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Epigenetic modification impacting brain functions: Effects of physical activity,
micronutrients, caffeine, toxins, and addictive substances
Rahul Mallick, Asim K. Duttaroy
PII: S0197-0186(23)00155-9
DOI: https://doi.org/10.1016/j.neuint.2023.105627
Reference: NCI 105627
To appear in: Neurochemistry International
Received Date: 23 August 2023
Revised Date: 6 October 2023
Accepted Date: 7 October 2023
Please cite this article as: Mallick, R., Duttaroy, A.K., Epigenetic modification impacting brain functions:
Effects of physical activity, micronutrients, caffeine, toxins, and addictive substances, Neurochemistry
International (2023), doi: https://doi.org/10.1016/j.neuint.2023.105627.
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© 2023 Published by Elsevier Ltd.
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Epigenetic modification impacting brain functions: Effects of
physical activity, micronutrients, caffeine, toxins, and addictive
substances.
Rahul Mallick1, and Asim K. Duttaroy2*
1A.I. Virtanen Institute for Molecular Sciences,
University of Eastern Finland, Finland
2 Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine,
University of Oslo, POB 1046 Blindern, Oslo, Norway
*Corresponding Author
Professor Asim K. Duttaroy
Department of Nutrition
Institute of Basic Medical Sciences,
Faculty of Medicine,
University of Oslo
Oslo, Norway
Email: a.k.duttaroy@medisin.uio.no
Tel: +47 22 82 15 47
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Abstract:
Changes in gene expression are involved in many brain functions. Epigenetic processes
modulate gene expression by histone modification and DNA methylation or RNA-mediated
processes, which is important for brain function. Consequently, epigenetic changes are also
a part of brain diseases such as mental illness and addiction. Understanding the role of
different factors on the brain epigenome may help us understand the function of the brain.
This review discussed the effects of caffeine, lipids, addictive substances, physical activity,
and pollutants on the epigenetic changes in the brain and their modulatory effects on brain
function.
Keywords: Epigenetics; DNA methylation; brain; abusive drug; cannabis; caffeine, physical
activity
Abbreviations: CpG: CG dinucleotide; MRI: Magnetic resonance imaging; 5mC: 5-
methylcytosine; 5hmC: 5-hydroxymethylcytosine; PM: particulate matter.
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Introduction
Epigenetics (the Greek word “epi” means over / around) studies chemical processes that
regulate gene expression by modulating DNA or its associated proteins without changing the
underlying DNA sequence. Various enzymes add epigenetic marks to the DNA to signal
specific genes to be active or silent, which drives cell and tissue differentiation. These
epigenetic marks vary from person to person or tissue to tissue and from cell type to cell type
within the tissue. Unlike DNA sequences, epigenetic modification is unique, changeable, and
partially heritable (Wang et al., 2022). DNA methylation, histone modifications, and the
actions of non-coding RNA molecules are epigenetic processes (Figure 1). Epigenetic
regulatory enzymes such as DNA methyltransferases, histone methyltransferases, and
histone deacetylases catalyze these alterations (Han et al., 2019). Changes in the amino acid
sequence of these enzymes have been demonstrated in studies to be closely associated with
various diseases (Han et al., 2019).
The addition of a methyl (-CH3) group to the fifth position carbon in the cytosine carbon ring
(in the context of a CG dinucleotide [CpG site]) to form 5-methylcytosine is defined as DNA
methylation (Youk et al., 2020). 70 – 80 % of CpG sites are methylated in humans (Youk et
al., 2020). Non-CpG methylation also occurs in the mammalian genome, specifically in the
brain (de Mendoza et al., 2021). However, the functional implication of this methylation has
yet to be made clear. Near the gene transcription starting site, CG content is enriched in
specific stretches of DNA known as CpG islands. Most gene promoters are associated with
CpG island (de Mendoza et al., 2021). Transcriptional initiation is inhibited by methylation
of promoter-associated CpG islands (Hughes et al., 2020). DNA methylation directly blocks
the binding of transcription factors to recognition sequences containing CpG sites and gene
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expression (Héberlé and Bardet, 2019). Removal and reestablishment of DNA methylation
occur during gametogenesis and shortly following fertilization (Ivanova et al., 2020). DNA
methylation is carried out by a family of enzymes known as DNA (cytosine-5)-
methyltransferases, which are classified into three types: DNA (cytosine-5)-
methyltransferase 1, DNA (cytosine-5)-methyltransferase 2, and DNA (cytosine-5)-
methyltransferase 3 (Hervouet et al., 2018). DNA (cytosine-5)-methyltransferase 1 enzyme
maintains the methylation process during cell division (Hervouet et al., 2018), while de novo
methylation is maintained by DNA (cytosine-5)-methyltransferase 3a and 3b during early
development (Hervouet et al., 2018). DNA (cytosine-5)-methyltransferase 3l is
predominantly expressed during development to imprint genes and regulate DNA (cytosine-
5)-methyltransferase 3a and 3b (Hervouet et al., 2018). The functions of DNA (cytosine-5)-
methyltransferase 3l are still a mystery (Hervouet et al., 2018).
