Developing Data on the “Developmental Origins of Health and Disease”

The Developmental Origins of Health and Disease (DOHaD) paradigm suggests that there are specific windows of development that are highly susceptible to disruption from environmental exposures and that these early life exposures can lead to adverse outcomes later in life. The British epidemiologist David Barker is credited with pioneering this field in the 1980’s, with his research on the link between prenatal nutrition and adult coronary heart disease.

Last month, researchers published a review of the environmental epidemiological literature on DOHaD in a special “Developmental Origins of Disease” issue of Reproductive Toxicology. This review paper, which summarizes 425 articles published between 1988-2014, provides a helpful overview of the state of the science and identifies key areas for future study.

Chemical Culprits

Across these hundreds of publications, which chemicals emerged as the most commonly examined culprits?

Figure 3 from their review, below, displays this information. Polychlorinated biphenyls (PCBs), organochlorine pesticides (such as DDT), metals (such as mercury and lead), and air pollutants (including polycyclic aromatic hydrocarbons and particulate matter) were the most frequently studied across the literature.

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Chemical exposures examined in DOHaD epidemiology studies (1988-2014)

Just because these chemicals are the most highly studied does not necessarily mean that they are the most harmful, however. This research could be subject to observational bias from the “streetlight effect,” and investigators may be overlooking other chemicals that also disrupt early life processes.

Concerning Outcomes

The vast majority of DOHaD work to date has examined neurobehavioral and neurodevelopmental outcomes, such as changes in IQ and executive function. The authors hypothesize that one of the reasons that these outcomes have received the most attention is that there are multiple relevant assessments that can be performed in early life. By contrast, outcomes with longer latency periods or fewer clear assessment methods may pose challenges for researchers.

Less frequently studied DOHaD outcomes included cancer as well as adverse impacts on the respiratory, reproductive, immune, and metabolic systems. [Note: companion publications in this journal issue provide reviews of the developmental origins of reproductive disorders and metabolic disorders.] Very few studies have focused on the cardiovascular system, thyroid regulation, and gastrointestinal system, among others.

Key Areas for Future Research

Additional Exposure Periods

Most DOHaD studies have focused on environmental exposures that occur in utero. Research on this vulnerable period is extremely important, yet exposures during other periods of life can be problematic as well.

For example, emerging evidence suggests that even preconception exposures in the mother and father – particularly to persistent pollutants or to chemicals and experiences that alter epigenetic marks– may impact child health outcomes.

Additionally, because of the substantial brain changes that take place between the last trimester of pregnancy and two years of age, the “first 1000 days of life” movement has highlighted the importance of optimal nutrition during the prenatal and postnatal period. If the young brain can be affected by nutrition, it can also be altered by environmental pollutants – and thus studies that capture this timeframe are crucial.

Additional Outcomes

As mentioned above, much of the research in the field of DOHaD has focused on the neurodevelopmental consequences of early life exposures. In the coming years, researchers should also expand their work to other organ systems and processes, such as the cardiovascular, immune and gastrointestinal systems.

Moreover, while challenging, researchers should attempt to address the possibility that exposures may impact multiple biological processes through related pathways. For example, given the central role of hormonal signaling in the body, it is highly plausible that disruption of these processes could lead to adverse effects on the reproductive system, neurological system, and metabolic system, among others.

Additional Chemical Exposures

Persistent pollutants and metals have dominated the DOHaD field, perhaps because exposure information is more easily obtainable. More recent efforts have utilized advanced methods to examine additional chemicals, and future research should continue to assess a broadened group of exposures. Even chemicals that are non-persistent (short-lived) in the body may be problematic, particularly if their ubiquitous presence in our society ensures near constant exposures.

In addition, given that 1) combinations of chemicals may act differently than single chemicals, and 2) we are all exposed to numerous chemicals at the same time, it will be important to examine the effects of early life exposures to complex mixtures.

Later Life Assessment of Adverse Health Outcomes

The authors note that of the 425 publications reviewed, only 43 examined adverse outcomes in individuals over the age of 18. Thus, the environmental health field lacks the long-term follow-up that would provide evidence comparable to Barker’s early work on adult cardiovascular outcomes.

Such studies are challenging and costly; yet, they are crucial for elucidating the implications of exposures over the life course. Continued funding of longitudinal cohorts over extended periods of time will ensure that these data are generated.

Systematic Review

The purpose of this work was not to draw conclusions about the strength of the evidence of links between certain chemicals and outcomes. The authors did, however, suggest that the most commonly studied chemical/outcome combinations may be ready for systematic reviews, including:

  • Pesticides and cancer
  • Air pollution and respiratory effects
  • Organochlorine pesticides and respiratory effects
  • Polyfluoroalkyl substances (PFAS) and immune outcomes

My Take on the Bottom Line: Science & Ethics

This summary of DOHaD literature from an environmental health perspective can direct researchers to focus their future work on key areas that need further attention, as noted above. Continued epidemiological research, in conjunction with toxicological studies that can elucidate mechanistic pathways, will help advance our understanding of the implications of early life exposures.

Yet for many chemicals, such as lead, there is already ample evidence of harm from early life exposures. In this situation – and as data continue to be generated for other chemicals in the coming years – the essential next step is to take action to protect children during vulnerable periods of development.

As described in “Science and Social Responsibility in Public health,” “…environmental health researchers have a joint responsibility to acquire scientific knowledge that matters to public health and to apply the knowledge gained in public health practice.”

This responsibility not only to conduct strong research but also to ensure implementation of science-based policies is our ethical duty – and the health of the next generation depends on it.

Mother’s Day Ethics

A few weeks ago, I had the privilege of hearing Dr. Steven Gilbert, founder of the Institute of Neurotoxicology and Neurological Disorders and Toxipedia, give a talk entitled “The Ethics of Epigenetics.” Epigenetics, an increasingly important concept in environmental health, introduces the possibility that environmental exposures can have trans-generational impacts. That is, certain compounds may be able to alter the way in which genes are expressed, so the effects of these exposures can manifest in the children and grandchildren of the exposed population.

As a graduate student in toxicology, the idea of epigenetics was not new to me. However, Dr. Gilbert incorporated a critical ethical dimension to his discussion that was inspiring and moving. He suggested the obvious yet often not explicit enough implication of epigenetics: that it demands an altered framework for policy and action, since what we are being exposed to (most of the time, without our consent) may impact not only ourselves but also future generations.

Mother’s Day may be an especially appropriate time to think about the consequences of epigenetics. As I celebrate my mother, I can’t help but think about how her mother’s exposures may have impacted her life and her health. I wonder the same about myself: how will my life course and health be affected by my mother’s and my grandmother’s exposures to chemicals? And, similarly, what about the effects of my own exposure to unregulated chemicals on my future children? (I should note, though, that epigenetic changes can also be passed down on the paternal side.)

How can we end this cycle? What will it take to ensure that Mother’s Day can be a celebration of family health instead of a reminder of family exposures and disease?

The only real solution is reform of the nation’s severely outdated and ineffective chemical safety law, the Toxic Substances Control Act (TSCA). We need a TSCA reform that is robust and can gain bipartisan support – now. Further delay is unethical, putting ourselves and our children at risk.