Environmentally induced epigenetic toxicity: Potential public …epigenetics.setac.eu/embed/EPIGENETICS/Files/46.pdf · 2016-09-26 · AD = Alzheimer’s disease, BPA = bisphenol

Environmentally induced

epigenetic toxicity: Potential

public health concerns

Emma Marczylo 15th September 2016

Overview • Scope of review

• Current evidence for putative environmentally induced

epigenetic toxicity

• Research considerations for public health

• Implications for regulatory toxicology and intervention

• What next?

2 SETAC-iEOS, 15th Sep 2016 Marczylo et al, 2016, Crit Rev Toxicol, DOI:10.1080/10408444.2016.1175417

Epigenetic changes

Scope of review

3 SETAC-iEOS, 15th Sep 2016

Gene expression Epigenetic

changes Health

effects

Marczylo et al, 2016, Crit Rev Toxicol, DOI:10.1080/10408444.2016.1175417

Environmental factors

• Chemicals

• Radiation

• Lifestyle factors

• Alcohol

• Nutrition

• Smoking

Toxicity/Adverse effects

• Growth retardation

• Fertility problems

• Hormonal changes

• Organ/system specific

abnormalities

• Reproductive

issues

• Immune disorders

• Obesity/diabetes

• Cancer

Limited to: Human epidemiological and in vivo rodent studies; Excluded stress, pharmaceutical/recreational drug exposures, maternal immune activation/infection and parental age


Contents of review

Examines present understanding of epigenetic mechanisms

involved in the mammalian life cycle

Evaluates the current evidence for putative environmentally

induced epigenetic toxicity in human cohorts and rodent models

Highlights the research considerations and implications of this

emerging knowledge for public health and regulatory toxicology

Only studies that measured both adverse effects and associated epigenetic changes in response to an environmental

exposure in the same experimental cohort were evaluated

76 studies (up to 7th March 2016); 10 demonstrating associations between environmental exposure(s), specific epigenetic changes(s) and

adverse phenotype(s) that were confirmed in a relevant in vivo or in vitro system

Current evidence: Human cohorts

5

AD = Alzheimer’s disease, BPA = bisphenol A, COPD = chronic obstructive pulmonary disease, ECAT = elemental carbon attributable to traffic, NSCLC = non-small cell lung cancer,

PAHs = polycyclic aromatic hydrocarbons, PBL = peripheral blood lymphocyte.

Epigenetic changes

Epigenetic machinery


DNA methylation

miRNAs


DNA methylation

miRNAs

Adverse effects/Toxicity

Asthma Multiple systems • Behavioural abnormalities

• AD

• Skin abnormalities

• NSCLC

• PBL chromosomal

aberrations

Multiple systems • COPD

• Breast & lung tumours

• ↓ Lung cancer survival

Air pollution • ECAT

Smoking


Chemicals • BPA

• Formaldehyde

• Metals

• PAHs

SETAC-iEOS, 15th Sep 2016 Marczylo et al, 2016, Crit Rev Toxicol, DOI:10.1080/10408444.2016.1175417

147 studies (up to 7th March 2016); 37 demonstrating associations between environmentally induced adverse phenotypes and epigenetic

changes that were reversed by an inhibitor/treatment, absent in a knock out/down model, mechanistically linked in a relevant in vitro

system, and/or identified in both rodent model(s) and human cohort(s)

Current evidence: Rodent models

6

BPA = bisphenol A, NNK = 4-(methylnitrsamino)-1-(3-pyridyl)-1-butanone (Nicotine metabolite), PhIP = 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (Meat).


Nutrition • High fat diet

• Under-nutrition

• PhIP

• Peanut

Chemicals • BPA

• Formaldehyde

• Metals

• Phthalates

• Urethane

• Vinyl carbamate

Smoking • Cigarette smoke

• Nicotine

• NNK


Alcohol Caffeine

Epigenetic changes

Histone modification

DNA methylation


miRNAs


miRNAs

DNA methylation DNA methylation


miRNAs


DNA methylation


miRNAs

Multiple system abnormalities

Adverse effects/Toxicity

• Neurological

• Behavioural

• Cardiac

• Mesenchymal stem

cell

• Reproductive

• Neurological

• Behavioural

• Metabolic

• Cardiac

• Hepatic

• Hormonal

• Tumours/carcinogenesis

• Cardiac • Metabolic

• Hepatic

• Prostate

• Allergy

• Growth retardation

• Neurological

• Adrenal

• Pulmonary

• Tumours

• Not all environmentally induced adverse phenotypes are associated with

epigenetic changes (18 human cohort and 20 rodent studies reported a lack of epigenetically related toxicity)

• Human cohort studies:

• Association vs causality

• Timing and type of biosample collected (7 of the 10 studies either directly sampled the target tissue or

validated the same change in the blood and target tissue of an appropriate in vivo model)