Histone determines the accessibility of stretched DNA to transcription-regulating molecules.
The tight-bound stretch of DNA to histones reduces the transcription activity. Amino acid
tails of histones can be modified post-transcriptionally to modulate the interactions among
histones, between histones and DNA, or support the recruitment of extra chromatin-
modifying proteins (Zhao and Shilatifard, 2019). Histone modifications and the enzymes that
carry them out can help in chromatin compaction, nucleosome dynamics, and transcription
(Zhao and Shilatifard, 2019). These changes can be made in response to both internal and
external stimuli. Histone acetylation, methylation, phosphorylation, and ubiquitination are
the four most prevalent modifications written by histone acetyltransferases, histone
methyltransferases, protein kinases, and ubiquitin ligases, respectively. Histone deacetylases,
histone demethylases, protein phosphatases, and deubiquitinating enzymes, on the other
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hand, remove histone acetylation, methylation, phosphorylation, and ubiquitination,
respectively (Morgan and Shilatifard, 2020).
Translation-unable RNAs are non-coding RNAs that participate in epigenetic regulation by
recruiting histone- or DNA-modifying enzymes or directly modifying other RNAs or RNA-
protein complexes (Bure et al., 2022).
External factors e.g., physical activity, diet, and drugs, strongly influence epigenome (Galkin
et al., 2023; Toranõ et al., 2016). These modifications can impact any development phase and
modulate disease susceptibility (Galkin et al., 2023; Toranõ et al., 2016). Epigenetics may
influence biological changes, but nurture strongly impacts biological activities and behavior
(Figure 2). Various studies demonstrated the crucial role of histone modifications and non-
coding RNAs in memory formation in the brain and other forms of neuroplasticity (Dias et
al., 2015; Levenson and Sweatt, 2005; Saab and Mansuy, 2014; Sillivan et al., 2015). In addition,
existing variability in DNA methylation can modulate brain activities (Rasmi et al., 2023).
Albeit cell-specific nature of these dynamic epigenetic processes in human brain function
and behavior are quite unknown. Therefore, epigenetic mechanisms will help better
understand unexplained variability in neural phenotypes and precise molecular mechanisms
that may drive the emergence of inter-individual variability in brain activities. The human
genome's epigenetic modification is the subject of this article, focusing on how it links to the
effects of physical activity, micronutrients, caffeine, toxins, and addictive substances, which
addresses critical aspects of human health, genetics, and lifestyle choices. The selection
criteria of the mentioned factors can potentially inform healthcare, public policy, and
personal decision-making, ultimately contributing to improved health outcomes and a deeper
understanding of our genetic and epigenetic makeup.
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Epigenetics and adult brain function
Recent studies have demonstrated that epigenetic processes are vital for brain function. The
impact of epigenetics on imaging genetics embraced the significance of environmental
factors in associations between brain function and sequence variants. Table 1 demonstrates
that psychiatric epigenetic studies targeting methylation within or near a gene's promoter
correlate with diminished gene expression and downstream neural phenotypes. These studies
indicate that DNA methylation patterns are influenced by an individual’s specific
environment, which explains the reason for variability in brain function than DNA sequence-
based variation alone (Liu et al., 2018). However, where and how these methylation patterns
start and how the mapping of methylation patterns in peripheral tissues onto the patterns in
the brain are still burgeoning fields. Despite variation in methylation, epigenetic marks are
partially heritable and modifiable in response to environmental factors (Liu et al., 2018).
Due to having similar DNA sequences in every cell (except in rare cases) of an organism
(Vijg, 2014), derived DNA from peripheral tissues should be similar to DNA in the human
brain. In contrast, epigenetic marks vary between cell types and tissues. Whether methylation
patterns measurable in DNA derived from peripheral tissues vary from methylation patterns
in brain needs to study further. Despite having varied methylation status among tissues, few
studies demonstrated blood-brain correlations in DNA methylation (Nishitani et al., 2023).
The exact mapping of entire brain and peripheral tissues methylomes remains unknown.
Several questions need to figure out to know better the epigenetics of human brain functions.
Are the mechanisms of different methylation processes in the brain and the peripheral tissues
similar or different? How does small-scale inter-individual variability in DNA methylation
affect gene expression, are the other epigenetic marks than DNA methylation correlate
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between brain and peripheral tissue, and do the activities of DNA (cytosine-5)-
methyltransferase 1 through several cell divisions share the similar developmental origin of
cells or reflect experiences in adulthood, determining best proxy peripheral tissue for DNA
methylation in the brain, the correlation between the temporal stability of DNA methylation
markers in the brain and peripheral tissue methylomes demands further studies. Then
epigenetic marks can be used for diagnostic purposes accurately.
