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.