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Environmental exposures and mechanisms of transgenerational - - PowerPoint PPT Presentation

Aug 27, 2023 659 likes •911 views

Environmental exposures and mechanisms of transgenerational epigenetic inheritance To eat or not to eat: Is that the (only) question? Raquel Chamorro-Garcia Assistant Professor Department of Microbiology and Environmental Toxicology

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Environmental exposures and mechanisms of transgenerational epigenetic inheritance

Raquel Chamorro-Garcia Assistant Professor Department of Microbiology and Environmental Toxicology University of California, Santa Cruz To eat or not to eat: Is that the (only) question?

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Global impact of obesity

  • Cardiovascular disease
  • Diabetes
  • Musculoskeletal disorders
  • Cancer

Global Burden of Obesity Economy

  • $2.0 trillion worldwide
  • Direct costs
  • Indirect costs

Health Social

  • Developing countries cannot

afford the costs

  • Stigma
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Positive energy balance (calories in vs. calories out) Genetics Stress Gut microbiome Infections Smoking Malnutrition

Contributing factors to obesity

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Lumey & Poppel, 2013

Preconception & in utero exposure to famine Health Outcomes in

  • ffspring

Obesity, lipid profile, metabolic syndrome Diabetes, glucose metabolism Fertility Cognition, psychiatric disorders Adult mortality

F2 offspring from F1 women

Poor health

Multigenerational studies in humans Dutch famine

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Multigenerational inheritance

Mendelian laws Dominant vs recessive phenotype Homozygous vs heterozygous vs WT

One mutation One phenotype ?

Obesity Lipid profile Metabolic syndrome Diabetes Glucose metabolism Fertility Cognition Psychiatric disorders Adult mortality Genetics Epigenetics

Environmental perturbation

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Alterations that lead to a “stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence”

  • Cold Spring Harbor Conference, 2008

Epigenetics

Conrad H. Waddington

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Positive energy balance (calories in vs. calories out) Genetics Stress Gut microbiome Infections Smoking Malnutrition

Contributing factors to obesity EDCs?

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Initial alteration Final endpoint Transgenerational epigenetic inheritance Epigenetic Characterization

DNA methylation Histone modifications Noncoding RNAs

Which parental line?

Epigenetic marks in germline

Mechanisms of propagation? Epigenetic reprogramming? Modes of action Target tissues

Tributyltin Phthalates Methoxychlor Glyphosate Dioxin BPA Caloric restriction High-fat diet EDCs Diets

Exposure

  • f F0

Pregnant Females Metabolic disruption F4 animals F1 F2 F3 F4 ?

Chamorro-Garcia et al., 2013 Skinner et al., 2013 Tracey et al., 2013 Manikkam et al., 2013 Manikkam et al., 2014 Öst et al., 2014 Chamorro-Garcia et al., 2017 Camacho et., 2018 Kubsad et al., 2019 Diaz-Castillo et al., 2019

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Tributyltin

Biocide Seafood Metabolic disruptor

Exposure

  • f F0

Pregnant Females Metabolic disruption F4 animals F1 F2 F3 F4

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Tributyltin

Biocide Seafood Metabolic disruptor

SD: Standard Diet HFD: High Fat Diet Chamorro-Garcia et al., Nat Comms, 2017

Exposure

  • f F0

Pregnant Females Metabolic disruption F4 animals F1 F2 F3 F4

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Tributyltin How? F4 Adipose tissue Alterations in methylome & transcriptome

Chamorro-Garcia et al., Nat Comms, 2017

Hypothesis I: TBT alters DNA methylation of promoters for metabolically-relevant genes Hypothesis II: TBT alters nuclear genome organization Rejected Exposure

  • f F0

Pregnant Females Metabolic disruption F4 animals F1 F2 F3 F4

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Alterations that lead to a “stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence”

  • Cold Spring Harbor Conference, 2008

Epigenetics

Conrad H. Waddington

National Institutes of Health - http://commonfund.nih.gov/epigenomics/figure.aspx

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Nuclear genome organization

Hildebrand & Dekker, 2020 – Trends Biochem Sci Compartment A Euchromatin Active genes, Higher accessibility High GC content Compartment B Heterochromatin Transcriptionally inactive Less accessible High AT content