Epigenetics and brain memory function and dysfunction
Several enzymes have been found to modulate DNA or histone proteins for proper neuronal
signaling for learning and memory (Park et al., 2022). Epigenetic processes support long-
term memory formation (Feng et al., 2010; Korzus et al., 2004). Cognitive impairments can
be reversed by drugs acting on defective epigenetic components (Gräff et al., 2010; Koshibu
et al., 2011, 2009). Thus, it’s clear that epigenetic processes can modulate memory
performance. Epigenetic therapies could be potential therapeutic strategies for memory and
cognitive function disorders (Franklin and Mansuy, 2010; Gräff and Mansuy, 2009, 2008;
Urdinguio et al., 2009). For example, histone deacetylase inhibitors (histone-modifying
enzymes) could be beneficial in treating memory impairment, age-related cognitive decline,
Alzheimer’s disease, etc. (Peleg et al., 2010).
Epigenetics and brain development
As epigenetic modulations are the basis for cellular development, impetuous changes of the
nervous system during prenatal and postnatal development are influenced by environmental
conditions. Thus, innate genetic programming and sensory experiences maintain the
functional neuronal circuits and brain development. Environmental influence impacts natural
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variability in the quality and quantity of interactions between mother-infant, which modulates
the infant’s response to living conditions later in life and can influence their response to stress
and aversive conditions (Table 2). Changes in these responses have been found to be
correlated to the development of anxiety and depression (Beery and Francis, 2011). In addition,
variability in maternal care stabilizes epigenetic modifications that remain beyond the period
of maternal care (Weaver et al., 2004). Severe chronic stress during early life alters a mother's
behavior in adulthood and ultimately influences children's behavior across generations.
Depression, impulsive behavior, and altered social skills are common in adults who
experienced separation from their mothers in childhood (Franklin et al., 2010; Weiss et al.,
2011). Significant brain epigenetic profile alteration (results in changes in the methylation
profile of stress-related genes) occurs in those who experience childhood abuse and commit
suicide later in life (McGowan et al., 2009). Experiences during adulthood also modulate
epigenome, even in the case of (monozygotic) twins (Fraga et al., 2005). These behavioral
changes have been found to be correlated with the alteration of epigenetic processes,
specifically in DNA methylation in various genes in the brains, which demonstrates that early
stress modulates epigenome in various cells and tissues that transmit on subsequent
generations. Epigenetic divergence, known as epigenetic drift, can happen with or without
environmental influence.
Epigenetic factors impacting brain and behavior.
1) Physical activity
Physical activity modulates brain plasticity and functions by releasing factors from
contracting muscles in children and adults into circulation (Biddle and Asare, 2011; Hillman et
al., 2008; Lees and Hopkins, 2013; Ma et al., 2017; Niederer et al., 2011; Rodriguez-Ayllon et al.,
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2019; Schmidt-Kassow et al., 2014; Suwabe et al., 2017; van Praag, 2009). Regular aerobic exercise
reduces the DNA methylation of various genes (Barrès et al., 2012; King-Himmelreich et al.,
2016; Ling and Rönn, 2014; McGee et al., 2009). Studies suggested that brain capillaries regulate
positive effects on mental health and abilities in neurogenic niches that supply growth factors
(e.g., VEGF, GDF11, BDNF) to activate cellular survival pathways to induce gene
transcription responsible for neuroplasticity (Chen and Russo-Neustadt, 2009; Niederer et al.,
2011). For instance, Exercise influences BDNF chromatin regulation, DNA demethylation of
the BDNF promoter IV, and phosphorylation of MeCP2 to stimulate BDNF mRNA and
protein synthesis (Gomez-Pinilla et al., 2011). Different neurotransmitters (e.g. GABA,
glutamate, serotonin) are also secreted by neurons in the neurogenic niche (Niederer et al.,
2011). Studies found strong links among physical activity, brain health, and epigenetic
mechanisms that affect neurogenesis, brain plasticity, and function (Christiansen et al., 2016;
Fernandes et al., 2017; Horvath et al., 2015; Hunter et al., 2019; Lista and Sorrentino, 2010; Schenk
et al., 2019; van Praag, 2008; van Praag et al., 1999; Woelfel et al., 2018). It’s clear now that
inactivity is epigenetically deleterious.
2) Abusive substances
Despite adverse consequences, compulsive seeking and taking of abusive substances (e.g.
psychostimulants, opiates) is termed drug addiction (Koob and Volkow, 2016). Epigenetic
modulation plays a crucial role in the vulnerability of drug addiction. All abused or chronic
use of drugs act on mesolimbic dopamine circuitry in the fundamental cell type within the
nucleus accumbens as well as midbrain ventral tegmental area and innervation of medium
spiny neurons to induce long-lasting structural, electrophysiological, and transcriptional
changes via epigenetic maladaptations (Feng et al., 2014; Hyman et al., 2006; Kelley and Berridge,
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2002). Hyperacetylation of histones (H3 and H4) in nucleus accumbens due to an imbalance
between histone acetyltransferases (e.g. cAMP response element binding protein-binding
protein) and histone deacetylases due to acute or chronic exposure to abusive drugs facilitates
rapid expression of associated genes at the specific locus to contribute to addiction (Barrett
and Wood, 2008; Botia et al., 2012; Ferguson et al., 2015, 2013; Kumar et al., 2005; Levine et al.,
2011; Malvaez et al., 2011; Pandey et al., 2008; Renthal et al., 2009, 2007; Schroeder et al., 2008;
Shen et al., 2008; Shogren-Knaak et al., 2006; Taniguchi et al., 2012). Further research demands to
know the consequences of gene-specific histone-post translational modifications within the
context of drug addiction. Alcohol addiction has been found to modulate epigenetically.
