Table Of ContentAdvances in Experimental Medicine and Biology 1012
Takeo Kubota
Hideoki Fukuoka Editors
Developmental
Origins of Health
and Disease
(DOHaD)
From Biological Basis to Clinical
Significance
Advances in Experimental Medicine
and Biology
Volume 1012
Editorial Board
IRUN R. COHEN, The Weizmann Institute of Science, Rehovot, Israel
ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research,
Orangeburg, NY, USA
JOHN D. LAMBRIS, University of Pennsylvania, Philadelphia, PA, USA
RODOLFO PAOLETTI, University of Milan, Milan, Italy
NIMA REZAEI, Children’s Medical Center, Tehran University of Medical
Sciences, Tehran, Iran
More information about this series at http://www.springer.com/series/5584
Takeo Kubota • Hideoki Fukuoka
Editors
Developmental Origins
of Health and Disease
(DOHaD)
From Biological Basis to Clinical
Significance
Editors
Takeo Kubota Hideoki Fukuoka
Faculty of Child Studies Research Organization for Nano & Life
Seitoku University Innovation
Matsudo, Chiba, Japan Waseda University
Tokyo, Japan
ISSN 0065-2598 ISSN 2214-8019 (electronic)
Advances in Experimental Medicine and Biology
ISBN 978-981-10-5525-6 ISBN 978-981-10-5526-3 (eBook)
https://doi.org/10.1007/978-981-10-5526-3
Library of Congress Control Number: 2018944390
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Preface
We have the great pleasure of presenting the first book entitled Developmental
Origins of Health and Disease (DOHaD): From Biological Basis to Clinical
Significance. The editors sincerely appreciate the contributions from all of the
authors and their valuable reviews on the theme of this book.
Recent epidemiological studies conducted in various countries, such as
England, the Netherlands, and China, suggested that early life deprivation
leads to cardiovascular, metabolic, and mental disorders later in life. The
DOHaD concept now encompasses a wider scope of early life exposures and
a longer list of health outcomes at different life stages. Despite substantial
growth in this field of study, major challenges remain, including: (1) identify-
ing the environmental factors responsible for the origins of noncommunica-
ble disorders in fetuses and infants, (2) clarifying the biological mechanisms
involved in how environmental factors ultimately cause adult disorders in
fetuses and infants, and (3) developing biological markers that can be used
during infancy to predict adult disorders in infants exposed to such environ-
mental factors.
Recent studies have also reported that the number of patients with environ-
mental factor-induced noncommunicable disorders, such as diabetes melli-
tus, is increasing not only in Western countries but also in Eastern countries,
such as Asia, the South East, and Africa. Environmental effects during early
development can accelerate this trend, resulting in decreased economic
power. Therefore, advances in DOHaD studies are important not only for
natural science but also for social science.
We hope that this collection of articles will help readers gain a better
understanding of the biological mechanisms of DOHaD that affect cardiovas-
cular, metabolic, and neurological systems. We also hope that some of the
readers will contribute to the field of DOHaD and make the world healthier.
Chiba, Japan Takeo Kubota
Tokyo, Japan Hideoki Fukuoka
v
Contents
Part I Biological Basis
One-Carbon Metabolism and Lipid Metabolism in DOHaD � � � � � � � 3
Hideoki Fukuoka and Takeo Kubota
Novel Models of Epigenetic Gene Regulation in the Nutritional
Environment � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 11
Kazuki Mochizuki, Natsuyo Hariya, and Takeo Kubota
Epigenetic Switching and Neonatal Nutritional Environment � � � � � � 19
Koshi Hashimoto and Yoshihiro Ogawa
Part II D isease and Environment
Developmental Origins of Nonalcoholic Fatty Liver
Disease (NAFLD)� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 29
Hiroaki Itoh and Naohiro Kanayama
Fetal Origins of Hypertension � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 41
Yuichiro Arima, Koichi Nishiyama, Yasuhiro Izumiya,
Koichi Kaikita, Seiji Hokimoto, and Kenichi Tsujita
Involvement of Noncoding RNAs in Stress-Related
Neuropsychiatric Diseases Caused by DOHaD Theory � � � � � � � � � � � � 49
Takahiro Nemoto and Yoshihiko Kakinuma
Part III Transgenerational Mechanism and Its Consequences
Placental Development and Nutritional Environment � � � � � � � � � � � � 63
Kosuke Taniguchi, Tomoko Kawai, and Kenichiro Hata
Risk of Neurodevelopmental Disease by Paternal Aging: A Possible
Influence of Epigenetic Alteration in Sperm � � � � � � � � � � � � � � � � � � � � 75
Ryuichi Kimura, Kaichi Yoshizaki, and Noriko Osumi
Part IV C linical Significance
Preemptive Epigenetic Medicine Based on Fetal Programming � � � � 85
Takeo Kubota
vii
Part I
Biological Basis
One-Carbon Metabolism and Lipid
Metabolism in DOHaD
Hideoki Fukuoka and Takeo Kubota
Abstract desaturase, that potentially induces dyslipid-
The predisposing factors to lifestyle- emia in adulthood. It has been known that
associated diseases are established in the early overnutrition also increased the risk of cardio-
period of life with underlying gene- vascular diseases. Recent animal studies
environment interaction. Epigenetics is a revealed that high-fat diet increased DNA
chemical modification-based genetic mecha- methylation in the promoter region of delta-6
nism that is affected by various nutritional fac- desaturase gene (Fads 2) that downregulates
tors. One-carbon metabolism is a metabolic the gene expression in the arterial smooth
system associated with methyl residue that is muscle, which potentially contributes to car-
supplied from folic acid. Therefore, from the diovascular diseases. Taken together, either
epigenetic point of view, proper intake of folic insufficient or excessive nutrition alters epi-
acid is important for pregnant women not only genetic modification of genes that encodes
to prevent congenital abnormalities such as enzymes associated with lipid metabolism.