• Many additional studies that may provide useful information:

• Other exposures (eg. stress, recreational drugs, maternal immune activation/infection, parental age and

pharmaceutical drugs)

• Other mammalian species (eg. sheep and monkeys)

• Environmentally induced epigenetic changes without assessment of phenotypic

endpoint

• Other models (eg. in vitro models and simpler systems such as C. elegans, D. melanogaster & D. rerio)

• Challenge is to identify and investigate specific functional epigenetic

mechanisms and biological pathways relevant to humans so that the risks to

public health can be properly assessed

Current evidence: Points to note


Research considerations for public health

8

Mechanisms

& model

systems

Is environmentally induced epigenetic toxicity is a real

concern for public health?

Priority questions:

1. What are the detailed epigenetic mechanisms that link exposure to effect?

2. Do these mechanisms function in humans?

Human studies restricted to epidemiological

cohorts, ex vivo or in vitro models

Majority of whole system studies performed in animal

models, which exhibit differences with humans

New technologies & novel information

Key task: correct integration and interpretion at the in vitro vs in vivo and

human vs non-human levels



9



Priority questions:

1. What doses via what routes of administration are human populations actually

exposed to, and what metabolites are formed?

2. Do low-level exposures induce epigenetic toxicity?

3. Is any part of the life cycle more sensitive?

4. Are multiple exposures additive and/or cumulative?

Dose, route,

metabolism, timing

and mixtures of

exposure

Dose: High (often single)

Route: ip vs oral/inhalation

Metabolism: Model system vs in vivo human

metabolism

Timing: Susceptible life stages

Mixtures: Multiple exposures



10



Priority question:

1. How can we identify susceptible individuals or populations?

Human

variability

Driven by diverse genetic backgrounds

Not all humans will respond to an

environmental exposure in the same way

Many examples of SNPs that affect the response of individuals and

populations to exposures (including DNA methylation or miRNA binding sites)



11



Priority questions:

1. What is the ‘normal’ epigenome?

2. What are the real short- and/or long-term consequences of environmentally

induced epigenetic changes?

Adaptive vs

adverse epigenetic

change

Adaptation

Normal cell

(Homeostasis)

New homeostasis

Adverse effect

Cell death

x x

Exposure

Irreversible

Reversible

Inability

to adapt


• A robust, dose-dependent, causal relationship between a specific

environmental exposure, an epigenetic change and an adverse public health

outcome is required to classify a chemical/factor as an epigenetic toxicant

• While a similar robust, dose-dependent relationship is also crucial to facilitate

testing methods for regulatory toxicology and intervention, establishing

causality is not necessarily essential (eg. markers of exposure)

Implications for regulatory toxicology and

intervention What is important for application of epigenetics in regulatory toxicology?


What next? What is important for application of epigenetics in regulatory toxicology?

13

Research/

next steps

More

sensitive/earlier

end points of

toxicity within

existing TGs

Potential

rewards

Identify public health

relevant putative

mechanisms/markers

of epigenetic toxicity

from current literature

Perform retrospective

analyses of key epigenetic

mechanisms/markers in

surplus biosamples from

existing regulatory studies

Develop guidelines for improved

molecular/bioinformatic study

designs to definitively identify

epigenetic mechanisms/markers

of exposures and adverse

outcomes

Improved human

exposure/biomonitoring

data to promote

relevance to humans

Inclusion of non-

compulsory epigenetic

measurements in

existing TGs*

Collection of

epigenetic data

in a regulatory

context

Better 3Rs use of

existing regulatory

studies/TGs

Extensive

sample

resource

*Greally & Jacobs 2012, ALTEX, 30:445-71

Use of

additional

model

systems

Collaboration

between academia,

industry,

government and

regulators

Novel TGs


• While many hundreds of studies have investigated environmentally-induced

epigenetic toxicity, relatively few (47 up to 7th March 2016) have demonstrated a

mechanistic association between specific environmental exposures, epigenetic

changes and adverse phenotypes

• Even fewer (18 of the 47) further established a degree of causality, all of which

were studies in rodent models

• The majority of these studies represent exploratory in vivo high (often single)

dose range experiments, many orders of magnitude above likely human

exposures

• Nevertheless, they do set a precedent for the existence of environmentally

induced epigenetic toxicity

• Thus, although the current literature remains incomplete regarding relevance to

public health, there is sufficient information to begin further (focussed) research

within a regulatory context

Conclusions


Acknowlegements • Miriam Jacobs

• Tim Gant


Thank you!

Documents

Environmentally induced epigenetic toxicity: Potential public …epigenetics.setac.eu/embed/EPIGENETICS/Files/46.pdf · 2016-09-26 · AD = Alzheimer’s disease, BPA = bisphenol