Excessive alcohol drinking not only affects individuals but also affects their offspring
throughout various stages of their development. Excessive alcohol exposure during
pregnancy leads to fetal alcohol spectrum disorder and induces various epigenetic changes
(Resendiz et al., 2013; Ungerer et al., 2012). Excessive alcohol exposure during pregnancy
induces DNA methylation at 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC)
during embryonic and brain development (Chen et al., 2013; Guo et al., 2011; Ito et al., 2011;
Kriaucionis and Heintz, 2009; Liu et al., 2009; Tahiliani et al., 2009; Zhou et al., 2011a). Alcoholism
also raises histone 3 acetylation globally and changes miRNA expression in neural stem cells
in a cell-type and stage-specific manner (Kim and Shukla, 2006; Miranda, 2012; Pal-Bhadra et al.,
2007; Shukla et al., 2007; Wang et al., 2009). Opium, an old analgesic medication, causes severe
effects on the offspring's nervous system by increased methylation at the OPRM1 promoter
region (Chorbov et al., 2011; Das et al., 2004). Prenatal exposure to methamphetamine,
another known abusive drug, led to oxidative stress in the embryonic brain and postnatal
neurodevelopment and cognitive and behavioral defects (Jeng et al., 2005; Kwiatkowski et
al., 2014). Prenatal methamphetamine exposure results in differentially methylated regions
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in the hippocampal DNA of adolescent offspring and leads to abnormal behavior (Itzhak et
al., 2015). The hypermethylated and hypomethylated differential methylated regions are
enriched for “cerebral cortex GABAergic interneuron differentiation” and “embryonic
development.”
3) Cannabis
Chronic cannabinoid exposure maintains protracted effects. The epigenome provides the
cellular context for cannabinoid exposure to modulate the functionality of genes and related
behavior (Szutorisz et al., 2016; Szutorisz and Hurd, 2018, 2016). Epigenetics contribute to
regulating the endocannabinoid system, which is critical in controlling different synaptic
communication and plasticity in healthy brain and different neuropsychiatric disorders over
short and long period (Batool et al., 2019; Bayraktar and Kreutz, 2018; D’Addario et al., 2013;
Dambacher et al., 2013; Dillon, 2012; Meccariello et al., 2020; Weaver, 2014). Table 3
demonstrates the epigenetic mechanisms of developmental cannabis exposure. These studies
suggest that cannabis exposure during multiple stages of development modulates epigenetic
mechanisms to change neural and behavioral phenotypes. Cannabis acts through the germ
line to modulate synaptic development and behavior across generations (Szutorisz et al.,
2014; Watson et al., 2015).
4) Micronutrients:
Research focusing on dietary impact on gene expression via epigenetic mechanisms on brain
development and neuropsychiatric diseases/disorders is evolving (Canani et al., 2011; Levi and
Sanderson, 2004; Prado and Dewey, 2014; Roseboom et al., 2006). Studies found that
neuropsychiatric diseases during adulthood were linked with prenatal exposure to inadequate
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nutrition (Roseboom et al., 2006; St Clair et al., 2005; Susser et al., 1996; Susser and Lin, 1992).
Early malnutrition induces lasting epigenetic changes in the brain, leading to behavioral
consequences and diseases/disorders in later life (Canani et al., 2011; Kundakovic and Jaric,
2017). For instance, studies found an association between maternal iron deficiency and the
risk of autism spectrum disorders among offspring due to epigenetic modulation (Insel et al.,
2008; Schmidt et al., 2014). The effects of folic acid on epigenetics through the methionine
pathway to generate methyl donors for DNA and histone methylation might support fetal
neural tube development (Akchiche et al., 2012; Berry et al., 1999; Guéant et al., 2013; “Use
of Folic Acid for Prevention of Spina Bifida and Other Neural Tube Defects—1983-1991,”
1991). N-3 polyunsaturated fatty acids (PUFAs) are also known to control DNA methylation
state globally and via gene-specific methylation of promoter sequences during development
(Heberden and Maximin, 2019). Higher intake of n-3 PUFAs during pregnancy supports fetal
brain development (Basak and Duttaroy, 2022). Despite some studies on epigenetic changes in
neurodevelopmental-related genes (Kundakovic et al., 2013; Toledo-Rodriguez et al., 2010),
there is no established epigenetic mechanism for how the environment does have
confounding effects on neurodevelopment disorders. Therefore, more studies need to be done
to deepen the knowledge about the relationship between nutrition, epigenetics, and
neurodevelopment.