neural tube defect but also to prevent various This altered epigenetic state persists during
adult disorders of the offspring. Dyslipidemia one’s lifetime, which is potentially involved in
is an important risk factor of coronary heart noncommunicable diseases in adulthood.
disease, and epidemiological studies on Dutch
winter famine, Jewish holocaust survivors, Keywords
and Chinese famine suggested that prenatal One-carbon metabolism · Lipid metabolism ·
malnutrition was associated with the dyslipid- DOHaD · Epigenetics · Fads 2
emia. Recent animal studies revealed that mal-
nutrition in utero causes an epigenetic change
in the Pparα gene, which accelerates the
activity of delta-6 desaturase and delta-5 1 Introduction
A number of epidemiological studies provided
H. Fukuoka (*) evidence that support the concept of developmen-
Research Organization for Nano & Life Innovation,
tal origins of health and disease (DOHaD). Recent
Waseda University, Tokyo, Japan
animal studies revealed that malnutrition affects
e-mail: [email protected]
epigenetic modifications, and this is a potential
T. Kubota
molecular mechanism for DOHaD. These dis-
Faculty of Child Studies, Seitoku University,
Matsudo, Chiba, Japan eases are caused via the two stages, first and sec-
© Springer Nature Singapore Pte Ltd. 2018 3
T. Kubota, H. Fukuoka (eds.), Developmental Origins of Health and Disease (DOHaD), Advances
in Experimental Medicine and Biology 1012, https://doi.org/10.1007/978-981-10-5526-3_1
4 H. Fukuoka and T. Kubota
Fig. 1 One-carbon X
ATP
metabolism SAM
dTMP DHF Methionine
X-CH3
THF
dUMP (cid:16116)(cid:16127)(cid:16121)(cid:16128) Dimethylglycine
(cid:16110)(cid:16130)(cid:16098) VB12 MTR (cid:16134)(cid:16154) SAH
5,10 Methylene
Naiacin Betaine
THF
Homocysteine
VB2 5 Methyl
Adenosine
THF Serine
VB6 Cystathionine
cysteine
ond insults. The predisposing factors to such as neural tube defect or other central ner-
lifestyle-associated diseases are e stablished in the vous system defects. It is recommended globally
early period of life, such as periconceptional, for women to take folic acid and multivitamins
embryonic, fetal, and neonatal periods with under- from 1 to 3 months prior to conception through-
lying gene-environment interaction (first insult). If out the pregnancy. In fact, folic acid is now forti-
individuals with epigenetic changes during fetal fied to grain or cereal in North and South America.
period induced by malnutrition have an unideal Folic acid is an important nutrient that acts as
lifestyle, such as taking excessive nutrition or sed- donor for methyl residue that is a potent regulator
entary lifestyle after birth (second insult), they in epigenetic gene regulation. One carbon metab-
may develop lifestyle-a ssociated diseases [1]. olism is the metabolic pathway that consists of
Epigenetic modifications include DNA meth- methyl residue donating cycle, nucleotide pro-
ylation, histone modifications, chromatin rear- viding and sulfur transsulfuration (Fig. 1). Many
rangements, and noncoding RNAs. Methyl enzymes and coenzymes, such as vitamins B,
2
residue is an essential substrate to chemical modi- B, and B , and zinc, participate to this system.
6 12
fication of DNA and histone proteins. One-c arbon Final metabolic product, S-adenosylmethionine
metabolism is a metabolic system associated with (SAM), donates the methyl residue to the DNA,
the methyl residue that is donated by folic acid histone, and neurotransmitters. SAM is changed
(folate) (Fig. 1). Numerous nutraceuticals directly into S-adenosylhomocysteine (SAH) by releas-
supply methyl donors in the methyl activation ing methyl residue, and then SAH is changed into
cycle or serve as cofactors in this metabolic path- homocysteine.
way which includes methionine, vitamin B, beta- Homocysteine is methylated and changed into
6
ines (trimethylglycine), vitamin B , and zinc. In methionine via two enzymes: 5-m ethyltetrahydro
12
this chapter, I would like to review the relation folate-h omocysteine methyltransferase (MTR)
between fetal nutritional environment and epigen- and betaine-homocysteine methyltransferase
etic modification as predisposing factors, the (BHMT), respectively [2]. MTR is an enzyme
metabolism of one-carbon metabolism, epigene- that catalyzes the final step of methionine biosyn-
tic change of PPARα in malnutrition in utero, and thesis from 5-methyl tetrahydrofolate (5-methyl-
fatty acid desaturases induced by PPARα. THF) and homocysteine. It is known as methionine
synthase. MTR contains m ethylcobalamin
(Me-Vitamin B ) as cofactor. 5-Methyl-T HF and
12
2 Importance of Folic Acid in One- homocysteine are used as substrates. This enzy-
Carbon Metabolism matic reaction proceeds with a two-step ping-
pong mechanism. At the first step, MTR transfers
It has been known that deficiency dietary of folic methyl residue from 5-methyl-THF to cobalamin
acid in the periconceptional and early stage of (vitamin B ; VB ), and Me-VB and tetrahydro-
12 12 12
pregnancy causes serious congenital anomalies, folic acid (THF) are produced. At the second step,
