ReviewEpigenetic regulation of neurodevelopmental genes in response to in utero exposure to phthalate plastic chemicals: How can we delineate causal effects?
Section snippets
Fetal programming and environmental exposures and an example of epigenetic mechanisms in linking the two
During pregnancy the developing fetus adapts to its environment to maximize survival. This is often referred to as ‘fetal programming’ and is usually associated with optimising growth while minimising the potential adverse effects of harmful exposures experienced in utero. Whilst beneficial in pregnancy, such adaptations can also be potentially deleterious to long-term health. The Developmental Origins of Health and Disease (DOHaD) hypothesis states that the intrauterine environment can
Plastic product chemicals as ubiquitous environmental exposures in pregnancy
The potential impact of environmental man-made chemical exposure in early life is a significant public health concern, because even subtle chemical-induced changes during early development may increase subsequent risk of multiple diseases, particularly metabolic and neurodevelopmental disorders (Grandjean and Landrigan, 2006). Chemicals of concern include the plastic product chemicals (PPC), such as phthalates, detectable in 96%-100% of pregnant women in modern populations (Centres for Disease
Phthalate exposure and child neurodevelopmental outcomes
The developing pregnancy undergoes the most rapid differentiation in the earliest stages and this is therefore likely to be a critical period of exposure. Of course, the developing infant also undergoes considerable postnatal brain development, so the window of any PPC-induced neurotoxic and vulnerability may not be confined to the prenatal period. For example, brain derived neurotrophic factor (BDNF) expression from gene promoters 1 and VI in the dorsolateral prefrontal cortex of humans occurs
Plastic exposure and epigenetic variation at neurodevelopment genes – BDNF
Emerging data, predominantly from animal studies, indicate that environmentally induced alterations to the vulnerable epigenome may have long-term consequences, particularly during the prenatal or early postnatal period. Several psychiatric and neurodevelopmental disorders have now been directly associated with epigenetic variation in physiologically relevant target genes, both in specific brain regions and the peripheral blood, predominantly from cross-sectional studies (Kundakovic et al., 2015
Investigating causality between phthalate exposure and adverse neurodevelopment, mediated through epigenetic alteration of neurodevelopmental genes such as BDNF
Molecular evidence is available in animal models (Lee et al., 2006, Ishido et al., 2004, Masuo et al., 2004b, Ishido et al., 2005). This has been well reviewed recently (Miodovnik et al., 2014, Holahan and Smith, 2015, Kay et al., 2014, Kay et al., 2013) and is not the purpose of this review. In contrast, all human studies to date have been based on only epidemiological associations rather than molecular evidence (Table 1). Such associations could reflect non-causal explanations.
Appropriately
Conclusion
In conclusion, we have highlighted the potential public health importance of observed associations between prenatal exposure to phthalates and suboptimal offspring neurodevelopment. The evidence is not conclusive and RCTs in this setting will be difficult to conduct well. In the absence of RCTs, alternative approaches are needed. We have highlighted the value of conducting epidemiological and molecular epigenetic analyses in parallel with a view to assessing if detected phthalate- offspring
Conflict of interest
None.
Acknowledgements
We thank Rianna Chapman and Helen Raschella for literature review and manuscript preparation. Anne-Louise Ponsonby, Peter Sly and Richard Saffery are supported by NHMRC fellowships. Christos Symeonides is supported by a NHMRC PhD scholarship. Research at Murdoch Childrens Research Institute is supported by the Victorian Government's Operational Infrastructure Support Program.
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