5) Caffeine
As an adenosine receptor blocker, caffeine is a widely used stimulant worldwide. Caffeine
accumulation aggravates stress response (Yeomans et al., 2007). Chronic caffeine ingestion
activates the maternal and placental renin–angiotensin system (RAS) and induces p53-
dependent placental apoptosis, which leads to fetal intrauterine growth retardation (Huang et
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al., 2012). Soellner and colleagues have demonstrated that chronic prenatal caffeine exposure
interrupts novel object recognition and radial arm maze behaviors in adult rats (Soellner et
al., 2009). Caffeine exposure during pregnancy inhibits the development and function of the
fetal hypothalamic-pituitary-adrenal axis-associated neuroendocrine metabolism (Liu et al.,
2012; Xia et al., 2014; D. Xu et al., 2012b, 2012a; Xu et al., 2011). Prenatal caffeine exposure
inhibits fetal adrenal steroidogenesis by blocking the enzymes (StAR/P450scc, 3β-HSD,
P450c21, and P450c11) due to altered epigenetic modifications (DNA methylation and
histone acetylation) of the promoter region for the transcriptional activator SF-1 (Yan et al.,
2014). However, further studies might clarify the role of epigenetic modification by caffeine.
6) Pollutants
Different types of pollution are increasing daily due to industrialization, which is contributing
to causing various diseases or disorders. For example, tobacco smoking is the most common
pollutant that modulates early neurobehavioral development. Prenatal smoking increases
children's risk of attention deficit hyperactivity disorder due to DAT1, DRD4, and CHRNA4
gene variations (Becker et al., 2008; Kahn et al., 2003; Todd and Neuman, 2007). The epigenetic
effects transmitted intergenerationally due to smoking predict family dysfunction and poor
health (Miles and Weden, 2012; Seeman et al., 2010; Taylor et al., 2006). However, the necessity
of a better understanding of underlying microprocesses doesn’t preclude policies, sanctions,
and universal public health campaigns against childhood exposure to tobacco smoke in
domestic settings.
Traffic-related air pollution is also a significant source of air pollution in urban areas,
particularly for particulate matters (PMs) [according to size, categorized as "coarse" (PM10),
"fine" (PM2.5) μm, and "ultrafine" (PM0.1), having an aerodynamic diameter less than 10 μm,
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less than 2.5 μm and less than 0.1 μm, respectively], which is composed of gases like nitrogen
oxides (e.g., NO2, NOx) and sulfur dioxide (SO2) as well as black carbon, absorbed metals,
and polyaromatic hydrocarbons of various size fractions (Johnson et al., 2021; Rider and
Carlsten, 2019). Traffic-related air pollution modulates brain development and function
through DNA methylation (Rider and Carlsten, 2019). Studies found that prenatal exposure
to PM2.5 results in thinning of the cortex in many regions of the brain and impaired inhibitory
control, which is related to neurobehavioral dysfunctions such as addictive behavior and
attention deficit hyperactivity disorder due to altered DNA methylation, including global
hypomethylation, gene-specific changes in methylation process as well as downregulated
expresión of miR-21, miR-146a, and miR-222 (Johnson et al., 2021).
Lead toxicity is also quite common. Lead exposure is commonly caused by food, water,
tobacco smoke, air, dust, and soil. The fetus can be exposed via placental transfer (“Scientific
Opinion on Lead in Food,” 2010; World Health Organization, 2010). Surprisingly,
bioavailable lead is absorbed better in infants than adults and developmental neurotoxicity is
a significant health effect of lead exposure (“Scientific Opinion on Lead in Food,” 2010; Tarragó
and Brown, 2017). Lead can interrupt epigenetic modulation (Khalid and Abdollahi, 2019). In
newborns, prenatal lead exposure results in genomic DNA methylation (CLEC11A, DNHD1,
LINE1) (Pilsner et al., 2009; Wu et al., 2017). Epigenetic modulations, including DNA
methylation, influence BDNF expression across tissues, including the brain and blood
(Ikegame et al., 2013; Kundakovic et al., 2015; Stenz et al., 2015). Therefore, BDNF can be
used as a peripheral biomarker of psychiatric disorders (Kundakovic et al., 2015; Stenz et al.,
2015). However, further research might explain lead exposure-mediated psychiatric diseases.
