This document discusses several key concepts related to epigenetics and environmental influences on health. It begins with an overview of fetal programming, in which the environment during early development can influence cell differentiation through epigenetic changes. It then discusses developmental plasticity and how the same genome can result in different cell types based on environmental information processed epigenetically. The document also highlights the role of the environment in health, noting that many diseases have increased dramatically in recent decades and exploring possible environmental contributions, such as endocrine disrupting chemicals, heavy metals, and other pollutants that can influence the epigenome even at low levels. Overall, the document emphasizes that the epigenome acts as an interface between the environment and genome,

1. ERNESTO BURGIO
ISDE Scientific Committee
ECERI - European Cancer and
Environment Research Institute

2. Fetal programming
1
5
3
2
Ontogenesis
Phylogenesis
Developmental Plasticity
Devo-Evo
4
Mismatch/DOHA6
7
XX Century
Epidemiological
TransitionEnvironment
From Genetics..
FOREWORD : the 7 key words
Epigenetic versus genetic origins of health and diseases
Evolutionary Medicine
Is DNA a sort of project
inscribed in our cells?
Synaptogénese
Connectome
Cablage fin
Cablage ancestral
Homo sapiens
Pre-wired brain
..to Epigenetics

3. This is a graph taken from a famous article published 10 years ago on NEJM,
showing the rapid decrease of the infectious/acute diseases
and the simultaneous increase of the chronic/inflammatory diseases
in the North of the World

4. This is a figure taken from the same article, showing the presence
of a South  North Gradient concerning this epidemiological transition

5. ENVIRONMENTAL FACTORS >> DNA
TIPE I DIABETES
X 10
& Non-
Communicable
Diseases
Here we see that environment and lifestyles have, in this epidemiological transition,
a much greater role that the DNA: migrants from the South to the North
will soon get sick of the typical, chronic “Non-Communicable Diseases”

6. Obesity Trends* Among U.S. Adults 1985
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
In the next 6 slides (taken from JAMA)
we’ll follow, in quick succession, the
dramatic, TRULY EPIDEMIC SPREAD

7. Obesity Trends* Among U.S. Adults 1987
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

8. Obesity Trends* Among U.S. Adults 1993
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

9. Obesity Trends* Among U.S. Adults 1995
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

10. Obesity Trends* Among U.S. Adults 1997
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

11. Obesity Trends* Among U.S. Adults 1999
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10

12. Obesity Trends* Among U.S. Adults 2001
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Today the situation has further deteriorated:
65% of Americans are overweight, 35% morbidly obese

13. The Childhood Obesity Epidemic
US DHHS, 2001; Hedley et al., 2004; Ogden et al., 2006, 2008
Matthew W. Gillman, MD, SM
in the 70s
childhood
obesity
virtually did
not exist
(it was
associated
with rare
genetic
syndromes):
since then
the increase
has been
rapid and
relentless
Yet the most dramatic increase
concerns children and adolescents

14. … with a constant anticipation of the age of onset …
The most serious consequence of the epidemic of obesity is the association with many
chronic diseases: first of all with diabetes 2 ( today affecting 180 million people)

15. The origin of insulin resistance is due both to an accumulation of fat in
adipocytes, and to the related inflammation. But, above all, both conditions
seem to be the product of a poor prenatal metabolic programming…
The link between obesity and
metabolic 2 diabetes is complex …

16. No one likes to talk about a CANCER PANDEMIC.. But we must
not forget that today, practically all over the North of the world,
one person out of two is likely to have a cancer ..

18. 0
2000
4000
6000
8000
10000
12000
14000
2002 2005 2010 2015 2020
Less Developed More Developed
ThousandsperAnnum
0
2000
4000
6000
8000
10000
12000
14000
2002 2005 2010 2015 2020
Less Developed More Developed
the significant increase in the Less Developed Countries & in young people all over
the world demonstrates the limits of the SMT (necessary link between aging &CA)
(1) Cancer continuous increase

19. Poumon 80
60
40
20
4
2
1,5
Sein
Colon
Estomac
Lymphôme
10
Leucémie
lymphati
que
Leucémie lymphatique
Encéphale
Lymphômes
Neuroblastoma-Retinoblastoma1
<1 Tessuti molli, rene (Wilms), gonadi
5
Rein
Cerveau
It is generally argued
that childhood
cancers are a rare
condition.
But it should be
reminded
that CANCER is the
main cause of
death by disease
in childhood
that there is a constant
and significant
increase of tumors
in the world for
this age group
that 1 : 5-600 children
falls ill with
cancer
That more than
13 000 children fall ill
with cancer each
year in the U.S.
Bleyer A, O’Leary M, Barr R, Ries LA,
editors. Cancer epidemiology in older
adolescents and young adults 15-29
ears of age, including SEER incidence
and survival: 1975-2000. NIH Pub. No.
06-5767. Bethesda (MD): National
Cancer Institute; 2006. Jemal A, Siegel
R, Ward E, et al. Cancer statistics,
2008. CA Cancer J Clin 2008;58:71 – 6.
Alberto Tommasini,
Laboratorio Immunologia
Pediatrica, IRCCS
Burlo Garofolo
is the leading cause of death due to
diseases among children over the first
year of age
(2) Child cancer increase
Incidenza di tumori (anno/100.000)

20. We should always consider the epidemiological data in the medium and long term, not to be
deceived by the inevitable fluctuations. It's evident that the incidence rates have increased
dramatically over the past 30 years in the US, from 130 to 170-180 new cases/year per
million inhabitants (to demonstrate the importance of these data, it is useful to remember
that a very similar increase occurred in Europe in the same period)

21. CA incidence in childhood and adolescence IN EUROPE ( 1970-1999)
mother
latency
A first draft of the report, published on the Lancet in 2004, demonstrated an annual increase of 1-1,5% for
all cancers (with more marked increases in lymphomas, soft tissue sarcomas, tumours of the nervous
system…) . But the most troubling was the increase - almost the double - for all cancers in the very first
year of life (apparently due to transplacental or even trans-generational exposure)
Steliarova-Foucher E, Stiller C, Kaatsch P, Berrino F, Coebergh
JW, Lacour B, Parkin M. Geographical patterns and time trends
of cancer incidence and survival among children and
adolescents in Europe since the 1970s (the ACCISproject): an
epidemiological study. Lancet. 2004 Dec 11-17;364(9451):2097-
105
http://www-dep.iarc.fr/accis.htm

22. Many scientists and researchers claim that Autism is
the fastest-growing developmental disorder in the world,
with the prevalence of diagnosis having increased
by 600 per cent over the last 20 years.. And from
1:1200 to 1:90 children in US in the last 30 years
FOREWORD 1
L’autisme, une épidémie ?

23. http://arstechnica.com/science/2012/04/new-autism-studies-find-new-mutations-many-genes-behind-the-disorder/
2014 1 : 65
L’autisme: une épidémie ?
2014 1 : 65
2008 1 : 88
2006 1 : 110
2002 1 : 150
1980 1 : 1500

24. L’autisme, une épidémie ?

25. AUTISME
(ASD :Autism Spectrum Disorders)
• Les nouveaux cas d'autisme diagnostiqués (incidence) aux
États-Unis sont passés de 15,580 en 1992 à 163,773 en 2003.
• Prévalence estimée:
6-7  12 (2012)
cas/1000 enfants
L’autisme, une épidémie ?

