Dr. Frances A. ChampagneDepartment of Psychology

Columbia University

Epigenetic Impact of Toxins, Stress & Social Interactions: Transgenerational Perspectives

Our changing brain…

Brain Physiology

Behavior

Early Environmental

Experiences

Our experiences or “nurture” can have long-term effects on our brain and behavior

HOW DOES THIS OCCUR?

Epigenetic Control of Gene Activity

Genes can be turned “on” or turned “off” through epigenetic changes

MATERNAL EXPERIENCES

stress, toxin exposure, nutritional status

OFFSPRING DEVELOPMENT

oocyte

prenatal environment

transcription/translation

placental function, physiology

postnatal maternal behavior

sensory stimulation, frequency & stability of care

Parental Experience Influences Offspring Development

Programming of Fetal Stress Response

maternal fetalrisk of prematurity

lower birth weight

increased stress response

risk of depression & anxiety

Stress

Pathways of Prenatal Stress Effects

Monk, Spicer & Champagne (2012) Development & Psychopathology

A Prenatal Stress Effects on Epigenetics & Fetal Neurodevelopment

Catherine Monk & Ben Tycko

Genes Altered in the Rat Placenta Following Chronic Variable Exposure to Stress

Gene Gene Function Stress Effect

11BHSD-2 metabolizes corticosterone Decreased

DNMT1 maintenance DNA methyltransferase Decreased

Nr3c1 glucocorticoid receptor Decreased in male

11BHSD-1 metabolizes corticosterone Decreased

AFP Alfa-fetoprotein (binds estradiol) Decreased

AR Androgen receptor Decreased in females

AVPR1a Vasopressin receptor (social behavior) Decreased in males

DIO3 Iodothyronine deiodinase 3 (inactivates thyroid hormone)

Decreased in females

DLK1 Delta-like 1 homolog (adipogenesis) Decreased

DNMT3L DNA methyltransferase Decreased

IGF1R Insulin growth-like factor 1 receptor Decreased

IGF2 Insulin growth-like factor 2 Decreased

cccctctgctagtgtgacacacttcgcgcaactccgcagttggcgggcgcggaccacccctgcggctctgccggctggctgtcaccctcgggggctctggctgccgacccacgggcgggctccgagcggttccaagcctcggagtgggcgggggcg ggaggg agcctggg agaa

cccctctgctagtgtgacacacttcgcgcaactccgcagttggcgggcgcggaccacccctgcggctctgccggctggctgtcaccctcgggggctctggctgccgacccacgggcgggctccgagcggttccaagcctcggagtgggcgggggcg ggaggg agcctggg agaa

Prenatally Stressed Non-Stressed

11BHSD-2 DNA Methylation in the Placenta

M

M M

M M

M

M

M

M

M M

Anita Thapar & colleagues

Prenatal Exposure

to Bisphenol A (BPA)

Tissue specific changes in

gene expression

neurodevelopmental, metabolic, immune outcomes

DNA Methylation

maternal exposure to

bisphenol A (BPA) during pregnancy

tissue specific changes in gene

expression

neurodevelopmental, metabolic,

immune outcomes

SEX-SPECIFIC EFFECTS

Boys: high prenatal BPA exposure associated with increased behavior problems (CBCL), including scores on Emotionally Reactive and Aggressive Behavior syndromes

Girls: prenatal BPA exposure associated with lower scores on all syndromes, particularly Anxious/Depressed and Aggressive Behavior

Placental Gene Expression

DNMT3L IGF2 PEG3

Exposures:

1) vehicle/control (corn oil)2) 2µg/kg low dose BPA3) 20µg/kg low dose BPA4) 200µg/kg low dose BPA

BPA x Sex interaction

Hippocampal-Dependent Memory & Gene Expression

Kundakovic et al. (2015) Proc Natl Acad Sci U S A

BPA x Sex interaction

PN 28 PN 60

Are BPA-associated changes in DNA methylation present in both brain and blood?