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Another known pollutant is bisphenol A. Due to industrialization, the endocrine-disrupting
chemical bisphenol A induces neurotoxicity through ingesting contaminated foods and drinks
or inhalation (Chianese et al., 2017). Bisphenol A interrupts androgenic activities via binding
with steroid receptors, e.g., estrogen receptor α, estrogen receptor β, estrogen-related
receptor γ, androgen receptor, GPER30, etc (Chianese et al., 2017; Murata and Kang, 2018;
Tavares et al., 2016; Vandenberg et al., 2013). Bisphenol A and its analogs change methylation
of CpG islands in the promoter regions of specific genes or the genome-wide methylation in
fetal and adult brain through DNA methyltransferases modulation, while is transmitted across
the generations (Doshi et al., 2011; Drobná et al., 2018; Wolstenholme et al., 2011; Yaoi et
al., 2008). Bisphenol A and its analogs modulate histone methylation and acetylation to affect
chromatin remodeling by NAD+-dependent deacetylase sirtuin 1 (Chen et al., 2017; Doherty
et al., 2010; Eichenlaub-Ritter and Pacchierotti, 2015; Viré et al., 2006). Even Bisphenol A
mediated post-transcriptional modification of other RNA species by non-coding RNAs (e.g.,
microRNA, long non-coding RNA, circRNA) affects brain physiology in health and disease
(Godlewski et al., 2019; Leighton and Bredy, 2018; Noack and Calegari, 2018; Sekar and Liang, 2019;
Shi et al., 2017). Bisphenol A-induced impaired hippocampal neurogenesis correlates with
upregulated DNA methylation of the CREB-regulated transcription coactivator 1 (Jang et al.,
2012). Bisphenol A also increases histone H3 acetylation in the cerebral cortex and
hippocampus to promote memory and cognitive dysfunction (Bale, 2015; Keverne, 2014; Kumar
and Thakur, 2017). Not only gestating mothers but also paternal exposure to bisphenol A
influences fetus development [as spermatozoa use non-coding RNAs to carry paternal
hereditary information] (Dobrzyńska et al., 2015; Guerrero-Bosagna et al., 2013; Kuruto-
Niwa et al., 2007; Mendonca et al., 2014). Bisphenol A exposure causes sex-specific, dose-
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dependent (linear and curvilinear), and brain region-specific changes in the expression of
epigenetic regulators (DNMT1 and DNMT3A) as well as genes encoding estrogen receptors
and estrogen-related receptor-γ (Kundakovic et al., 2013). Bisphenol A increases DNA
methylation levels in the promoter region of the GRIN2B gene (Alavian-Ghavanini et al.,
2018). Bisphenol A has been shown to induce hypermethylation of the 5-prime end promoter
region of the BDNF gene in female offspring but enhances DNA methylation of the
transcriptional regulators of the glucocorticoid receptors FKBP5 was found within the
hippocampus of male rats to influence spatial learning and memory capabilities (Alavian-
Ghavanini et al., 2018; Cheong et al., 2018; Kitraki et al., 2015). Interestingly, bisphenol A
exposure in the fetal stage did not significantly affect hippocampal DNA methylation (Aiba
et al., 2018). Overall, bisphenol A induces behavior-related and sex-specific epigenetic
modifications predominantly targeting the expression pattern of sexually dimorphic genes.
However, further studies are needed to determine the exact dose range and exposure time
during development by which bisphenol A can induce epigenetic modifications.
7) Hypoxia
Maternal and fetal hypoxia in pregnancy disorders influences normal fetal development and
pathological processes (Pouyssegur and López-Barneo, 2016). Various reviews accredit
maternal-fetal hypoxia affects organogenesis and brain functions (Faa et al., 2016; Newby et
al., 2015; Schlotz and Phillips, 2009). Abnormal levels of fetal hypoxia provoke epigenetic
modulation that modifies target gene expression (Cerda and Weitzman, 1997; Luo et al., 2006).
However, more mechanistic studies are necessary to study hypoxia-mediated direct and
indirect effects on fetal development, gene expression, epigenetic changes in specific genes,
and consequences later in life.
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Conclusions
This thorough review sheds light on the complex interplay between epigenetic modifications
and their substantial impact on brain functions. The critical impacts of the micronutrients,
physical activity, caffeine, toxins, and harmful substances in the brain's epigenetic landscape
are now evident. The intricate links between epigenetic changes and behavioral outcomes
emphasize the possibility of targeted therapies that could harness the power of epigenetic
control to improve cognitive function and attenuate the detrimental consequences of
substance addiction and environmental pollutants. Despite strong evidence of the different
roles of epigenetic alterations in gene expression and phenotypic outcomes, translating the
findings from animal studies to the health effects of environmental exposure to humans needs
to be improvised. To untangle the intricacies of epigenetic modifications and their long-term
impact, there is still a need for interdisciplinary collaboration, advanced technical
breakthroughs, and longitudinal investigations.
Declarations
Funding: No funding was available
Conflicts of interest/Competing interests: Authors express no conflicts of interest
Authors Contributions: Conceptualisation RM writing—original draft preparation, RM
review and editing, RM and A.D.R. Both authors have read and agreed to the published
version of the manuscript.
Ethics approval: Not applicable
Availability of data and material (data transparency): Not Applicable
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Figures Legend
Figure 1: Epigenetic processes
Most common epigenetic processes: (1) DNA methylation, which inhibits the transcription
process (2) Histone modification, such as methylation and acetylation (histone acetylation
results in relaxation of the chromatin and ultimately greater transcription) (3) non-coding
RNAs block transcription and/or translation process.
Figure 2: Influence on brain development and functions by aversive environmental
exposure
The continuous increment of different types of environmental factors influences epigenetic
marks, including DNA methylation (5mC, 5hmC) and histone modification (H3ac, H3K4me,
etc.) to affect synaptogenesis and neurogenesis together affect the brain function and
neuropsychiatric disease at a given time of the life.