27. Il 17% dei bambini US < 18°a. ha un
disturbo dello sviluppo, per lo più a
carico del SN
Disturbi dell’apprendimento
ADHD
Disordini dello spettro autistico
Ritardo mentale
Problemi comportamentali
Analoghe sono le
cifre europee
Il cervello è un organo prezioso e vulnerabile e,
poiché il suo funzionamento ottimale dipende dalla
sua integrità, anche danni limitati possono avere
conseguenze serie ( Grandjean 2006)
ISDE Palermo - Maria Vittoria Di Matteo

29. Since 2000 there has been a 66% increase in Alzheimer's diagnoses.
6th leading cause of death in the United States.
5.4 million Americans are living with the disease.
15-20 million more Americans will be diagnosed by 2040
An equally dramatic
trend show
neurodegenerative
diseases and
in particular
Alzheimer's
disease

30. Interphase chromosomes Mitotic chromosome
Euchromatin
Heterochromatin
...revolving
around it and
playing an
important role
in
transferring
information
from outside
to DNA and
in
modulating
the
response, to
the extent
that some
scientists
have used
the term
natural
genetic
engineering
Multiple
levels
of
packing
are
required
to fit the
DNA into
the cell
nucleus
The first keyword: Epigenetics

31. DNA
double
helix
(2-nm
diameter)
Metaphase chromosome
700
nm
Tight helical fiber
(30-nm diameter)
Nucleosome
(10-nm diameter)
Histones
“Beads on
a string”
Supercoil
(200-nm diameter)
Campbell NE et al (Eds):
Biology: Concepts & Connections
4th Edition, 2003
Euchromatin
Heterochromatin
Multiple
levels
of packing are
required to fit
the DNA into
the cell
nucleus
Nuclear DNA is
normally tightly
wrapped around
histones
The first keyword: Epigenetics

32. http://news.sciencemag.org/sciencenow/2009/04/21-03.html IN FACT Genes need to be told
to switch “off” and “on”:
• Genes need to be told how much expression
(protein) is required and where.
• Genes need to be regulated – this regulation is
not performed by DNA but by many other
controls arranged in a complex network
• DNA has been called the Book of Life by the
Human Genome Project scientists, but many
other biologists consider DNA to be simply a
random collection of words from which a
meaningful story of life may be assembled…
• In order to assemble that meaningful story, a
living cell uses a second informational system.
(...) The key concept here is that these
dynamic-epigenetic networks have a
life of their own —they follow
network-rules not specified by DNA
From directing the fate of stem cells to determining how.. we grow, the genes in our body
act in complex networks.. the whole Genome is a Complex and highly dynamic molecular
Network of interacting Genes and non-codifying sequences.. and proteins
Strohman R. , April 2001 Beyond genetic determinism….Genes Know How to Network…BUT...

33. Rudolf Jaenisch Whitehead Institute
& Dept. of Biology, MIT, Cambridge, MA

34. Nuclear Receptor
DNA Response Element
Histone
Lysine
Acetylation
Histone Deacetylases.
Histone Acetyltransferases;
Histone Methyltransferases
ATP-dependent Nucleosome
Remodeling Complex
Many toxicants cause
rapid alterations in gene
expression by activating
protein kinase signaling
cascades.
The resulting rapid,
defensive alterations in
gene activity require the
transmission of a signal
directly to the histones
present in the chromatin
of stress response genes:
within minutes
of exposure
the phosphorylation of
serine 10 of histone H3
and the
acetylation
of lysines 9 and/or 14
take place
H3-K9 H3-S10
P
The “meeting-point” between the information coming from the
environment and the information encoded in the DNA
(hardware) is the epigenome (software): mimetic molecules
(EDCs) and other pollutants or danger-signals induce the
epigenome to change
Chromatin itself is the direct target of many toxicants *
… toxicant-induced perturbations in chromatin structure
may precipitate adverse effects.. Forcing genome to change

35. TCDD
Viruses
HERVs
EMF
3
2
1
SYNERGISM !!
“FLUID EPI-GENOME”
4
We may represent the environment as a continuous
stream of information (simple: photons: individual
packages of E = M = Information) or complex (organic
molecules, viruses etc) interacting with our cells
[membrane /transmembrane receptors, signal
transduction proteins, nuclear receptors, genome
(DNA + Epigenome)] forcing them to adapt
The second keyword: Environment

36. Everyday levels matter
At truly low levels …
it interferes with gene
activation
At high levels… arsenic kills people
At moderately low levels… it causes a range of diseases
Kaltreider et al. 2002
Many of these substances (Dioxins,
Heavy Metals, Polycyclic aromatic
Hydrocarbons) are dangerous for
humans health at very low-every day-
doses (which are very difficult to be
assessed by the ordinary toxicological
studies)

37. this is not a generic concept,
concerning the way in which the
"genetic program" contained in
DNA is translated, during the
nine months of the ontogenetic
process, in a specific complex
phenotype.
on the contrary,this is a precise
technical term that refers to the
ability, and at the same time to
the necessity, of embryo-fetal
cells to define their epigenetic
setting in adaptive (and
predictive) response to the
information coming from the
mother and, through her, from
the outer world.
Dioxin and
Dioxin-like
molecules
(Ultra)-fine
particles
Heavy Metals
Polycyclic Aromatic
Hydrocarbons (PAH)
Benzene
1
2
3
The third key word is fetal programming

38. Fetal Programming
Differentiation
epi-mutations
Cellular Differentiation: an Epigentic process The actual genetic program of a
particular individual is actually the
product of nine months of
epigenetic adaptive-predictive
“formatting” of billions of cells)..
This is the stage of life which is far more sensitive to
information coming from the environment
(particularly to maternal-fetal stress, to nutritional
errors, to pollutants ..)
1
2
Nature 447, 425-432 (24 May 2007)
PLASTICITY

39. This image clearly shows the "power" of the epigenome and the
predominant role of environmental information in the phenotypic
shaping of cells, tissues , organisms .. the huge phenotypic (morpho-
functional) difference between a lymphocyte and a neuron is not due to
DNA, which is virtually identical in the two cells , but to the manner in
which the same genome has been utilized by the two cells, on the
basis of the information (positional and environmental) received
during the first months of life (for neuron in the first 2 years) and
processed by the epigenetic networks
The fourth keyword is developmental plasticity

40. The chimpanzee DNA is for 98.77% identical to the human .
On average, a gene encoding a protein in a man differs from its
chimpanzee ortholog by only two aa substitutions
.. almost one third of
human genes
has exactly the same
protein translation as their
orthologs
in chimpanzee
Species phylogeny
Orangutan Gorilla Chimpanzee Human
From the Tree of the Life Website,
University of Arizona
Sanger Institute
We are quite stable (for
millions of years) both
genetically and
phenotypically
Evo
The fifth key word is phylogeny

41. et de 9 mois de
développement individuel
de 4 milliards d'années de coévolution
moléculaire* (en particulier, notre ADN est
le produit de ce long parcours) ..
Phylogenèse
Nous ne devrions
jamais oublier que
nous sommes
en même temps
le produit
l'ontogenèse
récapitule
la phylogenèse
Devo-Evo
(..notre epigénome est le
produit de 9 mois de
programmation cellulaire
et tissulaire adaptative à un
environnement qui est en
train de changer très vite..
Un risque majeur: les EDCs et d’autres xénobiotiques (n'étant pas le produit de cette coévolution
moléculaire*) peuvent interférer à ce niveau, en agissant comme des pseudo-morphogènes..
Ontogenèse
Mismatch ?

