Department of Psychology Epigenetic Impact of Toxins, Stress & Social Interactions: Transgenerational Perspectives Dr. Frances A. Champagne Department of Psychology Columbia University

Our changing brain…

HOW DOES THIS OCCUR? Epigenetic Control of Gene Activity Early Environmental Experiences Brain Physiology Behavior Our experiences or “nurture” can have long-term effects on our brain and behavior Genes can be turned “on” or turned “off” through epigenetic changes HOW DOES THIS OCCUR?

OFFSPRING DEVELOPMENT Parental Experience Influences Offspring Development MATERNAL EXPERIENCES stress, toxin exposure, nutritional status oocyte transcription/translation prenatal environment placental function, physiology postnatal maternal behavior sensory stimulation, frequency & stability of care OFFSPRING DEVELOPMENT

Programming of Fetal Stress Response maternal fetal risk of prematurity lower birth weight increased stress response risk of depression & anxiety Stress

Pathways of Prenatal Stress Effects Monk, Spicer & Champagne (2012) Development & Psychopathology

Prenatal Stress Effects on Epigenetics & Fetal Neurodevelopment Catherine Monk & Ben Tycko

Genes Altered in the Rat Placenta Following Chronic Variable Exposure to Stress Gene Function Stress Effect 11BHSD-2 metabolizes corticosterone Decreased DNMT1 maintenance DNA methyltransferase Nr3c1 glucocorticoid receptor Decreased in male 11BHSD-1 AFP Alfa-fetoprotein (binds estradiol) AR Androgen receptor Decreased in females AVPR1a Vasopressin receptor (social behavior) Decreased in males DIO3 Iodothyronine deiodinase 3 (inactivates thyroid hormone) DLK1 Delta-like 1 homolog (adipogenesis) DNMT3L DNA methyltransferase IGF1R Insulin growth-like factor 1 receptor IGF2 Insulin growth-like factor 2

11BHSD-2 DNA Methylation in the Placenta Prenatally Stressed Non-Stressed cccctctgctagtgtgacacacttcgcgcaactccgcagttggcgggcgcggaccacccctgcggctctgccggctggctgtcaccctcgggggctctggctgccgacccacgggcgggctccgagcggttccaagcctcggagtgggcgggggcg ggaggg agcctggg agaa M cccctctgctagtgtgacacacttcgcgcaactccgcagttggcgggcgcggaccacccctgcggctctgccggctggctgtcaccctcgggggctctggctgccgacccacgggcgggctccgagcggttccaagcctcggagtgggcgggggcg ggaggg agcctggg agaa

Anita Thapar & colleagues

Prenatal Exposure to Bisphenol A (BPA) DNA Methylation Prenatal Exposure to Bisphenol A (BPA) Tissue specific changes in gene expression neurodevelopmental, metabolic, immune outcomes

maternal exposure to bisphenol A (BPA) during pregnancy tissue specific changes in gene expression 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 neurodevelopmental, metabolic, immune outcomes

Placental Gene Expression Exposures: vehicle/control (corn oil) 2µg/kg low dose BPA 20µg/kg low dose BPA 200µg/kg low dose BPA Placental Gene Expression DNMT3L IGF2 PEG3

Hippocampal-Dependent Memory & Gene Expression BPA x Sex interaction Kundakovic et al. (2015) Proc Natl Acad Sci U S A

Are BPA-associated changes in DNA methylation present in both brain and blood? PN 28 PN 60 BPA x Sex interaction

Are BPA-associated changes in DNA methylation present in fetal cord blood? BPA x Sex interaction Low BPA < 1 µg/L (F=22; M=21) High BPA > 4 µg/L (F=19; M=19)

OFFSPRING DEVELOPMENT Parental Experience Influences Offspring Development MATERNAL EXPERIENCES stress, toxin exposure, nutritional status oocyte transcription/translation prenatal environment placental function, physiology postnatal maternal behavior sensory stimulation, frequency & stability of care 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

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LG-Associated Changes in Histone Tri-Methylation at Esr1 Jensen-Pena et al. Endocrinology (2013)

Mother to Daughter Transmission of Maternal Care Kundakovic & Champagne (2015) Neuropsychopharmacology REVIEWS

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 MPOA VTA Jensen-Pena et al. Developmental Neurobiology (2015)

Epigenetic Impact of the Postnatal Parental Care Kundakovic & Champagne (2015) Neuropsychopharmacology REVIEWS

OFFSPRING DEVELOPMENT OFFSPRING DEVELOPMENT MATERNAL EXPERIENCES PATERNAL EXPERIENCES oocyte prenatal environment ? postnatal maternal behavior paternal care of offspring OFFSPRING DEVELOPMENT OFFSPRING DEVELOPMENT

Influence of paternal experience on offspring Mashoodh et al (2013) PNAS

Effects of Paternal Food Restriction on Mothers and Offspring Offspring assessment Mashoodh et al (2013) PNAS

Reproductive Compensation Effects of Paternal Food Restriction on Female Mate Preference & Discrimination FR CF Reproductive Compensation

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

OFFSPRING DEVELOPMENT OFFSPRING DEVELOPMENT MATERNAL EXPERIENCES PATERNAL EXPERIENCES oocyte prenatal environment germline effects postnatal maternal behavior paternal care of offspring OFFSPRING DEVELOPMENT OFFSPRING DEVELOPMENT

OFFSPRING DEVELOPMENT MATERNAL EXPERIENCES PATERNAL EXPERIENCES oocyte prenatal environment germline effects postnatal maternal behavior paternal care of offspring OFFSPRING DEVELOPMENT

Plasticity vs. Stability

Extended Evolutionary Synthesis

Contrasting views of development PROGRAMMED CONSTRUCTED

Thanks Columbia University James P. Curley Rahia Mashoodh Cate Jensen Emily Jordan Zoe Donaldson Marija Kundakovic Kathryn Gudsnuk Columbia Center for Children’s Environmental Health Rachel Miller Frederica P. Perera Columbia University Catherine Monk Ben Tycko Canadian Institutes of Health Research NIH Director's New Innovator Award Centers for Children's Environmental Health & Disease Prevention Research