Moderate malnutrition in rats induces somatic gene mutations

Pacheco-Martínez, M. Monserrat; Cortés-Barberena, Edith; Cervantes-Ríos, Elsa; Garcia‐Rodriguez, María del Carmen; Rodríguez-Cruz, Leonor; Ortiz-Muñiz, Rocío

doi:10.1016/j.mrfmmm.2016.01.008

Cited by 6 publications

(5 citation statements)

References 39 publications

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“…Fats are important and necessary dietary macronutrients but under conditions of excessive intake, it is possible that increased lipid peroxidation and excess fatty acid metabolism through b-oxidation or by phase I metabolic enzymes increases the systemic content of genotoxic intermediates [Refsgaard et al, 2000;Robertson et al, 2001;Day, 2002;Gonzalez 2005;Reddy and Sambasiva Rao, 2006;Porubsky et al, 2008;Toshiro et al, 2009;Pizzimenti et al, 2013]. Interestingly, a recent study in rats has found that malnutrition appears to increase the frequency of Pig-a mutants [Pacheco-Mart ınez et al, 2016]. In light of our study, this might suggest that caloric and nutrient imbalance is mutagenic under malnourishment as well as overnourishment.…”

Section: Discussionmentioning

confidence: 99%

Diet‐induced obesity increases the frequency of Pig‐a mutant erythrocytes in male C57BL/6J mice

Wickliffe

Dertinger

Torous

et al. 2016

Environ and Mol Mutagen

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Obesity increases the risk of a number of chronic diseases in humans including several cancers. Biological mechanisms responsible for such increased risks are not well understood at present. Increases in systemic inflammation and oxidative stress, endogenous production of mutagenic metabolites, altered signaling in proliferative pathways, and increased sensitivity to exogenous mutagens and carcinogens are some of the potential contributing factors. We hypothesize that obesity creates an endogenously mutagenic environment in addition to increasing the sensitivity to environmental mutagens. To test this hypothesis, we examined two in vivo genotoxicity endpoints. Pig-a mutant frequencies and micronucleus frequencies were determined in blood cells in two independent experiments in 30-week old male mice reared on either a high-fat diet (60% calories from fat) that exhibit an obese phenotype or a normal-fat diet (10% calories from fat) that do not exhibit an obese phenotype. Mice were assayed again at 52 weeks of age in one of the experiments. N-ethyl-N-nitrosourea (ENU) was used as a positive mutation control in one experiment. ENU induced a robust Pig-a mutant and micronucleus response in both phenotypes. Obese, otherwise untreated mice, did not differ from non-obese mice with respect to Pig-a mutant frequencies in reticulocytes or micronucleus frequencies. However, such mice, had significantly higher and sustained Pig-a mutant frequencies (increased 2.5–3.7-fold, p<0.02) in erythrocytes as compared to non-obese mice (based on measurements collected at 30 weeks or 30 and 52 weeks of age). This suggests that obesity, in the absence of exposure to an exogenous mutagen, is itself mutagenic.

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Section: Discussionmentioning

confidence: 99%

Diet‐induced obesity increases the frequency of Pig‐a mutant erythrocytes in male C57BL/6J mice

Wickliffe

Dertinger

Torous

et al. 2016

Environ and Mol Mutagen

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“…El presente trabajo apoya y complementa las observaciones anteriores. En un estudio reciente (Pacheco-Martínez et al, 2016) observaron un incremento en la frecuencia espontánea de mutantes en el gen Pig-a en ratas con desnutrición moderada, datos que coinciden con los aquí presentados. Sin embargo, se observó que al ser expuestas a ENU las FM fueron menores en las ratas DN2 0 , con respecto a las BN, aunque esas diferencias no fueron significativas.…”

Section: Discussionunclassified

“…La relación entre la DN y el daño genético ha sido ampliamente estudiada en humanos y en modelos animales (Ortiz, Medina, Rodríguez, González-Márquez & Cortés, 2004;Padula & Seoane, 2008;Ortiz, Medina, Cortés, Cervantes & Rodríguez, 2011). Recientemente se ha implementado un método a nivel génico, para estudiar los efectos de la DN tomando como indicador de daño las frecuencias de mutación (FM) somáticas en el gen Pig-a usando como controles positivos mutágenos y agentes potencialmente mutagénicos (Pacheco-Martínez et al, 2016). El ensayo se realiza por medio de citometría de flujo.…”

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“…El ensayo Pig-a in vivo no requiere el uso de animales transgénicos y se realiza en tiempos cortos de procesamiento de muestra de sangre periférica de rata para la obtención de resultados de la frecuencia de mutación en RET (eritrocitos inmaduros) y E (eritrocitos maduros) (Pacheco-Martínez, Cervantes-Ríos, García- Rodríguez & Ortiz-Muñiz, 2014). En México se ha reportado el ensayo Pig-a en el modelo de inducción de DN2 0 por competencia de alimento durante la lactancia y después del destete (Pacheco-Martínez et al, 2016). El objetivo de este estudio es evaluar las frecuencias de mutación en Pig-a en ratas con DN3° así como a la exposición al mutágeno ENU en RET y E provenientes de organismos con desnutrición grave o severa.…”