42. My brain? That's my
second favorite organ
Woody Allen
Allen Stewart Königsberg
L’on parle souvent
de ce qu'on connaît pas.
Ce qui est presque
inévitable dans le cas
du cerveau. Et pourtant
on ne peut parler de
l'autisme sans parler
du cerveau (notre
deuxième organe préféré)

43. How many research papers about the brain are published each year?
For 2013, a PubMed search using the term "brain" shows that 76,945 papers were published
For 2012, a PubMed search using the term "brain" shows that 74,303 papers were published
For 2011, a PubMed search using the term "brain" shows that 69,927 papers were published
For 2010, a PubMed search using the term "brain" shows that 64,929 papers were published
For 2009, a PubMed search using the term "brain" shows that 58,459 papers were published.
For 2008, a PubMed search using the term "brain" shows that 55,874 papers were published.
For 2007, a PubMed search using the term "brain" shows that 53,258 papers were published.
For 2006, a PubMed search using the term "brain" shows that 51,163 papers were published.
For 2005, a PubMed search using the term "brain" shows that 47,383 papers were published.
For 2004, a PubMed search using the term "brain" shows that 42,849 papers were published.
For 2003, a PubMed search using the term "brain" shows that 39,964 papers were published.
For 2002, a PubMed search using the term "brain" shows that 37,304 papers were published.
For 2001, a PubMed search using the term "brain" shows that 36,884 papers were published.
For 2000, a PubMed search using the term "brain" shows that 37,000 papers were published.
For 1999, a PubMed search using the term "brain" shows that 34,828 papers were published.
For 1998, a PubMed search using the term "brain" shows that 33,027 papers were published.
For 1997, a PubMed search using the term "brain" shows that 32,112 papers were published.
For 1996, a PubMed search using the term "brain" shows that 31,040 papers were published

44. Key words
Hardware: Devices that are required to store
and execute (or run) the software.
Phenotype
Brain (structure)
Ancestral Cablage
Software: Collection of instructions that
enables a user to interact with the
computer. Software is a program that
enables a computer to perform a
specific task, as opposed to the
physical components of the system
(hardware).
DNA Genome Epigenome
Genotype
Individual Cablage - Connectome
Mind/Soul
Input,storage,processing,
control, and output devices.
CD-ROM, monitor, printer,
video card, scanners , label makers,
routers , and modems
Quickbooks, Adobe
Acrobat, Winoms-Cs,
Internet Explorer ,
Microsoft Word ,
Microsoft Excel..
Hardware
Software

45. Brain and mind
What interests us here is not the hardware,
that is to say
• the anatomical and physiological structure: the
“projective organization of cortex”,
formed in millions of years *
• common to all human beings and, to some
extent, to all primates
• and also shared, to some extent,
by mammals and even by many vertebrates ...
* phylogenesis
The ancestral wiring

46. The general, species-specific, structure of the human
brain/cortex is, indeed, a product of phylogeny:
in particular, the lateralization and the resulting dominance of
an hemisphere over the other
and the functional connections between the various regions and
areas of the brain are under genetic control (body plans),
limiting (channelling) the transformative (evolutionary)
potential of the information coming from outside..
On the contrary
the fine, individual and soft-wiring structure of the cortex,
(i. e. the individual connectome), is the result of ontogeny
and develops under epi-genetic control.
http://www.humanconnectomeproject.org/
The Individual wiring
The ancestral wiring

47. As with the sensory cortex, Wilder Penfield was responsible for mapping the motor cortex…
Chimps also have a motor cortex, but the area of cortex devoted to vocal control is restricted
relative to what you see in the human animal.
Their brains are just not built for the detailed vocalizations you need to in order to
pronounce all the phonemes that comprise linguistic verbal communication. Neurologists
knew this, and had the chimp trainers consulted a neurologist before starting, they would
have saved themselves years of wasted effort, and moved directly to the more realistic goal
of seeing whether chimps could learn sign language
Carroll SB Genetics and the making of Homo sapiens Nature (2003) 422, 849-857
Comme pour le cortex sensoriel, Wilder Penfield est
responsable de la cartographie du cortex moteur
(Homunculus)...
Les chimpanzés ont également un cortex moteur, mais
la zone de cortex consacrée au contrôle vocal est
limitée par rapport à l'animal humain.
Leurs cerveaux sont tout simplement pas construits
pour les vocalisations détaillées afin de prononcer tous
les phonèmes qui composent la communication
verbale linguistique.
Le câblage ancestral

48. The Human Brain: a Rapidly Evolving Organ
The ancestral wiring

50. Why Are Our
Brains So
Big?
Science, 2012
Macaques live in complex social
groups and have brains larger
than expected for their body size

51. Homo Erectus
Homo Sapiens

52. Chimpanzee-human
divergence
Chimpanzees Humans
6-8
million
years
Hominids or hominins
Brain:
a rapidly
evolving
Organ ?
Evo
The ancestral wiring

53. La variabilità genetica umana è molto più bassa di quella dei primati
più vicini filogeneticamente nonostante che la dimensione delle
popolazioni umane sia di gran lunga maggiore
From Kaessman and Paabo, 2002
Questo è probabilmente dovuto alla recentissima espansione degli umani a
partire da una piccola popolazione e alla scarsa incidenza della selezione in
una specie che si adatta per differenziazione culturale e non genetica.
Marcello Buiatti - UniFI

55. From 6-2milion years ago
Brain size increase slowly
From 2 milion-800.000 years ago
Brain and body size increase
From 800.000-200.00 years ago
Brain size increase rapidly

56. Le connectome est un plan complet
des connexions neuronales dans un cerveau
http://www.humanconnectomeproject.org/

57. • Science. 2007 Sep 7;317(5843):1360-6.
• Humans have evolved specialized skills of social cognition: the cultural
intelligence hypothesis.
• Herrmann E, , Call J, Hernàndez-Lloreda MV, Hare B, Tomasello M.
• Humans have many cognitive skills not possessed by their nearest primate
relatives. The cultural intelligence hypothesis argues that this is mainly due to
a species-specific set of social-cognitive skills, emerging early in ontogeny, for
participating and exchanging knowledge in cultural groups. We tested this
hypothesis by giving a comprehensive battery of cognitive tests to large
numbers of two of humans' closest primate relatives, chimpanzees and
orangutans, as well as to 2.5-year-old human children before literacy and
schooling. Supporting the cultural intelligence hypothesis and contradicting
the hypothesis that humans simply have more "general intelligence," we
found that the children and chimpanzees had very similar cognitive skills for
dealing with the physical world but that the children had more sophisticated
cognitive skills than either of the ape species for dealing with the social world.

58. In the social domain, a very different pattern emerged. Averaging across all of the tasks
in the social domain, the human children were correct on ∼74% of the trials, whereas
the two ape species were correct about half as often (33 to 36% of the trials).
Statistically, the humans were more skillful than either of the two ape species (P < 0.001
in both cases), which did not differ from one another.

