non-exclusive explanations. Compensatory mechanisms such as autophagy-mediated clearance of damaged proteins and synaptic homeostatic plasticity may buffer locomotor circuits against moderate developmental insults, preserving function even as molecular wear accumulates beneath the surface. Alternatively, the five-day post-eclosion assessment may simply capture a pre-symptomatic stage, with late-onset motor decline emerging in older flies as accumulated DNA damage crosses a functional threshold. This latter possibility carries obvious translational weight, given that human manganese-associated neurological deficits also tend to manifest years after the initial exposure window. The researchers suggest that monitoring biomarkers such as plasma AGEs and urinary 8-oxodG in children from manganese-endemic regions could enable early risk stratification before symptoms appear.

The study has honest limits. Quercetin was never given concurrently with manganese, so the experiment speaks to independent programming effects rather than direct rescue, and the authors explicitly call a co-treatment trial the priority next step. Sex-specific vulnerabilities were not assessed, the adult endpoint was a single time point, and mechanistic pathways were inferred rather than genetically validated. Still, the central message lands with force: hydrogen peroxide levels and DNA fragmentation indices emerge as sensitive biomarkers of latent developmental toxicant injury, and low-dose dietary antioxidants appear capable of priming antioxidant defenses during critical windows without harm. In a world where manganese exposure affects communities near industrial sites and contaminated water supplies worldwide, the idea that a common dietary flavonoid might tip the developmental balance toward resilience, rather than vulnerability, is a proposition worth serious investigation in mammalian models.

Subject of Research: Developmental programming of adult oxidative stress, DNA damage and behaviour by manganese or quercetin in Drosophila melanogaster

Article Title: Developmental exposure to manganese or quercetin differentially programs adult oxidative stress, DNA fragmentation and behaviour in Drosophila

Article References: Arogundade, T. T., Olatomide, O. D., Adeleye, D. A., Ikegulu, P. S., Akinfaye, M. O., Arogundade, O. A., Omotoso, D. R., & Gbadamosi, I. (2026). Developmental exposure to manganese or quercetin differentially programs adult oxidative stress, DNA fragmentation and behaviour in Drosophila. Discover Toxicology, 3(1), Article 9. https://doi.org/10.1007/s44339-026-00054-0

Image Credits: AI Generated

DOI: 10.1007/s44339-026-00054-0

Keywords: manganese, quercetin, Drosophila, oxidative stress, DNA fragmentation, developmental programming, neurotoxicology, advanced glycation end-products, hydrogen peroxide, catalase, Nrf2 signaling, flavonoids