Inherited Brain Fitness Deficit caused by Light Stress Promotes Glioblastoma Progression in Drosophila

Environmental and lifestyle factors can influence long-term human health outcomes, including the development of complex diseases such as cancer. Glioblastoma is the most aggressive and fatal form of brain cancer, marked by its invasive nature and resistance to standard therapies. Despite similar genetic alterations, patients diagnosed with glioblastoma often show highly variable survival outcomes, suggesting that non-genetic influences may play a critical role in tumor progression. Here we show that environmental conditions experienced by the parental line, such as permanent exposure to artificial light, can affect the brains resilience to tumor growth in the next generation. This effect, described as reduced Brain fitness, does not impair brain development but accelerates glioma progression and shortens survival in the offspring. These findings point to a novel concept, the Brain fitness hypothesis, in which inherited susceptibility to brain tumors may be shaped by parental exposures. Our results suggest that non-coding RNAs could mediate this intergenerational transmission, offering new insight into the complexity of inherited traits beyond direct genetic mutations. This work broadens current understanding of glioma biology and highlights the importance of environmental health across generations. AbstractEnvironmental exposure including modern lifestyle habits and occupational exposures describe a wide spectrum of risk factors for human health including carcinogenesis. Glioblastoma is the most common, aggressive, and lethal type of glioma. It is highly proliferative and invasive, infiltrates the surrounding brain parenchyma and is resistant to current treatments. Patients suffering from glioblastoma have a wide heterogeneity in life expectancy, even with similar mutations, that can vary from weeks to years. Many potential risk factors for glioma have been studied to date, but few provide significant correlations for tumor prognosis. Here, we provide a novel perspective on the interaction between the tumor and host depending on paternal environmental or lifestyle determinants, coined as Brain fitness hypothesis. Permanent light exposure induces genetic stress hallmarks in the progeny that do not alter central nervous system development, but compromise Brain fitness to an accelerated glioma growth, ultimately reducing life expectancy. Reduced survival in the progeny correlates with an increase in the number of activated brain genes involved in neuronal dynamics as well as those relevant for glioma progression such as presynaptic, circadian genes or genes required for the tumoral network. Among the inheritable mechanisms, ncRNAs emerge as potential vectors for the transmission of parental exposure to the subsequent generations and might explain the complexity of inheritable traits and phenotypes acquired as a pleiotropic effect. O_TEXTBOXBOX OF DEFINITIONSLight pollutome/exposome: The sum of environmental exposures or modern lifestyle habits as a source of artificial lighting or solar radiation that compromise fitness and disease progression from early stages (prenatal/postnatal) to adulthood. Luminic/Light stress (LL): Continuous light exposure (24h) at low luminance intensity (1,000 lux) of white light. Brain fitness hypothesis: Molecular factors that precondition brain susceptibility to pathological aggressions modulated by environmental or lifestyle determinants. Luminic stress effects (LSE): Genetic changes in unexposed F1 brains in response to pre-conceptional parental luminic exposure as a memory of parental experiences. Intergenerational Inheritance: Transmission of parental(F0) environmental effects to the descendants (F1or F2 depending on gestational state). C_TEXTBOX Graphical abstractMaternal pre-cexceptional exposure to light stress (1000 lux white light) induces intergenerational changes in the offspring brain fitness leading on a sex dependent light stress memory hallmark (LSE). Thus, F1 flies acquire a brain with the fitness tatus altered and preconditioned to GB development Consequently, GB grows faster and causes worse prognosis in affected animals. In this context miRNAs emerge as a potential epigenetic mechanism mediating this intergenerational effect, describing rriRNA-979 expression as a risk factor. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/672790v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@15be67borg.highwire.dtl.DTLVardef@78baddorg.highwire.dtl.DTLVardef@341c07org.highwire.dtl.DTLVardef@11c3393_HPS_FORMAT_FIGEXP M_FIG C_FIG