4.5 Fructose consumption enhances genome damage and VPE can prevent this
The metabolization of fructose results in liver glycogen and de novo lipogenesis of free fatty acids (FFA) that can cause lipotoxicity (Zhang et al., 2019), which is defined as the deleterious effect caused by high concentrations of lipids and lipid derivatives that manifest as a set of metabolic disorders in non-adipose tissue cells. The mechanisms involved in lipotoxicity (also known as lipotoxic effects) include oxidative stress, endoplasmic reticulum (ER) stress, and induction of inflammation (Lipke et al., 2022). Since lipid peroxidation and oxidative stress can cause damage to the genome, the genotoxic and mutagenic effects of the fructose consumption was evaluated in the blood and liver of the mothers and their offspring through the comet assay and micronucleus test.
In our study, the exposure to fructose led to increased DNA damage in mothers and offspring and the intervention with physical exercise was able to modulate and reduce the detected genome damage. In the mothers increased DNA oxidation and DNA strand-breaks (considered as markers of short-term exposures) were observed in both the blood and liver in response to fructose consumption (during all the (pre/post)pregnancy periods), as well as an increased number of MN (marker of long-term exposures). Maternal fructose consumption led to increased DNA damage (markers of short-term damage) in the blood of the offspring, while DNA damage levels in the liver were only significantly increased in male offspring due to fructose. The number of MN (marker of long-term exposures) was increased in both female and male offspring from mothers who consumed fructose. The VPE intervention led to the reduced genotoxicity of fructose in mothers and offspring. Overall these results indicate that the consumption of high concentrations of fructose in a fetal programming model was genotoxic in the mother and their offspring and that physical exercise was capable to protect genomic stability. The genotoxic results found in liver in the offspring corroborate the results found in histology, where we observed an increase in the area of steatosis in the FRU group and a decrease in FRU+VPE.
Similar to these results, our previous studies also showed that fructose leads to genomic instability in the mothers and their offspring (Magenis et al., 2020; Magenis et al., 2022). The fructose can lead to decreased expression of hepatic PGC-1alpha, a regulator of mitochondrial biogenesis in fructose-fed rats, due to increased ROS and DNA damage (Cioffi et al., 2017).
Diet rich in fructose promotes ROS imbalance through the simultaneous increase in ROS production and the negative regulation of antioxidant defense mechanisms, having as a result, widespread damage to macromolecules such as lipids, proteins and DNA (Cioffi et al., 2017). Furthermore, we suggest that maternal voluntary exercise has the ability to positively modulate the antioxidant defense system, thus decreasing the action of ROS and other reactive species that lead to DNA damage (Saiyin et al., 2019). Tryfidou et al. (2020) also showed that physical exercise can decrease inflammation, ROS and increase mitochondrial biogenesis, thus improving genomic instability. Corroborating, Kasper et al. (2021) showed that maternal physical exercise mediates hepatic metabolic programming via activation of the AMPK-PGC1α axis in the offspring of obese mothers, which lead to reduced DNA damage in liver.