59. • Dev Psychobiol. 2014 Apr;56(3):547-73. doi: 10.1002/dev.21125. Epub 2013 Jun 14.
• Differences in the early cognitive development of children and great apes.
• Wobber V, Herrmann E, Hare B, Wrangham R, Tomasello M
• There is very little research comparing great ape and human cognition
developmentally. In the current studies we compared a cross-sectional sample of 2-
to 4-year-old human children (n=48) with a large sample of chimpanzees and
bonobos in the same age range (n=42, hereafter: apes) on a broad array of cognitive
tasks. We then followed a group of juvenile apes (n=44) longitudinally over 3 years to
track their cognitive development in greater detail.
• In skills of physical cognition (space, causality, quantities), children and apes
performed comparably at 2 years of age, but by 4 years of age children were more
advanced (whereas apes stayed at their 2-year-old performance levels). In skills of
social cognition (communication, social learning, theory of mind), children out-
performed apes already at 2 years, and increased this difference even more by 4
years. Patterns of development differed more between children and apes in the
social domain than the physical domain, with support for these patterns present in
both the cross-sectional and longitudinal ape data sets.
• These results indicate key differences in the pattern and pace of cognitive
development between humans and other apes, particularly in the early emergence
of specific social cognitive capacities in humans.

62. The brain grows at an amazing rate during
development. At times during brain
development, 250,000 neurons are
added every minute!
At birth, almost all the neurons that the
brain will ever have are present.
However, the brain continues to grow for
many years after birth.
By the age of 2 years old, the brain is
about 80% of the adult size
A stegosaurus dinosaur weighed approximately 1,600 kg but had a brain that weighed only
approximately 70 grams (0.07 kg). Therefore, the brain was only 0.004% of its total body
weight. In contrast, an adult human weighs approximately 70 kg and has a brain that weighs
approximately 1.4 kg. Therefore, the human brain is about 2% of the total body weight. This
makes the brain to body ratio of the human 500 times greater than that of the stegosaurus

63. Brain plasticity and modulation of its structure
and its functions
Motility of neurons and in particular
the formation of new
connections (synapses) can be
modified (perturbed) by
exposure to environmental
stressors
Wingate Imagining the brain cell: the neuron in visual culture. Nature Rev Neuroscience 2006; 7: 745-752.
The Individual wiring

64. Early critical periods in the development
of SYNAPTOGENESIS and brain functions
Formation of new synapses following stimulation..
The Individual wiring

65. B Weiss, P J Landrigan The developing brain and the
environment: an introduction. Environ Health Perspect.
2000 June; 108(Suppl 3): 373–374.
B Weiss Vulnerability of children and the developing
brain to neurotoxic hazards. Environ Health Perspect.
2000 June; 108(Suppl 3): 375–381.
J W Olney, N B Farber, D F Wozniak, V Jevtovic-Todorovic, C
Ikonomidou Environmental agents that have the potential
to trigger massive apoptotic neurodegeneration in the
developing brain. Environ Health Perspect. 2000 June;
108(Suppl 3): 383–388.
E A London The environment as an etiologic factor in
autism: a new direction for research.Environ Health
Perspect. 2000 June; 108(Suppl 3): 401–404
D C Rice Parallels between attention deficit hyperactivity
disorder and behavioral deficits produced by neurotoxic
exposure in monkeys.Environ Health Perspect. 2000 June;
108(Suppl 3): 405–408
G J Myers, P W Davidson Does methylmercury have a role
in causing developmental disabilities in children?
Environ Health Perspect. 2000 June; 108(Suppl 3): 413–
420.
S P Porterfield Thyroidal dysfunction and environmental
chemicals--potential impact on brain development. Environ
Health Perspect. 2000 June; 108(Suppl 3): 433–438.
SG Selevan, CA Kimmel, P Mendola Identifying critical
windows of exposure for children's health. Environ Health
Perspect. 2000 June; 108(Suppl 3): 451–455.
These are some articles concerning the
effects of pollutants on the CNS
development during the early stages of
life (windows of exposure)

66. At birth, each neuron in the cerebral cortex has approximately 2,500 synapses.
By the time an infant is two or three years old, the number of synapses is
approximately 15,000 synapses per neuron (Gopnick, et al., 1999).
This amount is about twice that of the average adult brain.
As we age, old connections are deleted through a process called synaptic
pruning
Ineffective or weak connections are "pruned" in much the same way a
gardener would prune a tree or bush, giving the plant the desired shape.
It is plasticity that enables the process of developing and pruning connections,
allowing the brain to adapt itself to its environment
https://faculty.washington.edu/chudler/plast.html
Developmental Plasticity: Synaptic Pruning

67. 09 A synaptic trek to autism
Schematic representation of the different phases of synaptogenesis in the human brain.
During the first three years of life, an excess of cell/synaptic growth rate and inhibitory
currents could increase the risk of ASD.

68. The Epigenome learns from its
experiences
• Epigenetic tags act as a kind of cellular memory.
• A cell's epigenetic profile -- a collection of tags
that tell genes whether to be on or off -- is the
sum of the signals it has received during its
lifetime
http://learn.genetics.utah.edu/content/epigenetics/epi_learns/

69. .. ce qui nous intéresse ici, c'est le software, le logiciel
(qui est essentiellement constitué par des circuits neuronaux
et donc par les connexions synaptiques)
et la façon dont - au cours de l'ontogenèse, principalement
au cours de la vie fœtale et des deux premières années
de la vie (c'est à dire dans la période de plasticité
maximale de développement):
des milliards d'arborescences dendritiques se
forment pour communiquer entres elles et en
réponse à des informations provenant de
l'environnement et du reste du "réseau"
en cours de construction
[ce qui est vraiment difficile est comprendre pourquoi tant de
scientifiques préfèrent, même dans ce contexte, un modèle
sélectif (néo-darwinien) de l'évolution plutôt qu’un modèle
instructive et constructive (Lamarckian et Darwinien au
même temps)]
Le câblage individuel

70. • Early in
development,
genes are
"poised" like
runners in the
starting blocks,
ready to jump to
action.
• In a differentiated
cell, only 10 to 20% of
the genes are active.
• Different sets of
active genes make a
skin cell different
from a brain cell.
• Environmental signals
such as diet and stress
can trigger changes in
gene expression.
• Epigenetic flexibility is
also important for
forming new memories.
http://learn.genetics.utah.edu/content/epigenetics/epi_learns/

71. • A questo proposito
si possono ricordare
gli studi che hanno
dimostrato come un
ambiente arricchito
permetta un
• maggior sviluppo
cerebrale (e in
particolare un
grande incremento
di sinapsi/circuiti)
• negli animali di
laboratorio
• e che gli animali
che vivono in
Natura hanno
cervelli più grandi,
complessi, attivi,
efficienti

72. Spine plasticity
is implicated in
motivation,
learning
and memory.
In particular
long-term
memory
is mediated
by the growth
of new dendritic
spines (or the
enlargement of
pre-existing
spines)
to reinforce
a particular
neural pathway.

73. I Neuroni al Microscopio Confocale
Microscopic marvels Nature, 2010

75. This discovery of a stimulus-dependent
alteration in the brain’s macroscopic
structure contradicts the traditionally held
view that cortical plasticity is associated with
functional rather than anatomical changes.

76. During the learning period, the gray matter increased significantly
in the posterior and lateral parietal cortex bilaterally.

