title: Epigenetic regulation of neurodevelopmental genes in response to in utero exposure to phthalate plastic chemicals: How can we delineate causal effects?
abstract: Accumulating evidence, from animal models and human observational studies, implicates the in utero (and early postnatal) environment in the 'programming' of risk for a variety of adverse outcomes and health trajectories. The modern environment is replete with man-made compounds such as plastic product chemicals (PPC), including phenols and phthalates. Evidence from several human cohorts implicates exposure to these chemicals in adverse offspring neurodevelopment, though a direct causal relationship has not been firmly established. In this review we consider a potential causal pathway that encompasses epigenetic human variation, and how we might test this mechanistic hypothesis in human studies. In the first part of this report we outline how PPCs induce epigenetic change, focusing on the brain derived neurotrophic factor (BDNF) gene, a key regulator of neurodevelopment. Further, we discuss the role of the epigenetics of BDNF and other genes in neurodevelopment and the emerging human evidence of an association between phthalate exposure and adverse offspring neurodevelopment. We discuss aspects of epidemiological and molecular study design and analysis that could be employed to strengthen the level of human evidence to infer causality. We undertake this using an exemplar recent research example: maternal prenatal smoking, linked to methylation change at the aryl hydrocarbon receptor repressor (AHRR) gene at birth, now shown to mediate some of the effects of maternal smoking on birth weight. Characterizing the relationship between the modern environment and the human molecular pathways underpinning its impact on early development is paramount to understanding the public health significance of modern day chemical exposures.
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia. Electronic address: anne-louise.ponsonby@mcri.edu.au.
authors.forename: Anne-Louise
authors.initials: AL
authors.lastname: Ponsonby
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Christos
authors.initials: C
authors.lastname: Symeonides
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia; Deakin University, Geelong, Victoria, Australia; Child Health Research Unit, Barwon Health, Geelong, Victoria, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Vuillermin
authors.affiliation: National Research Centre for Environmental Toxicology, University of Queensland, Brisbane, Australia.
authors.forename: Jochen
authors.initials: J
authors.lastname: Mueller
authors.affiliation: Child Health Research Centre, University of Queensland, Brisbane, Australia.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Sly
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Saffery
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D065886:Neurodevelopmental Disorders / Q000139:chemically induced* / Q000378:metabolism; D010795:Phthalic Acids / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000503:physiopathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D010795:Phthalic Acids; C032279:phthalic acid; C579455:BDNF protein, human
keywords: Bisphenol A; Causal evidence; DNA methylation; Developmental origins; Early birth cohort; Fetal programming; Intrauterine environment; Neonatal epigenome; Observational epidemiology; Phthalate