Epigenetics - the missing link

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Almost daily, scientists are demonstrating that DNA as genetic instructions of cellular biology, is only the tip of the iceberg when discussing human (and environmental) biology, from evolution to disease development. It is now understood that a liver cell is initially the same as a fingernail cell. The development and function of all living things are not solely dependent on our genetic instructions, but on epigenetic influences that arise from environmental exposures.

Genes are driven by a vast array of physiological drivers – epigenetic processes, which act to modify gene expression and phenotype (physiological characteristics), turning genes on and off or to make a protein - and influencing how they work. The DNA or gene sequence remains unchanged. Epigenetics loosely translated, means ‘above the gene.’ Humans have one genome, and hundreds of epigenomes (Ficz 2915)

Epigenetics has been referred to as the ‘missing link between genetics, the environment, and endocrine functions.’ (Zhang 2011) When a tadpole changes into a frog, the tadpole produces a surge of thyroid hormone which, as Dr Barbara Demeneix explains, turns into a series of epigenetic switches. ‘The epigenetic changes do not alter any DNA sequence, but they turn off certain genes and turn on others.’ (Demeneix 2017, p.120)

In the long debate of nurture versus nature, scientists considered that our phenotype – who we are as a result of our genes and environment, was predominantly due to the influence of genes (recognised as Darwinian natural selection or Mendelian inheritance). Yet the relatively new field of epigenetics is clearly challenging this, and evidence that epigenetic traits can be inherited (without changing the gene) further muddies the (gene) pool. It is complicated, for example genetic sequences can influence subsequent developmental epigenetic events. (Ficz 2015)

With this relatively new field of science, humanity doesn’t just need to know what is happening within the cell, we also need to understand what is going in and between cells – rather than cellular biology – it’s molecular biology. Instead of acting as a closed loop within a neat biological system, our bodies constantly respond and interact to both our internal biological environment and the external environment.

The vast majority of environmental factors and toxicants do not have the ability to alter DNA sequence or promote genetic mutations. In contrast, the environment can dramatically influence epigenetic processes to alter gene expression and development. Therefore, epigenetics provides a molecular mechanism for the environment to directly alter the biology of an organism. (Skinner 2014)

New mechanisms of epigenetic modifications are likely to emerge, however the

‘key mechanisms underlying epigenetic modifications include: chromatin remodeling, methylation of cytosinein CpG dinucleotides (often referred to as DNA methylation), histone tail N-terminal modification, and post-translational modification of genes regulation by non-coding/small RNA (ncRNA/sRNA). Collectively, these processes and the components upon which they act constitute the epigenome. Individually or in concert, they play a key role in turning gene expression on or off, thus facilitating or inhibiting the production of specific proteins.’ (Norouzitallab et al 2019)

Of these mechanisms, methylation, which plays a key role in cellular memory, is the most studied.

The developmental origins of health and disease (DOAD)

There are specific periods (or windows) of vulnerability in developmental life stages where the foetus, and the developing child, but also teenagers, are more susceptible to toxic environmental exposures. (WHO 2008) Further, in the first trimester the foetus is even more vulnerable. (Demeneix 2017) The impact of environmental chemicals on fertility is also recognised. (Trasande 2019)

The chemical body-burden of the mother is absorbed by the foetus. Infants and young children will frequently consume more than adults relative to their body-weight. As a result, they are exposed to higher doses. (Grandjean et al 2007) Chemicals can also persist and bioaccumulate in the body. (WHO UNEP 2013)

Prenatal and postnatal chemical exposures can alter the way genes are expressed and predispose the individual to disease in later life. The 2012 Faroes Statement noted

‘These epigenetic changes can cause lasting functional changes in specific organs and tissues and increased susceptibility to disease that may even affect successive generations.’ (Grandjean et al 2012)

One of the earliest demonstrations of epigenetic influence was where mice parents’ (dams) diets were supplemented with B12, folic acid, choline and betaine. The phenotype was altered as a result, and the obese, yellow parent gave birth to brown offspring. (Waterland and Jirtle 2003)

Image: James, P; Silver, M; Prentice, A (2018) Epigenetics, Nutrition, and Infant Health. In: The Biology of the First 1,000 Days. CRC Press, Boca Raton, FL, USA, p.341. ISBN 9781498756792

While epigenetic processes impact all cellular functions, many scientists are focussing on neurodevelopmental exposures which can result in neurological damage and IQ loss. Early life epigenetic changes can influence later gene expression in the brain. (Roth 2012)

Neurodevelopmental damage frequently arises via endocrinologic processes. Harm from endocrine disruption from environmental chemicals including delay and IQ loss, has been estimated at as much of 2% of global GDP. (Attina et al 2016)

The environmental etiology of disease is poorly understood, and research in this area, in contrast to studies funding for the genetic causes of disease, is poorly funded. (Demeneix 2017)

‘The root causes of the present global pandemic of neurodevelopmental disorders are only partly understood. Although genetic factors have a role, they cannot explain recent increases in reported prevalence, and none of the genes discovered so far seem to be responsible for more than a small proportion of cases.’ (Grandjean and Landrigan 2014)

Intergenerational Effect

Science is very clear that a wide range of chemicals not only exert epigenetic influences on the generation exposed to the particular chemical, but that these epigenetic influences can be carried through, in a process described as transgenerational epigenetic inheritance to subsequent generations. For example, exposing a parent rat to the endocrine disrupting fungicide vinclozolin resulted in higher disease incidence in the great and great-great grand offspring (F3 and F4 generation) who were never exposed to the chemical. The transgenerational inheritance was paternally transmitted via sperm, altering non-coding RNA. (Schester et al 2016) (Skinner 2014)

As such, with full awareness of the potential intergenerational consequences of harmful exposures, it is becoming rather critical to understand the ‘exposome’ - our cumulative environmental exposures over a lifetime. Epigenetic mechanisms don’t only push one way, many epigenetic modifications may be reversible.

