Phytochemicals and their effect on fetal epigenetics

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The Fetus as a Target:
Phytochemicals as Epigenetic
modulators
Tevfik Yoldemir MD BSc MA
Marmara University
School of Medicine, Istanbul
www.yoldemir.com
Epigenetics
• stable and heritable alterations of gene expression through
covalent modifications of DNA and core histones without
changes in the DNA sequence.
• the four mechanisms responsible for mediating epigenetic
effects :
a) chromatin modifications,
b) DNA methylation (occurring at the 5’-position of cytosine
residues within CpG dinucleotides throughout the mammalian
genome),
c) histone modifications (acetylation, methylation,
phosphorylation, ubiquitination, and sumoylation), and
d) RNA-based mechanisms such as small noncoding RNAs or
inhibitory RNAs
ANTIOXIDANTS & REDOX SIGNALING Volume 17, Number 2, 2012
Overviewof epigeneticmechanismsregulatinggene
expression
Seminars in Cancer Biology 40–41 (2016) 82–99
Impactsof maternal and paternal nutrition on fetal
programming
ANTIOXIDANTS & REDOX SIGNALING Volume 17, Number 2, 2012
fetalbasis of adult disease (FEBAD)
hypothesis
• In 1992, Barker and colleagues laid the groundwork for the
“fetal basis of adult disease” (FEBAD) hypothesis, postulating
that, because organs undergo developmental programming in
utero that predetermines subsequent physiologic and
metabolic adaptation during adult life, prenatal insults such as
nutritional deprivation or environmental exposures that
disturbed developmental programming could lead to a higher
risk of disease in adulthood.
• They showed that abdominal fatness in adult men, an indicator
of increased risk of cardiovascular disease and diabetes
independent of body mass, was associated with retarded fetal
growth, suggesting a persisting response to adverse conditions
in fetal life
Reproductive Toxicology 31 (2011) 363–373 Reproductive Toxicology 31 (2011) 363–373

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• Maternal diet during pregnancy, placental insufficiency,
psychosocial characteristics and other factors such as stress,
anxiety and fatigue induce changes in the epigenome of the
embryo.
• Although much effort has been focused on gene-environment
interactions, epigenetic alteration in response to in utero
nutritional and environmental factors also deregulates histone
modifications, microRNAs and alters the CpG methylation thus
playing an important role in disease susceptibility.
Nutr Rev. 2013 July ; 71(7): 441–457
Pregnancynutrients
• Key nutrients in pregnancy include
• vitamin B-12, vitamin D, iron, and folate
• Key nutrients in lactation include
• vitamin B-12, vitamin D, calcium, and zinc.
Journal of the AMERICAN DIETETIC ASSOCIATION 2009;
109(7): 1271
Flavonoids
• Due to the fact that flavonoids are present in a variety of food
sources, the incidental daily intake can be as high as 1 g but
can increase up to several grams in those supplementing their
diet with flavonoids.
• The average daily dietary intake of quercetin is in the range of
4–68 mg.
• Daily isoflavone intake in Western countries is approximately
1–9 mg.
• In Asian countries, however, the daily intake of isoflavones is
much higher, reaching levels of 20–240 mg, because of the
high consumption of soy (Skibola and Smith, 2000).
• It is also noteworthy that the metabolism of phytoestrogens is
different in the fetus and adults.
TOXICOLOGICAL SCIENCES 120(1), 59–67 (2011) Southeast Asian Journal of Tropical Medicine and Public Health; Sep
2011; 42, 5: 1214-1223
Southeast Asian Journal of Tropical Medicine and Public Health; Sep
2011; 42, 5: 1214-1223
Vegetablesand fruitfood: for acutelymphoblasticleukemia
inrelationto pre-pregnancy maternal diet
Cancer Causes & Control, Vol. 15, No. 6 (Aug., 2004), pp. 559-570