77. Changes in the structure of children's brains may account for some
of the risky business of adolescence Nature 442, 865-867 (24 August 2006)

79. The posterior hippocampi of taxi drivers were significantly larger
relative to those of control subjects.. volume correlated with the
amount of time spent as a taxi driver ( local plastic change in the
structure of adult human brain in response to the environment)

80. Ramón y Cajal
Death of a DOGMA

82. Scientific American, 2013
Online social network size is reflected in human
brain structures Proc. R. Soc. B, 2012
Gray matter abnormalities in Internet addiction: A
voxel-based morphometry Eur J Radiology 2009
Here, we show a biological basis .. by
demonstrating that quantitative variation in the
number of friends an individual declares on a
web-based social networking service
reliably predicted grey matter density in the
right superior temporal sulcus, left middle
temporal gyrus and entorhinal cortex

84. Les troubles du spectre autistique
De la génétique à l‘ épigénétique
Léo Kanner Hans Asperger
Angelman syndrome
ERNESTO BURGIO
ECERI - European Cancer and
Environment Research Institute
ISDE Scientific Committee

85. Autism
• Autism and autism
spectrum disorders (ADS)
are developmental
disorders of neural
connections
and, as we will see,
of synaptogenesis
• This affects the way
in which the brain
"processes information"
The Human Connectome Project

86. As for the causes of autism
many hypotheses have been advanced:
at present these disorders are usually
considered as essentially 'genetic' ..
while all the environmental causes
(including vaccines, mercury, heavy
metals, pesticides) have been
considered as highly improbable
Which is in contrast with the dramatic
increase of the autism spectrum
disorders
( generally explained with the
changing of the diagnostic criteria).

87. I will try to show why and in what
sense this approach is not only
simplistic, but also misleading
as
-the increase of the cases is
continuous and alarming,
- the traditional genetic risk factors
have not so far been found
-the most important mutations are
de novo (which is to say, they are not
found in somatic cells of the parents
.. but rather occur
- in parents’ gametes or
- during fetal development
And that makes autism a non-
hereditary genomic disease
Beaudet AL Autism: highly heritable but not
Inherited Nature Medicine (2007) 13, 534 - 536

88. • The fact that these problems
usually occur after a latency
period (of normal
intellectual and motor
development) shows
that
• the brain basic structures
(cerebral neuronal
differentiation and migration:
definition of the functional
areas of the brain), are not
changed
• but, so to speak, it is the
software (connectome)
- synaptic connections ..
- neuronal circuits ..
to be damaged

89. Together, results of clinical, neuroimaging,
neuropathological, and neurochemical
studies show that autism spectrum
disorders are disorders of neuronal-
cortical organization that cause deficits in
information processing in the nervous
system, ranging from synaptic and
dendritic organisation to connectivity
and brain structure

90. En corrélation avec les déficits fonctionnels observés au niveau comportemental, quelques
auteurs auraient relevé que les enfants autistes auraient un cerveau plus gros et un nombre de
neurones plus élevé * et ont supposé que l'origine de cette altération est un déficit du pruning
à savoir la réduction physiologique des synapses et des circuits redondants qui se produit au
cours du développement du cortex
Des travaux récents
suggèrent que les
synapses inapproprié
dans le cerveau en
développement sont
«marqués» par les
protéines du
complément (-C3)
et ensuite éliminés
par la microglie - les
macrophages du
système nerveux
central - dans le
cerveau post-natal ..
Kennedy et al. (2007) *ont observé un surcroît de neurones pyramidaux de 58 % chez l’enfant atteint d’autisme.
L’excès de ces neurones (représentant 80 % de l’ensemble des neurones dans le cortex) occasionne un excès d’axones,
de dendrites, de synapses et de myéline qui engendre un volume exagéré de substance grise et de substance blanche
(Courchesne et al., 2007).

91. A Silent Pandemic
Industrial Chemicals Are Impairing
The Brain Development of Children Worldwide
For immediate release: Tuesday, November 7, 2006
Grandjean P. Landrigan Ph
L’autisme, une épidémie ?

92. 1
2
3
1
2
3
L’autisme, une épidémie ?

93. The Lancet Neurology, Volume 13, Issue 3 , Pages 330 - 338, March 2014
Since 2006, epidemiological studies have documented six additional developmental
neurotoxicants — manganese, fluoride, chlorpyrifos, tetrachloroethylene,
dichlorodiphenyltrichloroethane,, and the polybrominated diphenyl ethers.
We postulate that even more neurotoxicants remain undiscovered
L’autisme, une épidémie ?

94. The gift our mothers
never wanted to give us
http://www.ewg.org/reports/generations/
CHEMICAL FALL OUT
ULTRAFINE PARTICLES
HEAVY METALS
ENDOCRINE DISRUPTORS
dioxin-like moleculles
1
2
3
That’s why at present many studies in various parts of the world
are evaluating the chemical body burden .. especially in
women, children, embryos / fetuses, providing dramatic results.

95. Giuseppe Giordano
Monitoring Body-Burdens
700 different synthetic chemicals or heavy
metals found in human blood,
POPs
“Diossina di Seveso”: sino a 10 anni negli adipociti !

96. E’ vero, in particolare, che metalli, diossine e altri inquinati lipofili accumulati nei tessuti materni
possono passare, anche a distanza di anni dal loro assorbimento, nel sangue e raggiungere il feto ?
Is it true that metals, dioxins and other lipophilic pollutants, accumulated in maternal tissue, may pass,
even many years after their absorption, into the blood and reach the fetus?

97. Johns Hopkins Bloomberg School of Public Health April 20, 2007
ENVIRONMENTAL SCIENCE & TECHNOLOGY
•
PFOA perfluorooctanoate
PFOS perfluorooctane sulfonate
300 CAMPIONI DI SANGUE DI CORDONE OMBELICALE
PFOS PRESENTE NEL 99 % DEI CAMPIONI
PFOA PRESENTE NEL 100 % DEI CAMPIONI
SOST. UBIQUITARIE (PELLICOLE x CIBI, TESSILI, MOQUETTE )
http://www.innovations-report.com/html/reports/medicine_health/report-83364.html

98. Estimating Burden and Disease Costs of Exposure to EDCs in the EU:
" The neurodevelopment panel estimated a strong probability (70–100%)
that each year in Europe, 13.0 million IQ points are lost (sensitivity
analysis, 4.24–17.1 million) due to prenatal organophosphate exposure"
L’autisme, une épidémie ?

