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The Impact of Nutrition & Environmental Epigenetics on Human Health & Diseases

Presentation By:

Anisa Binti Salleh [1710522]

Siti Balqis Binti Adnan [1716878]

Rosmanajihah Binti Mat Lazim [1717620]

Nurul Jasmeen Binti Baseer Ahmad [1710954]

Sahira Syamimi Binti Ahmad Zawawi [1710146]

Introduction

Introduction

Definition:

The control of gene expression without changes in DNA coding sequences

Epigenetics

histone post-translational modifications

histone acetylation

Various epigenetic marks

DNA methylation

non-coding RNA (eg: microRNA)

Affects epigenetic changes

Environmental factors

Lifestyle (behaviour, nutrition, toxins)

Environmental Epigenetics

Cancer

Cancer

Many evidences suggest have epigenetic origins

Nutritional Epigenetics

The Future

Nutritional Epigenetics

Nutritional Epigenetics in Health & Disease

Nutritional Epigenetics & Cancer

Nutritional Epigenetics: The Future

Histone modification, and chromatin remodeling

Previous diet-deficient status

  • Reversibly alter the DNA methylation pattern,

has contributed to;

Nutritional Epigenetics: The Future

a personalized nutrition intervention

  • Further alter gene expression
  • Induce long – term changes and in general expression

Nutritional Epigenetic in Health & Disease

Permanent hypomethylation of part of genome

Decreased DNA methylation but reversible

Folate or choline consume before or after birth

Methyl-deficient diet

Diets high in methyl-donating nutrients

Nutritional Epigenetic in Health & Disease

Effects of starvation during pregnancy

Molecular mechanism: methylation of gametes via paternal and maternal lineage, futger transmission in paternal lineage lead to modulation of spermatozoa nucleus

Transgenerational effects of poor maternal diet

Nutrition: one of the epigenetic factors

Increase risk of type 2 diabetes mellitus, cardiovascular disease, metabolic disorder, decreased cognitive function in later life

E.g. : the Dutch Famine Birth Cohort

Experience health complication

The grandchildren of the women exposed to famine or other dietary alterations during pregnancy

Dietary Factors

Nutritional Epigenetics & Cancer

1. Folic acid and Vitamin B12

  • DNA metabolism and DNA methylation
  • Folate is positively correlated with p16 tumor suppressor gene
  • Low folate intake has been linked to hypomethylation and increased risk of colorectal and pancreatic cancers

2. Antioxidants

  • Fruits and vegetables
  • Reductions in DNA hypermethylation of critical genes
  • Tumor suppression
  • Eg. Green tea (polyphenols)

Epigenetic roles against cancer

Dietary components with protective effects against cancer

Trangenerational effects

Western diet vs Mediterranean diet

  • Diet affects the epigenome to modify individual and transgenerational phenotypes.
  • Parental diet may affect their offspring's epigenetic modification

1. Western diet

Individual effect: ‘obese phenotypes’, fatty liver disease, cancer, immune disorder

Transgenerational effect: ‘disease phenotype’, cancer, growth abnormalities, increase risk of metabolic disorders, type ii diabetes

2. Mediterranean diet

Individual effect: ‘lean phenotype’, low disease risk, delayed aging

Transgenerational effect: ‘normal phenotype’, reduced risk of disease

Chemical Environmental Epigenetics

Chemical Environmental Epigenetics

Other Toxin Exposures & Epigenetic Effects

Other Toxin Exposures & Epigenetic Effects

Effects

Cause epigenetic modifications in buccal musocal cells

!

Effect 1

Prenatal maternal smoking

Maternal cigarette smoking during pregnancy can affect the infants:

!

  • Health
  • Neurodevelopment
  • Behaviour
  • Cognitive functions

Effect 2

Maternal tobacco smoking during pregnancy will mainly induce:

!

  • Respiratory diseases associated with immune system (asthma, allergies)
  • Cancers

Effect 3

Effects

Risk factors for various cancers (breast,liver,colorectal). Effects are dose-dependent

!

Effects 1

Alcohol

Deleterious/hazardous effects to growth, metabolism, and neural development

!

Effects 2

Impair particular memory & learning process, malformations & abnormal foetal development

!

Effects 3

Endocrine disrupting-chemicals

Exogenous agents of environmental chemicals that mimic natural hormones by interfering the hormone signaling pathway

Global effects (DNMT expression)

Endocrine-disrupting chemicals (EDCs)

Gene-specific targeting action

Regulation of other ncRNA expression (i.e. miRNA)

EDC Exposure Induce Abnormal Development, Behaviour & Disease

EDC Exposure Induce Abnormal Development, Behaviour & Disease

Environmental Epigenetics

Prenatal EDCs Exposures

EDCs

Hormonal Imbalance

Environmental Epigenetics

Several disorders related to interfering hormone signaling

Tumor

Succession of generations

BPA-doses deficient in prenatal (Very Low)

impaired semen quality, and the timing of puberty

Prenatal EDCs Exposures

Sexual

Development

Effects on hormone expression- thyroid

Behaviour

Hyperactive disorder

EDCs, Epigenetics and Cancer

EDCs, Epigenetics and Cancer

Introduction

It can also be heritable

Humans are exposed to EDC daily

Exposure of endocrine disruptors (EDC) can lead to cancer development

In utero toxin exposure- trigger childhood cancers (e.g.: brain tumours & haematological malignancies

Introduction

Environmental antiandrogens- lead to increase in risk of gynecomastia in adult males

EDC affects the epigenetic landscape. DNA methylation/ histidine methylation patterns are changed → affects global gene expression profiles and transcriptomes

Exposure of endocrine disruptors (EDC) can lead to cancer development

The effects of EDC vary based on different doses, different ages, and different target tissues

