Implementing food-based dietary guidelines for - United Nations ...

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should be anticipated in populations or population
subgroups when nutrients are administered at pharmacological
levels, as illustrated by the introduction
of high fructose into the food supply. Other genomic
consequences may also result, including permanent
alterations in genome-wide methylation patterns, as
observed in mouse embryos whose mothers received
elevated doses of folic acid and one-carbon donors
during gestation [24]. Methylation patterns that are
established in utero can be metastable and influence
gene expression and potentially mutation rates into
adulthood [24]. The effect of diet on DNA methylation
and genome programming in adult stem cells is
unknown. Although antioxidants can decrease mutation
rates, they also function as prooxidants in vivo
[98] and may be cancer-promoting at elevated intakes
by inhibiting cellular death programs in transformed
cells [99]. In conclusion, elucidation of robust gene-bynutrient
interactions will inform dietary approaches
for individuals and for population-based interventions
that prevent and/or manage rare inborn errors
of metabolism as well as complex metabolic disease.
Furthermore, these and other examples indicate that
rigorous hazard identification is essential prior to the
establishment of policies that result in pharmacological
intakes of nutrients and other food components.
Genomic criteria for setting requirements and
toxicities
Genomic technologies may provide new criteria for
establishing numeric standards for adequate levels of
nutrient intake by targeting the molecular antecedents
of disease. Mutation increases the risks of developmental
anomalies, degenerative diseases, and cancers and
can be quantified in controlled experimental settings,
indicating that the effects of key minerals and vitamins
on DNA mutation rates should be considered when
establishing RDAs (recommended dietary allowances)
[30]. Marginal deficiencies in folate, vitamin B 12 ,
niacin, and zinc can influence genome stability, and
antioxidants, including carotenoids, vitamin C, and
vitamin E, may prevent damage resulting from oxidative
stress. Validation of these protective effects on DNA
mutation rates in controlled human trials may indicate
benefits and lead to increased recommended intake
levels, perhaps at levels not normally achievable from a
natural food-based diet. Similarly, the use of functional
genomic approaches, including expression profiling
and proteomics to quantify gene expression and metabolomics
to quantify metabolic pathway flux, provides a
comprehensive set of quantitative and physiologically
relevant “biomarkers” to model and assess nutrient efficacy
in the context of optimal network function [100].
Other genomic outcomes are emerging as criteria for
hazard identification and may influence the establishment
of tolerable upper levels of nutrient intake during
P. J. Stover
pregnancy. Studies of animal models are revealing that
nutrients can rescue deleterious genetic mutations,
leading to the concept that “good diet hides genetic
mutations” [101]. Individual nutrients can rescue
severe genetic lesions in mice when administered in
supraphysiologic levels during critical developmental
windows. Maternal retinoic acid administration
between 7.5 and 9.5 days postconception rescued deafness
and inner ear development in Hoxa1 -/- mice [102],
and folic acid can rescue skeletal defects associated with
deletion of a Hox gene, as well as neural tube defects in
mice that have no evidence of disrupted folate metabolism
[101]. This rescue phenomenon is not established
in humans, but animal studies indicate that nutrients
can modify the viability of genomes, including genomes
that confer atypical nutrient requirements on the surviving
fetus [103].
There is increasing evidence that maternal nutrition
can induce epigenetic changes in the fetal genome
that may program increased risks of metabolic disease
and nutrient requirements throughout the lifespan
of the offspring. The effects of fetal glucocorticoid
exposure on adult chronic disease risk provide some
of the strongest evidence for the fetal origins of disease
hypothesis [104–107]. Fetal glucocorticoid levels are
maintained at low concentrations relative to maternal
concentrations primarily through the action of
placental 11β-hydroxysteroid dehydrogenase type 2
(11β-HSD2), which catalyzes the oxidative inactivation
of cortisol and corticosterone [108]. Elevated fetal glucocorticoid
exposures during late gestation, which can
result from 11β-HSD2 inhibitors, rare mutations in the
human 11β-HSD2 gene, or large existing variation in
placental 11β-HSD2 activity among humans, can have
lifelong consequences for the fetus, including low birthweight,
elevated plasma glucocorticoid, hypertension,
hyperglycemia, insulin resistance, hyperinsulinemia,
and anxiety [107]. Low maternal dietary protein intake
during gestation causes a specific loss of placental 11β-
HSD2 expression and similar outcomes resulting from
elevated fetal glucocorticoid exposure [109]. Similarly,
obstetric glucocorticoid therapy to accelerate lung
development prior to anticipated preterm deliveries
also increases the risk of reduced fetal birthweight and
long-term susceptibility to hypertension, hyperglycemia,
cardiovascular disease, and increased hypothalamic-pituitary-adrenal
axis activity. These disorders
persist not only into adulthood, but also into the next
generation [110]. Lifelong consequences associated
with fetal glucocorticoid exposure may result from
premature glucocorticoid receptor-mediated chromatin
remodeling in the hippocampus [107]. Prenatal
glucocorticoid exposure decreases fetal glucocorticoid
receptor expression which remains reduced through
adulthood. Maternal undernutrition can elicit the same
effect, presumably by decreasing placental 11β-HSD2
levels. Maternal GC exposure also affects glucose and