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Nutritionalcontent of selectedplants for daily
consumptionfor pregnant women
IJPR Volume 4 Issue 4 (2014)
Numberof phytochemicalspresentin each plant
IJPR Volume 4 Issue 4 (2014)
börülce
turp
semizotu
• Maternal nutrition and
environmental exposure
induce changes in the
epigenome of the
developing fetus.
• The most widely
recognized epigenetic
regulatory mechanisms
include DNA methylation,
histone modifications and
small interfering RNAs
Nutr Rev. 2013 July ; 71(7): 441–457
DNA methylation
• The methylation of DNA is catalyzed by DNA
methyltransferases (DNMT1, DNMT3a, and DNMT3b) and is a
reversible physiological process in the eukaryotic genome.
• Due to their presence in these regulatory regions, changes in
methylation status can either facilitate (hypomethylation) or
inhibit (hypermethylation) the expression of a gene.
• The process of demethylation and remethylation during the
development of germ cells is referred to as ‘‘reprogramming’’
ANTIOXIDANTS & REDOX SIGNALING Volume 17, Number 2, 2012
Histonemodifications
• Histones are basic proteins that facilitate the packaging of DNA
in the nucleus and the regulation of gene expression in cells.
• Posttranslational modifications imparted onto the N-terminal
tails of each histone protein alter the properties and structures
of chromatin.
• More than 100 specific modifications of chromatin are
associated with either actively transcribed or silenced genes.
Therefore, histone proteins play an important role in gene
expression.
• Histone acetylation is usually associated with activation of
gene transcription
ANTIOXIDANTS & REDOX SIGNALING Volume 17, Number 2, 2012
RNA-basedepigeneticmechanisms
• Epigenetic regulation of gene expression by RNA-based mechanisms
can occur at both the post-transcriptional level and the level of
chromatin.
• These mechanisms are mediated by small-interfering RNAs or small
non-coding RNAs which act through their respective pathways to
induce DNA methylation or histone modifications to silence or
enhance gene expression.
• The mature miRNA pairs with the target mRNA, resulting in:
a) induction of target mRNA deadenylation and, thus, degradation;
b) inhibition of the assembly of the 80S ribosome complex and, thus,
translation initiation; and
c) inhibition of translation elongation possibly through premature
termination and subsequent ribosome drop-off
ANTIOXIDANTS & REDOX SIGNALING Volume 17, Number 2, 2012

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Rolesof macro- and micro-nutrientsin epigenetics
and physiologicalresponses
ANTIOXIDANTS & REDOX SIGNALING Volume 17, Number 2, 2012
Nutritionalinterventionswith bioactivephytochemicals
• Besides specific nutrients, botanicals have been identified as
possible epigenetic modulators to ameliorate metabolic
syndrome by regulating expression and activity of DNA
methyltransferase (DNMT), histone methyltransferase (HMT,
histone acetyltransferase (HAT), and histone
deacetyltransferase(HDAC).
• Phytochemicals (including epigallocatechingallate, resveratrol,
genistein, curcumin, and isothiocyanates) can interfere with
enzymatic activities of DNMT, Class I, II, IV HDAC, HAT, and Class
III HDAC sirtuins (SIRT), thereby beneficially modulating
inflammatory responses and immunologicalsenescence
ANTIOXIDANTS & REDOX SIGNALING Volume 17, Number 2, 2012
• Plant extracts may also affect interactions among histone
proteins or between nucleosomes and binding factors. Thus,
dietary ingredients in food can be epigenetic medicine to
remedy abnormalities in DNA methylation, histone
modifications, chromatin remodeling, and microRNA patterns
ANTIOXIDANTS & REDOX SIGNALING Volume 17, Number 2, 2012
Pharmacologicaland nutritionalinterventionsof
epigeneticdefects
ANTIOXIDANTS & REDOX SIGNALING Volume 17, Number 2, 2012
Dietaryagents
• Alkaloids
• Coffee beans
• Flavanoids
• Curcumin
• Quercetin
• Epigallıcatechin-3-gallate
• Monoterpenes
• Limonene
• Isoflavones
• Daidzein
• Genistein
• Carotenoids
• ß-carotene
• Lycopene
• Isothiocyanate
• Sulpharaphene
• Indoles
• Stilbenes
• Resveratrol
Nutr Rev. 2013 July ; 71(7): 441–457
Bioactivedietaryphytochemicals
• Allium vegetables (garlic, onions, leeks, chives)
• Apigenin (grapefruit, parslay, onions, oranges, tea, chamomile, wheat
sprouts)
• Chrysin (fruits, vegetables, olive oil, tea, redwine)
• Cruriferous vegetables ( broccoli, brussels spprouts, cabbage,
couliflower, collard greens, kale, mustard, turnips, kohlrabi, bok choy)
• Curcumin (turmeric)
• Ginger
• Grape polyphenols
• Organoselenium compounds (garlic, onion, broccoli)
• Quercetin (fruit, vegetable, beverages, buckwheat)
• Soy isoflavone
Nutrition and Cancer 2017, 69:2, 184-200
Pırasa, frenk soğanı
Papatya