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Efecto de la desnutrición grave en las frecuencias de mutación en el gen Pig-a en reticulocitos y eritrocitos de rata

et al. 2018

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La asimilación deficiente de alimentos por el organismo conduce a un estado patológico con distintos grados y manifestaciones clínicas, conocido como desnutrición. En los últimos años ha surgido un nuevo ensayo in vivo de detección de mutación somática basado en el gen glucosilfosfatidilinositol de clase A (Pig-a). Este gen es necesario para la síntesis de glicosilfosfatidilinositol (GPI) que une proteínas específicas a la superficie de la célula. Cuando ocurre una mutación en Pig-a, no se puede sintetizar el GPI, ya que, las proteínas no se encuentran en la membrana celular, dando origen al fenotipo GPI negativo, el cual es de fácil detección por medio del análisis con citometría de flujo. En este estudio se utilizó el ensayo Pig-a para examinar el daño génico en ratas desnutridas expuestas al mutágeno N-etil-N-nitrosourea (ENU). Se efectuó el marcaje diferencial de reticulocitos (RET) y eritrocitos (E) de sangre periférica de rata de la cepa Wistar. Se tomó como indicador de daño al material genético de las células, el incremento en las frecuencias de mutantes (FM) Pig-a, que fueron analizadas en un 1 X 106 células, durante 8 semanas. Los resultados muestran que la desnutrición grave por sí misma tiene un efecto dañino sobre la integridad del material genético. La frecuencia de mutantes se incrementó con base en la dosis de ENU y el tiempo de exposición en los grupos con desnutrición (DN).

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“…The following four groups of six three-week-old rats were analyzed: WN and UN rats exposed to ENU or TMP-SMX. ENU dosage preparation and administration were performed as previously described for the gene mutation study (32). TMP-SMX was obtained as Bactrim, which was prepared in Mexico by Roche (Parque Industrial Lerma, Toluca, Estado de México, México).…”

Section: Methodsmentioning

confidence: 99%

In VivoGenotoxicity and Cytotoxicity Kinetics of Trimethoprim Sulfamethoxazole in Well-nourished and Undernourished Young Rats

ORTIZ-MUÑIZ,

CERVANTES-RÍOS,

SORIANO-CORREA

et al. 2024

In Vivo

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Background/Aim: Undernutrition is a serious health problem prevalent in poor countries, affecting millions of people worldwide, especially young children, pregnant women, and sick elderly individuals. This condition increases vulnerability to infections, leading to widespread use of antibiotic treatments in undernourished populations. The objective of the present study was to determine the in vivo genotoxic and cytotoxic effects of trimethoprimsulfamethoxazole (TMP-SMX) treatment according to nutritional conditions. Materials and Methods: The effects of TMP-SMX treatment were measured by analyzing the kinetics of micronucleated reticulocytes (MN-RET) induced in the peripheral blood of young, well-nourished (WN) and undernourished (UN) rats. Results: In the WN group, two distinct peaks of MN-RET were observed, while the UN group had a significantly higher basal frequency of MN-RET compared to the WN group and only a later peak. Reticulocyte (RET) frequency slightly decreased in WN, indicating a poor cytotoxic effect. In contrast, in the UN, the treatment caused a significant increase in RET frequency. The results indicate that SMX's aromaticity index decreases when formed with TMP, suggesting potentially fewer toxic effects. Conclusion: In vivo TMP-SMX produces two MN-RET induction peaks in WN animals, indicating two DNA damage induction mechanisms and consequent micronucleusproduction. The UN rats did not display the two peaks, indicating that the first MN induction mechanism did not occur in UN, possibly due to pharmacokinetic effects, decreased metabolism or effects on cell proliferation. TMP-SMX has a slight cytotoxic effect on WN. In contrast, in the UN, the antibiotic treatment seems to favor early erythropoiesis.

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Moderate malnutrition in rats induces somatic gene mutations

Cited by 6 publications

References 39 publications

Diet‐induced obesity increases the frequency of Pig‐a mutant erythrocytes in male C57BL/6J mice

Diet‐induced obesity increases the frequency of Pig‐a mutant erythrocytes in male C57BL/6J mice

Efecto de la desnutrición grave en las frecuencias de mutación en el gen Pig-a en reticulocitos y eritrocitos de rata

In VivoGenotoxicity and Cytotoxicity Kinetics of Trimethoprim Sulfamethoxazole in Well-nourished and Undernourished Young Rats

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