99. Neurodevelopmental Disorders and Prenatal Residential Proximity
to Agricultural Pesticides: The CHARGE Study
Janie F. Shelton,1 Estella M. Geraghty Environ Health Perspect; DOI:10.1289/ehp.1307044: 23 June 2014
970 participants, California Pesticide Use Report (1997-2008) linked to the
addresses during pregnancy. Pounds of active ingredient …
aggregated within 1.25km, 1.5km, and 1.75km buffer distances from the home
•Organophosphates higher 3rd trimester expos: 60% increased risk ASD
•Pyrethroid insecticide just prior to conception or for 3rd trimester at
greater risk for both ASD and DD (developmental delay)
•Carbamate: risk for DD increased (Arprocarb di uso anche domestico:
Undene, Propoxur = Baygon).
Giuseppe Giordano ISDE Palermo

100. Rischio ASDs molto
aumentato (OR > 50%)
ed in modo
statisticamente
significativo tra le
mamme esposte ad
inquinamento
atmosferico da polveri
(PM 2.5) e
non da PM 2,5-10
durante il terzo trimestre
di gravidanza
(sinaptogenesi!) ..
altri due studi caso-
controllo 2013 avevano
mostrato la correlazione
JAMA Psy
2013;70(1):71-7;
EHP 2013;121(3):380-6

101. JAMA Psychiatry. 2013 January ; 70(1): 71–77.
doi:10.1001/jamapsychiatry.2013.266
Living near a freeway, based on the location of the birth,
and third trimester address, and autism
PM2.5, PM10, and NO2 at residences were higher in children with autism.
The magnitude of these associations appear to be most pronounced during late gestation
(OR=1.98, 95%CI 1.20–3.31) and early life / first year of life (OR=1.98, 95%CI 1.20–3.31)
Giuseppe Giordano ISDE Palermo

102. Nano-tossicologia
Controllo delle emissioni del traffico veicolare
Politiche per una mobilità “sostenibile”
PM 10
PM 2,5
PM 0,1 PARTICOLATO
ULTRAFINE
Giuseppe Giordano ISDE Palermo

105. The frontal cortex of an 11-month-old healthy MC
dog exhibits Aβ42 staining of a diffuse plaque,
surrounded by a microglia-like nucleus
The frontal cortex of a 17-year-old MC boy… shows a diffuse
Aβ42 plaque (red product) and GFAP-negative astrocytes
The frontal cortex of a 36-year-old MC male with an E3/E4 ApoE genotype .. shows
abundant mature and diffuse Aβ42 plaques (red stain) along
with GFAP-positive reactive astrocytosis
Exposures to particulate matter and gaseous air pollutants have been associated with respiratory tract inflammation, disruption of the nasal
respiratory and olfactory barriers, systemic inflammation, production of mediators of inflammation capable of reaching the brain and systemic
circulation of particulate matter. Mexico City (MC) residents are exposed to significant amounts of ozone, particulate matter and associated
lipopolysaccharides. MC dogs exhibit brain inflammation and an acceleration of Alzheimer’s-like pathology, suggesting that the brain is
adversely affected by air pollutants. MC children, adolescents and adults have a significant upregulation of cyclooxygenase-2 (COX2) and
interleukin-1β (IL-1β) in olfactory bulb and frontal cortex, as well as neuronal and astrocytic accumulation of the 42 amino acid form of β-
amyloid peptide (Aβ42), including diffuse amyloid plaques in frontal cortex. The pathogenesis of Alzheimer’s disease (AD) is characterized by
brain inflammation and the accumulation of Aβ42, which precede the appearance of neuritic plaques and neurofibrillary tangles, the
pathological hallmarks of AD. Our findings of nasal barrier disruption, systemic inflammation, and the upregulation of COX2 and IL-1β
expression and Aβ42 accumulation in brain suggests that sustained exposures to significant concentrations of air pollutants such as
particulate matter could be a risk factor for AD and other neurodegenerative diseases.

106. Increased amyloid
A-deposition
Accumulation of hyperphosphorylated
microtubule associated protein  “tangles”
(LEARn) model : early environmental factors such as
exposure to Pb, nutritional deficiencies (e.g., folate or
B12), or oxidative stress alter DNA epigenetically, by
reducing the activity of enzymes as DNMTs…

107. Copyright ©2008 Society for Neuroscience
No Caption Found
Alzheimer’s Disease (AD)-Like Pathology in Aged Monkeys after Infantile Exposure to Environmental
Metal Lead (Pb): Evidence for a Developmental Origin and Environmental Link for AD
Environmental Trigger
Early life exposures
DOHA -Developmental
(Embrio-Fetal) Origin of AD.
The cause for most Alzheimer's
cases is still essentially unknown
(except for 1% to 5% of cases
where genetic differences have
been identified)………….
The Journal of Neuroscience, 2008 • 28(1):3–9 • 3

108. A marked reduction in DNA
methylation was observed
in post-mortem brain
(Mastroeni et al., 2010)
Epigenetics and Alzheimer disease
Folate and vitamin B12 restriction
induced demethylation of PSEN1
gene and increased a production
in both mice and neuronal cell
cultures (Fuso et al., 2008)
Aberrant methylation of genes related to
a production and deposition (PSEN1,
APOE) and to DNA methylation
(DNMT1, MTHFR) was found in DNA
from blood or brain of AD patients
(Wang et al., 2008)
Prenatal exposure of monkeys
to lead resulted in epigenetic
modifications of genes related to a
Production (APP, PSEN1) and increased
a deposition later in life (Wu et al., 2008)
Several studies point to a possible contribution
of epigenetic modifications in AD
Lucia Migliore
Università di Pisa
1
2
3

109. Des études scientifiques prouvent que l'exposition du fœtus à 800-1900 MHz
utilisés dans les radiofréquences des téléphones cellulaires peut conduire à des
altérations comportementales et neurophysiologiques qui persistent chez l’ adulte

110. • Les souris exposées pendant la
grossesse avaient une déficience
demémoire, étaient hyperactifs et
ont troubles de anxiété, ce qui indique
que l'exposition in utero aux
radiofréquences est une cause
potentielle de troubles
neurocomportementaux.
• Nous avons aussi démontré une
augmentation de la transmission
synaptique glutamatergique sur les
cellules pyramidales dans le cortex
préfrontal associés à ces changements
de comportement, suggérant un
mécanisme par lequel l’exposition aux
radiations de téléphone cellulaire in-
utero peut conduire à l'augmentation
de la prévalence des troubles
neurocomportementaux

111. Fetal Alcohol Spectrum Disorders (FASD)
Behavioral effects of acute, binge-like ethanol exposure
K. Mantha, M. Kleiber - Mouse Model of Fetal Alcohol Spectrum Disorder, J. of Behav. Brain Sc., Vol. 3 No. 1, 2013
1. Delay of development of basic motor skill reflexes and coordination
2. Spatial learning and memory impairment
3. Observed changes in activity and anxiety-related behaviors
Ethanol disrupts biological processes that are actively occurring at the time of
exposure.
Morgan L Kleiber, Katarzyna Mantha, Journal of Neurodevelopmental Disorders 2013, 5:6
Trimester one: Cell proliferation microcephaly
Trimester two: Cell migration and differentiation agenesis of the corpus callosum, cerebellar hypoplasia
Trimester three: Cellular communication and neurotransmission hippocampus
COSTUME
Giuseppe Giordano ISDE Palermo

112. Maternal cigarette smoking during pregnancy
and effects on child neurodevelopment
behavioral and psychiatric
disorders later in life
Affecting placental vasculature, and also by nicotinic
acetylcholine receptor binding in fetal membranes
Nicotine Tob Res. 2008, Feb; 10(2): 267-78 Shea AK Steiner M
Epigenetic changes: altered DNA methylation
and dysregulated expression of MicroRNA
(Knopik VS, Maccani MA, Dev. Psychopathol. 2012 Nov;24(4)
reduced birth weight
“thrifty phenotype
Brown LA, Khousbouei H, et al Down-regulation of early ionotrophic glutamate
receptor subunit developmental expression as a mechanism for observed
plasticity deficits following gestational exposure to benzo(a)pyrene.
Neurotoxicology. 2007; 28(5):965–78. [PubMed: 17606297]
dysregulation of the nicotinic and muscarinic,
catecholaminergic and serotonergic
Neuro-transmitter systems
long-term neurotransmitter
involvement in dysregulation of
emotion and attention
Giuseppe Giordano ISDE Palermo