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Table 1: Summary of imaging epigenetics study
Methods
Year
Gene
Findings
Structural
magnetic
resonance
imaging (MRI)
2013
FKBP5
Upregulated FKBP5 methylation reduces volume of the
right hippocampal head (Klengel et al., 2013).
2014
BDNF
Upregulated BDNF promoter methylation reduces white
matter integrity in patients with major depressive
disorder (Choi et al., 2015).
SLC6A4
Increased methylation in a functional element of the
SLC6A4 promoter upregulates hippocampal volume
(Dannlowski et al., 2014).
2015
SLC6A4
Increased SLC6A4 methylation was associated with
childhood trauma and decreased hippocampal volume
(Booij et al., 2015).
Functional MRI
2011
COMT
Reduced methylation of the Val158 COMT allele
diminishes cortical efficiency in a working memory task,
particularly in the context of stress (Ursini et al., 2011).
2012
OXTR
Raised methylation of the OXTR gene promoter increases
the activity in the temporal-parietal junction and dorsal
anterior cingulate cortex during a social perception task
(Jack et al., 2012).
2014
SLC6A4
Increased SLC6A4 promoter methylation increases
amygdala reactivity to threatening faces (Nikolova et al.,
2014).
COMT
Increased COMT promoter methylation upregulates left
dorsolateral prefrontal cortex activity during a working-
memory task across patients with schizophrenia and
controls (Walton et al., 2014).
NR3C1
Increased NR3C1 promoter methylation upregulates the
activity in the right ventrolateral prefrontal cortex and
cuneus, as well as reduced performance, in a memory
task in healthy men (Vukojevic et al., 2014).
2015
SLC6A4
SLC6A4 methylation modulates the activity differently in
the insula, operculum, hippocampus and amygdala in an
emotional attention-shifting task (Frodl et al., 2015).
OXTR
Upregulated methylation of the OXTR gene promoter
increases the activity in the amygdala, insula and
fusiform gyrus, as well as decreases the amygdala
connectivity with regulatory regions during threatening
face processing (Puglia et al., 2015).
Decreased OXTR methylation upregulates amygdala
activity during social-phobia related word processing in
individuals with social anxiety disorder (Ziegler et al.,
2015).
Positron emission
tomography
2012
SLC6A4
Increased SLC6A4 promoter methylation reduces 5-HT
synthesis in the orbitofrontal cortex (Wang et al., 2012).
MAOA
Increased methylation near the MAOA promoter was
associated with lower MAOA activity in healthy men
(Shumay et al., 2012).
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Table 2: Studies on prenatal exposure to environmental agents related with epigenetics changes
Agents
Histone
modification
DNA
methylation
miRNAs
Outcomes
Alcohol
H3Kac,
H3K4me,
H3K9me,
H3K27me (Pal-
Bhadra et al.,
2007; Shukla et
al., 2007;
Subbanna et al.,
2013)
5mC, 5hmC
(Chen et al.,
2013; Garro et
al., 1991; Otero
et al., 2012;
Ouko et al.,
2009; Wolff et
al., 1998)
miR148,
miR152,
miR21,
miR153,
miR335
(Kutay et al.,
2012;
Sathyan et al.,
2007)
• Delayed
formation in
the neural
tube,
forebrain,
hindbrain
(Zhou et al.,
2011b)
• Delayed
maturation
and
diminished
size of
hippocampus
(Chen et al.,
2013)
• Declined
neuron cell
number,
cortical plate,
thickness
(Zhou et al.,
2011b)
Arsenic
H3ac (Cronican
et al., 2013)
5mC
(Intarasunanont
et al., 2012; Kile
et al., 2012; Xie
et al., 2007)
let 7a, miR16,
miR17,
miR20a,
miR20b,
miR26b,
miR96,
miR98,
miR107,
miR126,
miR195, and
miR-454
(Rager et al.,
2014)
Interrupted
spatial and
episodic memory,
as well as fear
conditioning
performance
(Cronican et al.,
2013)
Bisphenol A
H3ac (Yaoi et
al., 2008)
5mC (Yaoi et al.,
2008)
N/A
Delay the
perinatal chloride
shift in cortical
neurons (Yeo et
al., 2013)
Caffeine
N/A
5mC
(Buscariollo et
al., 2014; Dan
Xu et al., 2012)
N/A
Growth
retardation (Dan
Xu et al., 2012)
Cannabis
H3K4me,
H3K9me
(Dinieri et al.,
2011)
N/A
N/A
Upregulated
opiate reward
sensitivity in adult
(Dinieri et al.,
2011)
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Cadmium
N/A
5mC (Castillo et
al., 2012;
Kippler et al.,
2013; Sanders et
al., 2014)
N/A
Decreased birth
weight and height
(Castillo et al.,
2012)
Folic acid
deficiency
H3ac (Akchiche
et al., 2012)
5mC (Guéant et
al., 2013)
miR124,
miR302a
(Kerek et al.,
2013; Liang
