Abstract
Maternal protein deficiency during the critical development period of the progeny disturbs mitochondrial metabolism in the brainstem, which increases the risk of developing cardiovascular diseases in the first-generation (F1) offspring, but is unknown if this effect persists in the second-generation (F2) offspring. The study tested whether mitochondrial health and oxidative balance will be restored in F2 rats. Male and female rats were divided into six groups according to the diet fed to their mothers throughout gestation and lactation periods. These groups were: (1) normoprotein (NP) and (2) low-protein (LP) rats of the first filial generation (F1-NP and F1-LP, respectively) and (3) NP and (4) LP rats of the second filial generation (F2-NP and F2-LP, respectively). After weaning, all groups received commercial chow and a portion of each group was sacrificed on the 30th day of life for determination of mitochondrial and oxidative parameters. The remaining portion of the F1 group was mated at adulthood and fed an NP or LP diet during the periods of gestation and lactation, to produce progeny belonging to (5) F2R-NP and (6) F2R-LP group, respectively. Our results demonstrated that male F1-LP rats suffered mitochondrial impairment associated with an 89% higher production of reactive species (RS) and 137% higher oxidative stress biomarkers, but that the oxidative stress was blunted in female F1-LP animals despite the antioxidant impairment. In the second generation following F0 malnutrition, brainstem antioxidant defenses were restored in the F2-LP group of both sexes. However, F2R-LP offspring, exposed to LP in the diets of the two preceding generations displayed a RS overproduction with a concomitant decrease in mitochondrial bioenergetics. Our findings demonstrate that nutritional stress during the reproductive life of the mother can negatively affect mitochondrial metabolism and oxidative balance in the brainstem of F1 progeny, but that restoration of a normal diet during the reproductive life of those individuals leads toward a mitochondrial recovery in their own (F2) progeny. Otherwise, if protein deprivation is continued from the F0 generation and into the F1 generation, the F2 progeny will exhibit no recovery, but instead will remain vulnerable to further oxidative damage.
Highlights
The Developmental Origins of Health and Disease Hypothesis posits that environmental stimuli encountered during critical periods of development, including embryonic, fetal and neonatal life, can induce long-lasting changes in the morphology and physiology of the fully developed individual (Bateson et al, 2004; West-Eberhard, 2005)
We have employed a maternal low-protein diet model to assess the effect of the protein deprivation on the mitochondrial bioenergetics and oxidative balance in the brainstems of progeny born to the protein-deprived mothers, and in the brainstems of rats in the succeeding generation
We evaluated whether the F2 offspring born and nursed by protein-deprived mothers can compensate for oxidative damage when they themselves are ‘re-exposed’ to the same low-protein nutritional insult
Summary
The Developmental Origins of Health and Disease Hypothesis posits that environmental stimuli encountered during critical periods of development, including embryonic, fetal and neonatal life, can induce long-lasting changes in the morphology and physiology of the fully developed individual (Bateson et al, 2004; West-Eberhard, 2005). There is evidence that the increased risk of CVD may not affect only the immediate offspring of an undernourished parent, but, it that might be transmitted across successive generations (i.e., children, grandchildren, great-grandchildren) in several possible ways, including non-Mendelian inheritance via maternal mitochondria (Zambrano et al, 2005; Zambrano, 2009; Dunn and Bale, 2011; Bale, 2015; Aiken et al, 2016; Saben et al, 2016) This means of transmitting parental damage to succeeding generations is relevant to nutritional deficits during development (Woods et al, 2018), as a number of experimental studies have demonstrated long-lasting changes in mitochondrial functions such as apoptosis, calcium control, redox homeostasis and energy supply (Bertram et al, 2008; Ponzio et al, 2012; Yin and Cadenas, 2015; Saben et al, 2016) following maternal malnutrition
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