BPA x Sex interaction Low BPA < 1 µg/L (F=22; M=21)High BPA > 4 µg/L (F=19; M=19)

Are BPA-associated changes in DNA methylation present in fetal cord blood?

MATERNAL EXPERIENCES

stress, toxin exposure, nutritional status

OFFSPRING DEVELOPMENT

oocyte

prenatal environment

transcription/translation

placental function, physiology

postnatal maternal behavior

sensory stimulation, frequency & stability of care

Parental Experience Influences Offspring Development

Dose-Dependent Effect of BPA on Postnatal Maternal Behavior

Pup Licking/Grooming Nursing

Kundakovic et al (2013) Proc Natl Acad Sci U S A 110(24):9956-61

0

5

10

15

20

25

30

35

*

**

offspring age (days)

High LGLow LG

0 6 21 660

5

10

15

20

25

30

35 *

*

offspring age (days)

rela

tiv

e E

Rα

mR

NA

rela

tiv

e E

Rβ

mR

NA

rela

tiv

e O

TR

mR

NA

High LGLow LG

PN0 PN6 PN21 Dam0

2

4

6

8

10

12

14

**

0 6 21 66

H3K4me3

Low LG High LG No-Ab Control

H3K9me3

PN6 PN21 PN660.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08 *

*

PN6 PN21 PN660.00

0.01

0.02

0.03

0.04

0.05

0.06

LG-Associated Changes in Histone Tri-Methylation at Esr1

Jensen-Pena et al. Endocrinology (2013)

Kundakovic & Champagne (2015) Neuropsychopharmacology REVIEWS

Mother to Daughter Transmission of Maternal Care

birth

cross-fostering

PN6 PN21 PN28

weaning

PN10

maternal sensitization≤ 12 days

High-Low 10High-Low 6Low-High 6Low-High 10

High

Low

Is there a sensitive period for the effects of maternal LG on offspring?

Jensen-Pena et al. Endocrinology (2013)

Effect of Neonatal ERα Up-regulation on Juvenile Maternal Sensitization

Jensen-Pena et al. Developmental Neurobiology (2015)

MPOA VTA

Epigenetic Impact of the Postnatal Parental Care

Kundakovic & Champagne (2015) Neuropsychopharmacology REVIEWS

MATERNAL EXPERIENCES

OFFSPRING DEVELOPMENT

oocyte

prenatal environment

postnatal maternal behavior

PATERNAL EXPERIENCES

OFFSPRING DEVELOPMENT

?paternal care of offspring

Influence of paternal experience on offspring

Mashoodh et al (2013) PNAS

Offspring assessment

Effects of Paternal Food Restriction on Mothers and Offspring

Mashoodh et al (2013) PNAS

Effects of Paternal Food Restriction on Female Mate Preference & Discrimination

Reproductive Compensation

CF

FR

Embryo transfer (ET) prevents the impact of paternal food restriction on maternal outcomes

CF vs FR Effects in Embryo transfer (ET) and Natural Mating (NM) Conditions

MATERNAL EXPERIENCES

oocyte

prenatal environment

postnatal maternal behavior

PATERNAL EXPERIENCES

OFFSPRING DEVELOPMENT

germline effects

paternal care of offspring

OFFSPRING DEVELOPMENT

MATERNAL EXPERIENCES

oocyte

prenatal environment

postnatal maternal behavior

PATERNAL EXPERIENCES

germline effects

paternal care of offspring

OFFSPRING DEVELOPMENT

Plasticity vs. Stability

Extended Evolutionary Synthesis

Contrasting views of developmentP

RO

GR

AM

ME

DC

ON

ST

RU

CT

ED

Thanks

Canadian Institutes of Health Research

NIH Director's New Innovator

Award

Centers for Children's Environmental Health & Disease Prevention Research

Columbia UniversityJames P. CurleyRahia MashoodhCate JensenEmily JordanZoe DonaldsonMarija KundakovicKathryn Gudsnuk

Columbia Center for Children’s Environmental Health Rachel MillerFrederica P. Perera

Columbia UniversityCatherine MonkBen Tycko