Governments and regulators in the areas of toxicity and risk assessment are yet to address epigenetics and the potential for chemical mixtures in food and environment to adversely effect biological function

Dedicated public funding is required to address the environmental drivers of disease, the toxic exposures and stressors (among other things) that directly influence not only the development of mutations to the DNA in our cells, but also the way chemical mixtures drive harm, damaging developmental and driving disease pathways.

This knowledge has the potential to change how civil society and governance approach non-communicable disease and how governments address health policy. It is already driving pharmaceutical enterprise, there is a burgeoning field of epigenetic medicine and therapy.

This new molecular spotlight naturally draws attention to the role nourishing food plays, complete with essential minerals and vitamins - which we can now observe acting epigenetically. However this also explains the toll on bodies of a bad diet, stress, chemicals and toxins. This can be extrapolated to understand environmental ecosystems.

References

Attina et al 2016. Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis. Lancet Diabetes Endocrinol 2016; 4: 996–1003

ERMA (2004) Transfer Notice. Hazardous Substances (pesticides) Transfer Notice 2004. Issue No. 72. P.1645-1718 https://www.epa.govt.nz/assets/Uploads/Documents/Hazardous-Substances/Policies/Hazardous-Substances-Pesticides-Transfer-Notice-2004.pdf

Ficz, G. (2015) New insights into mechanisms that regulate DNA methylation patterning. Journal of Experimental Biology 2015 218: 14-20; doi: 10.1242/jeb.107961

Grandjean et al 2008. The Faroes Statement: Human Health Effects of Developmental

Exposure to Chemicals in Our Environment. Basic & Clinical Pharmacology & Toxicology. 102(2):73-5. doi: 10.1111/j.1742-7843.2007.00114.x.

Grandjean, P., Landrigan, P.J. (2014) Neurobehavioural effects of developmental toxicity. Lancet Neurol. 2014:13, 330–338.

Gross L, Birnbaum LS (2017) Regulating toxic chemicals for public and environmental health. PLoS Biol 15(12): e2004814. https://doi.org/10.1371/journal.pbio.2004814

Norouzitallab et al 2019. Can epigenetics translate environmental cues into phenotypes? Science of the Total Environment. 647:1281-1293

Roth TL. (2012) Epigenetics of neurobiology and behavior during development and adulthood. Dev Psychobiol 2012; 54: 590–97.

Schuster A., Skinner M., and Yan W. (2016) Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs. Environmental Epigenetics. 2016; 2(1): dvw001.

Skinner. M. (2014) Endocrine Disruptor Induction of Epigenetic Transgenerational Inheritance of Disease. Mol Cell Endocrinol. 2014 Dec; 398(0): 4–12. 2014 Jul 31. doi: 10.1016/j.mce.2014.07.019 PMCID: PMC4262585

Trasande et al 2015. Estimating Burden and Disease Costs of Exposure to Endocrine-Disrupting Chemicals in the European Union. J Clin Endocrinol Metab, April 2015, 100(4):1245–1255doi: 10.1210/jc.2014-4324 http://press.endocrine.org/doi/pdf/10.1210/jc.2014-4324

Trasande et al 2016. Burden of disease and costs of exposure to endocrine disrupting chemicals in the European Union: an updated analysis. Andrology. 2016 Jul;4(4):565-72. doi: 10.1111/andr.12178. Epub 2016

Trasande L. 2019 Sicker, Fatter, Poorer: The Urgent Threat of Hormone-Disrupting Chemicals to Our Health and Future . . . and What We Can Do About It. Houghton Mifflin Harcourt.

Attina T, Hauser R., Sathyanarayana S., Hunt P., Bourguignon J.P., Myers J.P. , Digangi J., Zoeller R.T., Trasande L.. Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis. The Lancet Diabetes & Endocrinology, 2016 DOI: 10.1016/S2213-8587(16)30275-3

UN Human Rights Council. Report of the Special Rapporteur on the implications for human rights of the environmentally sound management and disposal of hazardous substances and wastes on his mission to Germany* 14 September 2016. A/HRC/33/41/Add.2

World Health Organization, United Nations Environment Programme, Inter-Organization Programme for the Sound Management of Chemicals, Bergman, Åke, Heindel, Jerrold J. et al. (‎2013)‎. State of the science of endocrine disrupting chemicals 2012. World Health Organization.

Waterland, R.A. and Jirtle R.L. (2003) Transposable Elements: Targets for Early Nutritional Effects on Epigenetic Gene Regulation. Molecular and Cellular Biology 2003; 23(15): 5293–5300.

WHO. Children are not little adults. Children's Health & the Environment, WHO Training Package for the Health Sector World Health Organization July 2008

Zhang, X., and Ho, S.M. (2011) Epigenetics meets endocrinology. Journal of Molecular Endocrinology. 46(1): R11–R32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071959/pdf/nihms-601840.pdf

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