113. Prenatal exposure to stressful life events is associated with
significantly increased risk of Autistic Disorders (AD), as well
as other disorders, such as schizophrenia and depression..
Prenatal stress can produce both
(a) abnormal postnatal behaviors that resemble the defining
symptoms of AD, and
(b) other abnormalities that have elevated rates in AD, such as
learning deficits, seizure disorders, perinatal complications,
immunologic and neuroinflammatory anomalies, and low
postnatal tolerance for stress

114. Early life experience can
persistently alter
expression levels of key
genes through epigenetic
marking which can
underpin changes in
behavior, neuroendocrine,
and stress responsivity
throughout later life.
Collectively, this process is
referred to as epigenetic
programming. The nature
of the environment
throughout later life, in
addition to the impact of
biological processes
associated with aging and
genetic sex, may
exacerbate the effects of
programming established
during early life resulting
in increased vulnerability
to mood disorders.

116. Encore faut-il activer une portion
bien précise de ce gène, grâce à
un interrupteur épigénétique.
L'analyse des cerveaux de rats
n'ayant pas reçu une ration
suffisante de léchage l'a
démontré : l'interrupteur lié au
gène NRC31 était défectueux
dans les neurones de
l'hippocampe des rats.
Conséquence: même en
l'absence d'éléments
perturbateurs, ils vivent dans un
état de stress constant..
Les bébés rats que leur maman lèche souvent
-le léchage remplissant chez le rat la même
-Fonction que la caresse chez l'humain- sont
-plus calmes que les rats mal léchés.

118. Sur le site vous pouvez voir directement comment l'Amour maternel peut libérer l’ADN ...
Expérience 1: mère anxieuse, sans amour: les marques épigénétiques (partiellement
réversibles) sur le gène du GR.. ont la tendance à produire des souris caractérisés par
anxiété, désarroi, angoisse.. tout au long de leur vie (et même pour quelques générations!)

120. Expérience 2: mère tranquille, aimable: les caresses "suppriment" les groupes
méthyle, libérant le gène du récepteur en permettant son expression. Les petits
souris seront rassurés , aimables, résistants au stress tout au long de leur vie (et
même pour quelques générations).

121. Maternal care influences the programming of the hypothalamic-
pituitary-adrenal Axis (HPA) through
epigenetic programming of glucocorticoid receptors expression...
We found a greatly increased methylation of cytosine in the
promoter of a gene codifying for a Glucocorticoids-Neuro-Receptor
(NR3C1) in the hippocampus of suicide victims with a history
of childhood abuse .. (post-mortem examinations)

122. ..our results clearly show that periodic maternal separation decreases hippocampal
granule cell neurogenesis beginning in early postnatal life. These alterations take
place without chronically increasing basal HPA axis activity during the SHRP. We
suggest that MS causes alterations in the development of the central nervous system
that are related to the long term HPA axis dysregulation and contributes to increased
depressive-like behavior in the adult.

123. Adults who experienced abuse or neglect as children seem to have an
enhanced emotional sensitivity to stress; they are more likely to
develop psychiatric disorders when confronting subsequent
stressors than adults who did not have a similarly troubled history
Childhood maltreatment is a particularly potent risk factor for depression
in adults, especially when individuals encounter stressful life events
Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB. The link
between childhood trauma and depression: insights from HPA axis studies
in humans. Psychoneuroendocrinology 2008;33:693–710
McLaughlin KA, Green JG, Gruber MJ, Sampson NA, Zaslavsky AM,
Kessler RC. Childhood adversities and adult psychiatric disorders in the
national comorbidity survey replication II: associations with persistence
of DSM-IV disorders. Arch Gen Psychiatry 2010;67:124 –32

124. A recent study suggested that early maltreatment might
even accelerate cell aging; young adults with an average
age of 27 years who reported childhood maltreatment had
shorter telomeres in peripheral blood mononuclear
cells (PBMCs) than those who reported no maltreatment…..
A growing literature has linked shorter telomeres with
health behaviors, including physical activity, obesity, and
smoking, as well as aging and age-related diseases,
including cancer, coronary heart disease, diabetes and
heart failure.
Tyrka AR, Price LH, Kao HT, Porton B, Marsella SA, Carpenter LL.
Childhood maltreatment and telomere shortening: preliminary
support for an effect of early stress on cellular aging. Biol
Psychiatry 2010;67:531– 4.
Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD,
Cawthon RM. Accelerated telomere shortening in response to
life stress. Proc Natl Acad Sci U S A 2004;101:17312–5
Willeit P, Willeit J, Mayr A, Weger S, Oberhollenzer F, Brandstatter A,
Kronenberg F, Kiechl S. Telomere length and risk of incident
cancer and cancer mortality. JAMA 2010;304:69 –75

125. Front Neurosci. 2013; 7: 123. Published online Jul 22, 2013. doi: 10.3389/fnins.2013.00123
PMCID: PMC3717511 Autism spectrum disorder in children born preterm—role of
exposure to perinatal inflammation Suzanne J. Meldrum, T. Strunk, A. Currie, S. L.
Prescott, K. Simmer, A. J. O. Whitehouse
Schendel D, Bhasin TK., Birth weight and gestational age characteristics of children
with autism, including a comparison with other developmental disabilities.
Pediatrics., vol. 121, maggio 2008, pp. 1155-1164.
… a markedly increased prevalence of ASD in children born
preterm, who are at highest risk of exposure to perinatal
inflammation. However, the mechanisms that underpin the
susceptibility to infection-driven inflammation during pregnancy
and risk of preterm birth, and how these intersect with the
subsequent development of ASD in the offspring, is not understood
….
.
Autism spectrum disorder in children born preterm &
role of exposure to perinatal inflammation
Giuseppe Giordano ISDE Palermo

126. Accumulating evidence supports the view that deregulation of the immune
system represents an important vulnerability factor for psychosis. In a
subgroup of psychotic patients, the high comorbidity with autoimmune and
chronic inflammatory conditions suggests a common underlying immune
abnormality leading to both conditions
This activation of the inflammatory response system may be
suggestive for microglia activation, as these cells are the
macrophages of the brain

127. Infection but also environmental stressors during gestation/early life activate microglia,
perturbing neuronal development, thereby setting the stage for vulnerability for later
psychotic disorders.
A second hit, such as endocrine changes, stress, or infection, could further activate microglia,
leading to functional abnormalities of the neuronal circuitry in the brain and psychosis

128. Hypothesized Model of the Modulation of Adult Brain and Behavioral Functions by
Imbalances in Fetal Brain Cytokines.
Meyer U et al. Schizophr Bull 2008;35:959-972
© The Author 2008. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights
reserved. For permissions, please email: journals.permissions@oxfordjournals.org.

129. Maternal immune activation and abnormal brain
development across CNS disorders
Nature Reviews Neurology 10, 643–660 (2014)
Epidemiological studies have shown a clear association between maternal infection
and schizophrenia or autism in the progeny.
Animal models have revealed maternal immune activation (mIA) to be a profound
risk factor for neurochemical and behavioural abnormalities in the offspring.

