Exposures and Heritable Health Effects

Transcription

1 Exposures and Heritable Health Effects Thaddeus T. Schug Population Health Branch National Institute of Environmental Health Sciences November 30, 2017

2 Outline Developmental exposures and health effects concept Heritable (multi- trans-generational) exposure concept Mechanisms of action Chemical and health effects State-of-the-Science review Epidemiology (Human) Studies Animal Studies Summary

3 Developmental Origins of Health and Disease In food supply to the Netherlands was cut off by German occupiers resulting in widespread famine Children born to women who were pregnant during the famine were smaller In 1989 David Barker observed an inverse relationship b/w birth weight and death from heart disease in the Dutch Famine Birth Cohort giving rise to the Developmental Origins of Health and Disease (DOHaD) concept Image from Life.com D. Barker, Trends in Endocrinology and Met. (2010)

4 Developmentally-Induced Diseases Reproductive/Endocrine Breast/prostate cancer (BPA) Endometriosis (Dioxin, PCBs) Infertility (Phthalates, Estrogens, Pesticides) Diabetes/metabolic syndrome (BPA) Early puberty (Estrogens, BPA) Obesity (BPA, Tributyl Tin, Organochlorine Pesticides) Immune/autoimmune Susceptibility to infection (Dioxin) Autoimmune disease (Dioxin) Pulmonocardiovascular Asthma (Air Pollution) Heart disease/hypertension (BPA) Stroke (PCBs) Brain/Nervous system Alzheimer s disease (Lead) Parkinson s disease (Pesticides) ADHD/learning disabilities (PCBs, Lead, Ethanol, Organochlorine Pesticides)

5 Developmental vs Heritable Exposures Multiple reports suggest early life exposures result in adverse effects in offspring However, the evidence for exposure-induced multi- and/or trans-generational health effects is complex Walker et. al. National Toxicology Program (2017)

6 Heritable Multi- and Trans-generational Exposures Father (F 0 ) Mother (F 0 ) Exposure Exposure Fetus (F 1 ) Reproductive Cells (F 2 ) Grandchildren Reproductive Cells (F 1 ) Children

7 Germ Cells Male- Sperm Develops beginning a puberty in the testis in ~60 days and Matures and retained in the epididymis for up to 3 months Female- Egg Arise from a finite number of follicles determined at birth Maturation from follicle to a fully developed oocyte can take up to 375 days

8 Germ Cell Development Period of rapid changes Cell growth Meiotic division Metabolic and redox changes Hormonal changes Estrogen, progesterone, GnRH,FSH, LH, androgen Epigenetic changes Sperm Egg Gametogenesis

9 Mechanism of Action Mechanism of exposure-induced germ cell changes that alter phenotype Epigenetic DNA methylation during early germ cell development causing reprogramming Micro RNA, Histone modifications Transcription cofactors Redox, cell stress, inflammation Mitochondrial changes Gene Expression (Dioxin: AhR regulated)

10 Epigenetic Programming

11 Literature Search Multi- and trans-generational studies are not specifically indexed in PubMed Text word search- Concepts Transgenerational Multigenerational or intergeneration Grandparent, grandmother, grandfather, grandchild Successive generations and offspring Limited the search to PubMed database (through November 2016) Walker et. al. National Toxicology Program (2017)

12 Further Selection Criteria Inclusion Criteria Transgenerational design Human or whole animal An exposure or stressor A health outcome Original data Exclusion Criteria Plants Cell and organ cultures Selective breeding studies Reviews Non-English language Walker et. al. National Toxicology Program (2017)

13 Study Selection Flow Diagram Identification References identified through other sources (n=4) References identified through database searches (n=63,789) 98% excluded Screening Included References after duplicate removal Title-abstract screened for relevance and eligibility (n=63,754) Full-text references assessed for relevance and eligibility (n= 1,126) References included for data extraction (n=257) Human studies (n=46) Animal studies (n=211) References excluded as not relevant to PECO criteria (n=62,671) Full-text references excluded n=869 No Exposure or Outcome (n=36) Not Transgenerational design (n=456) Review or commentary (n=286) Non-English language (n=91) Walker et. al. National Toxicology Program (2017)