Euchromatin Heterochromatin

Immunofluorescence Hi-C

Falk et al., 2019 - Nature

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Tributyltin How? F4 Adipose tissue Alterations in methylome & transcriptome

Chamorro-Garcia et al., Nat Comms, 2017

Hypothesis I: TBT alters DNA methylation of promoters for metabolically-relevant genes Hypothesis II: TBT alters nuclear genome organization Rejected Exposure

  • f F0

Pregnant Females Metabolic disruption F4 animals F1 F2 F3 F4

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Tributyltin F4 Adipose tissue Alterations in methylome & transcriptome

Isochores

  • Large regions of DNA (>300 Kb) with highly homogenous base

composition (GC- vs. AT-content)

  • Reflect multiple levels of organization (TADs, eu-/heterochromatin,

compartment A/B)

  • Are invariable across tissues, generations and sexes
  • Analysis of genomic traits with regards isochores before and after

randomly rearranging datasets 10,000 times

Exposure

  • f F0

Pregnant Females Metabolic disruption F4 animals F1 F2 F3 F4 How?

Compartment A Euchromatin GC-enriched Compartment B Heterochromatin AT-enriched

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L1 L2 H1 H2 H3

  • 1.0
  • 0.5

0.0 0.5 1.0

isochores AT-rich —> GC-rich heterochromatin —> euchromatin measure X [log(observed/5th-95th expected-by-chance)] Heterochromatin-euchromatin

  • rganization disruption

TBT vs Control

Significantly higher than expected by chance in heterochromatin Significantly lower than expected by chance in euchromatin Not significantly different than expected by chance

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Exposure

  • f F0

Pregnant Females Metabolic disruption F4 animals Molecular mechanism? F4 Adipose tissue F1 F2 F3 F4 Alterations in methylome & transcriptome Fat tissue Liver MSCs Males & Females Transcriptome & Methylome Nuclear genome

  • rganization

Diaz-Castillo et al., Sci Rep, 2019 Chamorro-Garcia et al., Nat Comms, 2017

Tributyltin

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Exposure

  • f F0

Pregnant Females Metabolic disruption F4 animals Molecular mechanism? F4 Adipose tissue F1 F2 F3 F4 Alterations in methylome & transcriptome Fat tissue Liver MSCs Males & Females Transcriptome & Methylome Nuclear genome

  • rganization

Self reconstructive propagation

Diaz-Castillo et al., Sci Rep, 2019 Chamorro-Garcia et al., Nat Comms, 2017 GO enrichment [log(observed/5th-95th expected)] Mouse GO distribution

  • 1.0
  • 0.5

0.0 0.5 1.0 %GC [log(observed/5th-95th expected)] Human GO distribution GO enrichment [log(observed/5th-95th expected)] Mouse GO distribution

  • 1.0
  • 0.5

0.0 0.5 1.0 [log(observed/5th-95th expected)]

Metabolic processes Chromatin organization

Tributyltin

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Exposure

  • f F0

Pregnant Females Metabolic disruption F4 animals Molecular mechanism? F4 Adipose tissue F1 F2 F3 F4 Alterations in methylome & transcriptome Nuclear genome

  • rganization

Diaz-Castillo et al., Sci Rep, 2019 Chamorro-Garcia et al., Nat Comms, 2017

Fat tissue Liver MSCs Males & Females Transcriptome & Methylome Self reconstructive propagation Initial alteration Tributyltin

Tributyltin Phthalates Methoxychlor Glyphosate Dioxin BPA Caloric restriction High-fat diet EDCs Diets

Modes of action Target tissues ?

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Acknowledgments

Blumberg Lab (UCI) Bruce Blumberg Riann Egusquiza Bassem Shoucri Heidi Kaech Ron Leavitt MGH-Harvard Med School Toshi Shioda INRA-Toxalim, Toulouse, France Daniel Zalko Chamorro-Garcia Lab (UCSC) Carlos Diaz-Castillo Stephanie Aguiar Tiffany Kluber Prithvi Singh Collaborators Camilla Forsberg, UCSC Diana Laird, UCSF

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