Increased incidence of testicular and prostate cancers in Europe and American population over the last 50 years

Prenatal Diethylstilbestrol (DES) Exposure

Can lead to uterine tumour, genital tract abnormalities among adults

Associated with a rare neoplasm; clear cell adenocarcinoma of the vagina

Second generation (F2) of DES having developmental abnormalities in males (e.g.: hypospadias and tumorigenesis)

Prenatal Diethylstilbestrol (DES) Exposure

Males with mothers exposed to DES during pregnancy:

Females with mothers exposed to DES during pregnancy:

  • Elevate natural oestrogen
  • Increase risk of breast cancer
  • Feminisation
  • Obesity
  • Infertility
  • Developmental malformations of genital tract

Genistein Exposure

  • Alters mammary gland structures
  • Increases risk of breast cancer

Environmental Dioxins Exposure

Genistein Exposure &

Environmental Dioxins Exposure

A developmental and reproductive toxin

In Utero Polycyclic Aromatic Hydrocarbons (PAHs) Exposure

1

Lowered immune functions

2

Increased risk of cancers

In Utero Polycyclic Aromatic Hydrocarbons (PAHs) Exposure

3

Poor neuro development

4

Poor foetal growth

5

Can cause immunotoxicity, dermal toxicity, endocrine toxicity, hepatic toxicity, and a few types of cancers such as lung, soft-tissue carcinoma, and haematological cancers

Environmental Epigenetics and Cancer: Breast Cancer as a Specific Example

Environmental Epigenetics and Cancer: Breast Cancer as a Specific Example

Methoxychlor (MXC) and Triclosan (TCS) Exposure

Methoxychlor (MXC) and Triclosan (TCS) Exposure

May contribute to ovarian cancer development through upregulation of cyclin D1 and downregulation of p21

Dioxin Prenatal Exposure (oestrogen-mimetic)

Delayed mammary gland proliferation and differentiation during puberty, later maximisation of sensitisation towards carcinogenic substances

Dioxin Prenatal Exposure (oestrogen-mimetic)

Delayed breast development in females

In Utero Atrazine (ATR) Exposure (oestrogen mimetic)

In Utero Atrazine (ATR) Exposure (oestrogen mimetic)

Will cause delayed early mammary gland development in female offspring and prolonged sensitivity to carcinogens

Epigenetic alterations in postnatal & adult mammary gland

Histological alterations of intraductal hyperplasia

05

04

Increased levels of histone H3K4me; an epigenetic biomarker

06

Global changes in mRNA expression profiles at sexual maturity

03

07

Ductal carcinoma in situ (DCIS)

02

Alterations of gene expression

08

DNA methylation status alterations & chromatin remodelling

BPA Exposure

Increased risk of mammary carcinogenics

09

Pre-neoplastic lesions such as intraductal hyperplasia and neoplastic lesions

BPA is oestrogen-mimetic

BPA exposure can cause alteration in both male & female mammary gland morphogenesis and later may lead to breast cancer

Vinclozolin Exposure

Vinclozolin Exposure

Alters structure of mammary gland

Increases risk of breast cancer

Induces male germline epigenome reprogramming --> produces defective sperms --> forms tissues that are differentially damaged epigenomes and transcriptomes --> changes the phenotypes --> causes development of adult-onset diseases in the next generations

Conclusions

Conclusion

The correlation between exposure to oestrogens, phytoestrogens, and high fat diets and breast cancer susceptibility is significant

The Potential of Epigenetics Drugs

  • Histone deacetylase (HDAC)
  • Histone deacetylase (HDAC) inhibitors
  • Current Research

The Potential of Epigenetics Drugs

Histone deacetylase (HDAC)

HDACs Class I:

HDACs Class IIB:

HDACs Class IIA:

Enzymes are expressed in cytoplasm

Enzymes are expressed in cytoplasm and nucleus

Enzymes are expressed in nucleus

HDACs 4

HDACs 1

HDACs 6

Histone deacetylase (HDAC)

HDACs 5

HDACs 2

HDACs 10

HDACs 7

HDACs 3

HDACs 9

HDACs 8

HDACs Class IV:

HDACs 11

Histone deacetylase (HDAC) inhibitors

Therapeutic mechanism

Help re-establish epigenetic control

Induce growth arrest, differentiation, apoptosis in malignant cells

Histone deacetylase (HDAC) inhibitors

Inhibit enzymes responsible for transcriptional repression and silencing -> reversing the gene repression observed in malignancies

Anti-cancer chemotherapy drug

EXAMPLE

Romidepsin

Vorinostat

Normally used to treat relapsed or refractory cutaneous T-cell lymphoma (CTCL)

Used to treat cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL)

Causes cell cycle arrest & cell death

Blocks HDACs so histones cannot be used properly, interfering with the genetic makeup of cancer cells -> cell death

Current Research

Current Research

Usage of the drugs to reverse immuno supression & restore T-cell mediated anti-tumour activity

Research 1

Act as immunomodulatory agents in treatment of cutaneous T-cell lymphoma

Research 2

Conclusion

Conclusion 1

Individual health depends on interaction of many environmental factors with its genetics

Conclusion 2

Conclusion

Lifestyle factors (nutrition, behaviour, environmental toxin exposure) can leads to epigenetic mechanism

Conclusion 3

The factors may lead to epigenomic alterations & changes in epigenetic marks will impact gene expression

Understanding molecular mechanism & signaling pathways in environmental epigenetics = reduce societal impact on public health

Nutrition & chemical pollutants are two important environmental factors affecting human health

Take-home

Messages

  • Have direct impact on individual, contributing to pathogenesis of various diseases (ex: cancer)
  • Factors leads to epigenetic transmission (hereditary) -> major global public health issue for future society
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