14 Evidence Map of Transgenerational Studies Walker et. al. National Toxicology Program (2017)

15 Human Multi-and Trans-Generational Studies Health Effects Studies Exposure Agents (n) Cancer 2 2 Different Exposures: radiation, smoking (1) Reproductive 5 1 Exposure: radiation (5) Growth and Development 6 Mortality 3 1 Exposure: food availability (3) Mutagenicity 1 1 Exposure: radiation (1) Neurological or Sensory 19 8 Different Exposures: born out of wedlock (1), diethylstilbestrol (1), education (1), income (1), positive parenting (1), radiation (1), socioeconomic status (1) and food availability (1) 8 Different Exposures: abuse (1), born out of wedlock (1), depression (4), Holocaust (8), positive parenting (1), radiation (1), socioeconomic status (1), substance use/abuse (2) Walker et. al. National Toxicology Program (2017)

16 Animal Multi-and Trans-Generational Studies Health Effects Studies Exposure Agents (n) Cardiovascular 5 4 Exposures Growth and Developmental Exposures: dioxin (3) Disease (General) 8 7 Exposures: dioxin (1) Endocrine Exposures Female Reproductive Exposures: dioxin (7) Gastrointestinal 3 3 Exposures Hepatic Exposures: dioxin (1) Immune Exposures: dioxin (1) Male Reproductive Exposures: dioxin (5) Metabolic or glucose-related Exposures Musculoskeletal Exposures: dioxin (1) Mutagenicity 7 9 Exposures Neurological and Sensory Exposures Renal Exposures: dioxin (1) Respiratory 4 4 Exposures Walker et. al. National Toxicology Program (2017)

17 Chemicals Most-Studies for Heritable Diseases Vinclozolin Cyclophosphamide Bisphenol A Phthalates Dioxin Benzo(a)pyrene Diethyltoluamide (DEET) Methoxychlor Jet Fuel Tributyltin

18 Rodent Male Studies on Dioxin (Female germline exposed) Male Reproductive Outcome 5 studies in male rodent pups from F3 generation (grandchildren) of dam exposure No effects on most reproductive endpoints One study from Bruner-Tran (2014), using10uk/kg oral gavage, reported abnormal sperm morphology 2 studies from the Skinner group (2012) reported dioxinassociated changes in testosterone concentrations (decrease at 3-4 month, increase at 12 month) using 100ng/kg/day injection

19 Data Extraction into HAWC HAWC Link: hawcproject.org/study/assessment/73/ Walker et. al. National Toxicology Program (2017)

20 Serum Testosterone Concentrations Following Dioxin Exposure Data visualization plot from HAWC Data presented as percent change compared to control 3 studies from 2 groups of researchers Effects reported in both the mouse and rat Walker et. al. National Toxicology Program (2017)

21 Rodent Female Studies on Dioxin (Female germline exposed) Female Reproductive Outcome 6 studies on female rodent pups from the F3 generation (grandchildren) of dam exposure 3 studies from the Skinner group (2012), using mg/kg/day injection reported a decrease in ovarian follicle number and increased number of small ovarian cysts 2 studies from the Skinner group (2012) reported early onset of puberty 1 study from Bruner-Tran group (2016) using10uk/kg oral gavage reported early onset of puberty reported elevated adenomyosis, an endometriosis-like phenotype

22 Ovarian Effects Following Dioxin Exposure 2 studies from 2 groups of researchers Effects reported in rat Reduction in Primordial Follicles and Increase in Ovarian Cysts Walker et. al. National Toxicology Program (2017)

23 Zebrafish Study on Dioxin (Male and Female germline exposed) Juvenile Exposure One study from Heideman (2014) using 50 pg/ml reported a significant increase in the number of female:male offspring in F2 and F3 generations and reduced fertility in male descendants The same study reported skeletal abnormalities in all descendants

24 Study Quality and Risk of Bias Evaluation Used to assess whether the design and conduct of study compromises credibility in the link between exposure and outcome Series of questions answered at the individual study level Answers equate to risk of bias rating for each question/criteria High Probability of Risk of Bias for Key Factors in Majority of Study Designs And Reporting Walker et. al. National Toxicology Program (2017)

25 Common Study Design and Reporting Issues Route of Exposure Exposure levels Animal numbers and strains Experimental Blinding Study Reproducibility (between research laboratories) Endpoint analysis

26 Summary A broad range of chemical exposures and outcomes have been reported to support transgenerational health effects There is very limited ability to evaluate the consistency of findings in general due to data limitations, and specifically with respect to the limited heritable studies on dioxin