et al., 2012)
Brain size
reduction, growth
retardation (Kerek
et al., 2013)
Lead
H3ac, H3K4me
(Bihaqi et al.,
2011)
5mC (Bihaqi et
al., 2011;
Schneider et al.,
2013)
N/A
Increased
neurodegeneration
in primate (Bihaqi
et al., 2011)
Methyl mercury
H3ac, H3K27me
(Onishchenko et
al., 2008)
5mC (Bose et
al., 2012;
Onishchenko et
al., 2008)
N/A
Depression like
behaviour
(Onishchenko et
al., 2008)
Methamphetamine
N/A
5mC (Itzhak et
al., 2015)
N/A
Increased cocaine
reward and hyper-
locomotion as well
as diminished
conditional fear
(Itzhak et al.,
2015)
Nicotine
H3ac (Levine et
al., 2011)
5mC (Breton et
al., 2009;
Maccani et al.,
2013; Suter et
al., 2011, 2010)
miR16,
miR21,
miR146a
(Maccani et
al., 2010)
• Increased
aggression,
locomotion in
adult male
(Yochum et
al., 2014)
• Birth weight
reduction
(Suter et al.,
2011)
Opioid
N/A
5mC (Chorbov
et al., 2011)
N/A
N/A
Stress
H3ac, H3K9me,
H3K27me
(Dalton et al.,
2014; Réus et
al., 2013)
5mC
(Champagne
and Curley,
2009;
Darnaudéry and
Maccari, 2008;
Heim and
Binder, 2012;
Szyf, 2013)
miR16, miR9,
miR29a,
miR124,
miR132,
miR212 (Bai
et al., 2012;
Uchida et al.,
2011)
Induces
depressive-like
behaviors, altered
response to
aversive
environments
(Champagne and
Curley, 2009;
Franklin et al.,
2010)
Valproic acid
H3ac (Balmer et
al., 2012; Monti
et al., 2010)
N/A
N/A
Diminished birth
rate, reduced
sociability, and
social preference
(Kim et al., 2011)
γ-hydroxybutyrate
H3ac (Klein et
al., 2009)
N/A
N/A
N/A
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Table 3: Studies on cannabinoid exposure related with epigenetics dysregulation
Cannabinoid types
Epigenetic
modifications
Exposure
period and
models
Studied brain region and effects
Δ9-
tetrahydrocannabinol
H3K4me2,
H3K9me3
Promoter, gene
body
Prenatal
male rats
↓ Drd2 mRNA levels in nucleus
accumbens of adult brain (Dinieri et
al., 2011)
Adolescent
male rats
↑ Penk mRNA levels in nucleus
accumbens shell of adult brain
(Tomasiewicz et al., 2012)
Global H3K9me3
levels,
promoters
Adolescent
female rats
↓ mRNA expression of genes
related to endocannabinoid system
and synaptic plasticity in prefrontal
cortex of adult brain (Cuccurazzu et
al., 2018)
H3K4me2,
H3K9me3,
Global H3K14ac
levels
Adolescent
and adult
female rats
Brain region-specific and age-
specific alterations of histone
modifications at different times
after exposure in hippocampus,
nucleus accumbens and amygdala
of adolescent and adult brains (Prini
et al., 2017)
CpG DNA
methylation at
promoters,
intergenic
regions,
especially in
gene bodies
Adolescent
female and
male rats
Altered methylation at loci
implicated in synaptic plasticity,
including the Dlg4 gene network of
nucleus accumbens in adult brains
(Watson et al., 2015)
DNA
methylation at
promoter
Adult male
rats
↓ DNA methylation of synaptic
Dlgap2 in nucleus accumbens of
adult brains (Watson et al., 2015)
WIN-55,212–2
cannabinoid agonist
Intragenic DNA
methylation
Adolescent
male mice
↑ DNA methylation and ↓ mRNA
expression of Rgs7 in hippocampus
of adult brains (Tomas-Roig et al.,
2017)
Chromatin
accessibility
(ATAC-seq) at
promoter, gene
body
↑ Accessibility at Npas2 and
splicing at prefrontal cortex of adult
brain (Scherma et al., 2020).
Global DNA
methylation
levels
↑ DNA methylation and ↑ DNMT
expression at prefrontal cortex of
adult brain (Ibn Lahmar Andaloussi
et al., 2019).
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HU-210 cannabinoid
agonist
microRNAs
Adolescent
male mice
Expression of various microRNAs
altered at entorhinal cortex of
adolescent male rat (Hollins et al.,
2014)
.
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Figure-1
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Figure-2
’
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Highlights
A complex interplay between epigenetic modifications and their substantial impact on brain
functions.
Micronutrients, caffeine, toxins, and harmful substances affect the brain's epigenetic
landscape.
The intricate links between epigenetic changes and behavioral outcomes emphasize the
possibility of targeted therapies in brain disorders
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Conflicts of interest/Competing interests: Authors express no conflicts of interest
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