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polyphenols
• Phenolic acids that are largely present in berry fruits,
kiwi, cherry, apple, pear, chicory and coffee represent a
third of the polyphenolic compounds and are divided into
two main classes:
hydroxybenzoic acids (C6-C1) (gallic acid, protocatechuic
acid, p-hydroxybenzoic acid) and
hydroxycinnamic acids (C6-C3) (caffeic acid, chlorogenic
acid, coumaric acid, ferulic acid, sinapic acid);
• Flavonoids (C6–C3–C6) including six subclasses:
antocyanins, flavanols, flavonols, flavones, flavanones, and
isoflavones;
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
2017, VOL. 57, NO. 12, 2589–2599
Üzüm
Kivi
Kiraz
Elma
Armut
Hindiba
Kahve
polyphenols
• Lignans (C6–C3–C3–C6),found in high concentrations in
linseed and other grains and cereals, largely known for
their phytoesterogenic activity;
• Stilbenes (C6–C2–C6), present in the human diet in low
quantities with resveratrol as the main studied
compounds of these groups and largely detected in
grapes and red wine.
• Curcuminoids (C6–C3–C1–C3–C6) constitute another
class of polyphenols, with curcumin being the main
molecule that is found principally in the rhizomes of
Curcuma longa.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
2017, VOL. 57, NO. 12, 2589–2599
Keten
tohumu
Tahıllar
Üzüm
Kırmızı
şarap
Zerdeçal
Polyphenolseffecton epigeneticmechanism
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
2017, VOL. 57, NO. 12, 2589–2599
Elma kabuğu
Soğan
Çay
Kırmızı şarap
Yeşil çay
Kamelya sinensis çayı
Soya
Zerdeçal
Üzüm
Şarap
Epigeneticmodifications
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
2017, VOL. 57, NO. 12, 2589–2599
Epigeneticmodifications
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
2017, VOL. 57, NO. 12, 2589–2599
Zerdeçal
Hint
safranı
Variousdietaryphytochemicalswith chemicalstructure
and role in general cancersand transplacentalmodels
zerdeçal
Elma kabuğu, soğan, çay, kırmızı şarap
Yeşil çay, kamelya yaprağı
Portakal kabuğu, lavanta, nane
Turpgiller, brokoli, brüksel lahanası,
lahana, karnabahar, kara lahana
Üzüm, fıstık, kırmızı şarap, kiraz
Soya fasulyesi
Meyve, sebze, tam tahıl
Domates, papaya, guava,
kayısı, karpuz
Brokoli, lahana, turp,
brüksel lahanası, tere

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Biochemical Pharmacology 80 (2010) 1771–1792 Biochemical Pharmacology 80 (2010) 1771–1792
Biochemical Pharmacology 80 (2010) 1771–1792 Biochemical Pharmacology 80 (2010) 1771–1792
Biochemical Pharmacology 80 (2010) 1771–1792 Biochemical Pharmacology 80 (2010) 1771–1792

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Biochemical Pharmacology 80 (2010) 1771–1792 Biochemical Pharmacology 80 (2010) 1771–1792
Summary
• Disruption of epigenetic mechanisms can result in oxidative
stress, obesity, insulin resistance, diabetes, and vascular
dysfunction in animals and humans.
• Despite a recognized role for epigenetics in fetal programming
of metabolic syndrome, research on therapies is still in its
infancy.
• Possible interventions include:
1) inhibition of DNA methylation, histone deacetylation, and
microRNA expression;
2) targeting epigeneticallydisturbed metabolic pathways;and
3) dietary supplementation with functional amino acids,
vitamins, and phytochemicals
Antioxid. Redox Signal. 2012;17, 282–301.
Questionsto be answered
• what is known about transplacental and translactation
exposure of these dietary phytochemicals to the
fetus/neonate?
• whether the exposure to dietary phytochemicals during
lactation and pregnancy could modify the fetal epigenome
providing protection to the offspring?
Nutr Rev. 2013 July ; 71(7): 441–457
Thank you for your attention.
Questions and Comments:
tevfik@yoldemir.com