130. Maternal immune activation and abnormal brain
development across CNS disorders
Nature Reviews Neurology 10, 643–660 (2014)
Microglial priming has been proposed as a major consequence of mIA representing
a critical link in a causal chain leading to the wide spectrum of neuronal dysfunctions
and behavioural phenotypes observed in the juvenile, adult or aged offspring.

131. Nature (2010)
An emerging and
intriguing trend is the
identification of rare
CNVs in the same
genes implicated
across
neurodevelopmental
disorders, including
schizophrenia, ADHD,
and intellectual
disability.

132. What is most striking is that the same
CNVs have been found, at least in some
cases, in the semen of parents, showing
that autism could be the consequence
of a parental exposure to pollutants
and a transgenerational transmission:
which could provide an explanation for the
unremitting "pandemic" increase of
these disorders.
All that said .. it is absolutely necessary to reconsider
the problem of many early environmental exposures
or even gametic, and their possible synergy ..
which can induce an epigenetic instability,

133. In autism many CNVs
involve genes controlling
- Cell proliferation
- Synapse formation
- cell motility and
- cell signaling ..
The CNVs are, in fact, in several
species defensive and reactive
changes
(.. deletion or amplification
of some sequences had been
discovered in the seventies of the
last century in animals and plants
exposed to situations of stress
and pollution)

134. All these CNVs were associated with genes already known to be involved
in autism.
A similar study documented the importance of rare CNVs in different
loci associated with schizophrenia.
Deletions and duplications de novo were present in 5% of controls versus 15% of
cases (20% younger) highly significant differences. The association was replicated
independently in patients with schizophrenia beginning in childhood compared to
their parents. Mutations in genes controlling the neurological development of
networks, including neuregulin and glutamate pathways were frequent

135. CNVS FROM THE AUTISM CHROMOSOME REARRANGEMENT DATABASE (ACRD) ARE PLOTTED TO THE RIGHT OF EACH
CHROMOSOME (BLACK). CNV DATA FROM THE AUTISM-SPECIFIC STRINGENT DATA SET FROM THE CURRENT STUDY
ARE SHOWN TO THE LEFT OF THE CHROMOSOME AND IS CATEGORIZED AS DE NOVO (BLUE),
OVERLAPPING/RECURRENT (GREEN), CNVS OVERLAPPING WITH STRUCTURAL VARIATION FROM THE ACRD (YELLOW),
AND SINGLETON CNVS (RED).

136. A similar situation is emerging from CNV
studies of schizophrenia. There is a high
frequency of de novo CNVs.. a large
heterogeneity in rare variants…
Which indicates that similar pathways
may be involved in phenotypically
distinct outcomes
Trends in Neuroscience Vol 32, 2, 2009, 69–72

137. Epigenetics and mental disorders
• Fragile X disease is associated
with an expanded (N250 copies)
number of hypermethylated CGG
repeats 5′ of the FMR1 gene that
results in downregulation of the
gene
• Disease severity in fragile X is
directly correlated with the
extent of methylation in the 5′
region of the FMR1 gene
• Rett syndrome, on the other
hand, is linked to mutations in
the gene encoding the
methylated cytosine binding
protein (MECP2)… which
recruits a variety of proteins
that form a complex..
repressing gene expression
Both fragile X and Rett syndrome are responses to well-established alterations
to a single gene. However, recent work in autism spectrum disorders suggests
a major epigenetic component to the origin of the(se) disease(s)
Free Radical Biology & Medicine 46 (2009) 1241–1249

138. the severity of the disease is directly related to the number of
methylation in the 5 'region of the FMR1 gene
méthylations
Fragile X disease

139. Rett syndrome
• In at least 95% of Rett syndrome cases, the cause
is a de novo mutation in the child. Parents are generally
genotypically normal, without an MECP2 mutation.
• In sporadic cases of RTT, the mutated MECP2 is usually
thought to be derived from the male copy of the X
chromosome.
• It is not yet known what causes the sperm to mutate,
and such mutations are rare.
Trappe R, Laccone F, Cobilanschi J et al MECP2 mutations in sporadic cases of Rett's
Disorder are almost exclusively of paternal origin
American Journal of Human Genetics 2001; 68 (5): 1093–101

140. Starting from the new models of (epi)genetic fluid genome
autism and other neurodevelopmental disorders (as well as
neurodegenerative diseases such Alzheimer's disease)
are the most emblematic
- epigenetic diseases (ie genetic and environmental at the same
time)
- trans-generational diseases (owing to genetic and epigenetic
changes that occur in gametes) and/or
- disorders of fetal programming: that is, so to say, changes in the
embryo-fetal development related to early transplacental exposure
to genotoxic agents (especially heavy metals) with the possible
assistance of other epigenotoxic agents ( including EDCs and
electromagnetic fields).
CONCLUSION

141. It is obvious that this requires a
total change of perspective:
instead of looking into the DNA for
pre-disposing causes (mutations
and polymorphisms)
we should search for epigenetic
marks and active genetic
modification (reactive and
defensive)..
which can explain much better
the pathogenesis and symptoms
that characterize behavioral and
neuropsychiatric diseases
CONCLUSION

143. How Music shapes our Brain
"You are your synapses. They are who you are."
--- Joseph LeDoux, 2002 (in Synaptic Self)
Un caso estremamente interessante è quello del cervello del
musicista che presenta una struttura alquanto particolare,
almeno nei casi in cui lo studio della musica ha avuto inizio nelle
primissime fasi della vita..

144. Music training can
significantly improve our
motor and reasoning skills
We generally assume that
learning a musical instrument
can be beneficial for kids, but
it’s actually useful in more
ways than we might expect.
One study showed that
children who had three years
or more musical instrument
training performed better
than those who didn’t learn
an instrument in auditory
discrimination abilities and
fine motor skills.
08 PLOS ONE Practicing a Musical Instrument in Childhood is
Associated with Enhanced Verbal Ability and Nonverbal Reasoning

145. Music affects many different areas of the brain
http://blog.bufferapp.com/music-and-the-brain

146. Some of the brain areas that have been found to be enlarged in musicians in
morphometric studies based on structural magnetic resonance imaging. Red,
primary motor cortex; yellow, planum temporale; orange, anterior part of the
corpus callosum.
http://www.nature.com/nrn/journal/v3/n6/fig_tab/nrn843_F2.html#figure-title

147. Structural brain differences between different musician groups (e.g., keyboard and string
players) are consistent with a “nurture” hypothesis (Bangert and Schlaug 2006). The omega
sign, an anatomical landmark of the precentral gyrus associated with hand and finger
movement representation, was found to be more prominent on the left hemisphere for
keyboard players but was more prominent
on the right hemisphere for string players

150. Everybody know that Albert Einstein, when he
was young, did extremely poor in school… and
that his grade school teachers told his parents
to take him out of school because he was "too
stupid to learn" and it would be a waste of
resources for the school to invest time and
energy in his education. The school suggested
that his parents get Albert an easy, manual
labor job as soon as they could. His mother
did not think that Albert was "stupid". Instead
of following the school's advice, Albert's
parents bought him a violin. Albert became
good at the violin. Music was the key that
helped Albert Einstein become one of the
smartest men who has ever lived. Einstein
himself says that the reason he was so smart is
because he played the violin and loved the
music of both Mozart and Bach ..

152. Many thanks for your attention