We are exposed to numerous chemical contaminants and non-chemical stressors (e.g., diet, infectious agents, and stress) on a daily basis. A “single-environmental-exposure” approach, which focuses primarily on health effects associated with individual chemicals and stressors, has typified related toxicological and human studies in the past. This raises the question of whether adding a “systems-biology approach” (which requires the integration of high-throughput multi-omics data, which are used to construct predictive models of the dynamic interactions between environmental exposures and our genetic system) would benefit planning for future research on cancer susceptibility and, if so, what methodological challenges need to be addressed in doing so?
Some of the extramural research projects supported by the Epidemiology and Genomics Research Program’s (EGRP) Modifiable Risk Factors Branch investigate how environmental exposures such as chemical contaminants and non-chemical stressors may affect the risk of developing cancer. The President’s Cancer Panel’s 2008-2009 Annual Report and the National Institute of Environmental Health’s (NIEHS) 2012-2017 Strategic Plan highlighted the need for such research and the importance of studying how the combination of environmental exposures and genetic processes can affect disease pathogenesis.
Candidates for Environmental Exposure Research
It would be impracticable to characterize the effects of all possible mixtures and combinations of environmental exposures, so priority must be given to those of greatest public health concern. For example, lead exposure may warrant prioritizing. Epidemiological studies have shown an association between lead exposure and risk of lung and stomach cancer in occupational settings, and approximately half a million U.S. children ages 1-5 have blood lead levels (BLL) above 5 micrograms per deciliter (µg/dL), which is the reference level at which the Centers for Disease Control and Prevention (CDC) recommends intervention. Children living in low-socioeconomic-status (SES) communities are especially vulnerable to lead exposure, and non-Hispanic African-American children typically have higher BLL when compared to children in other ethnic or racial groups.
The Effect of Chemical Exposures on Pubertal Development
It is becoming increasingly evident that early-life events and exposures to chemicals, such as polybrominated biphenyls and polychlorinated biphenyl, may influence the development of early puberty in girls. These experiences can increase a woman’s lifetime exposure to estrogen and progesterone, thereby establishing an increased long-term risk for breast and endometrial cancer.
Few human studies have associated lead exposure with delayed puberty in girls; however, a study of data from the third National Health and Nutrition Examination Survey (NHANES) found that blood lead concentrations of 3 µg/dL were associated with significant pubertal delays in Mexican-American and non-Hispanic African-American girls. Co-exposure to mixtures of high levels of lead and cadmium appear to have an even greater impact on puberty-related hormonal biomarkers than single exposures in girls, and such findings are consistent with those from animal studies.
However, most human studies do not support a positive association between lead exposure and obesity (a risk factor associated with early puberty in girls). From the use of a single-exposure approach to understanding the impact of lead exposure on health, a complex picture emerges; but is it a correct one? Such a picture can be deciphered by using a systems-biology approach that would provide a better understanding of how gene-environmental interactions are associated with health outcomes.
Addressing a Piece of the Puzzle and Future Directions
To further illustrate the need for addressing combined environmental exposures, various components of mixtures that confound or modify the effects of each other are usually unaccounted for in epidemiological studies. For instance, children living in low-SES communities are more likely to be concurrently exposed to higher concentrations of lead and other contaminants, which might produce a synergistic effect and affect pubertal development in unexpected ways. Using a systems-biology approach that moves beyond the current concept of considering specific mixtures, as illustrated above with lead and cadmium, may be especially critical for research in these instances.
What Do You Think?
The use of a single-environmental-exposure approach may not capture typical daily combined human environmental exposures and their interactions with our genetic system. A systems-biology approach would be more appropriate, because it utilizes high-throughput multi-omics data derived from research employing combinations of improved methods for exposure assessment and statistical analysis of complex mixed environmental exposures.
EGRP invites you to tell us what methodological challenges you think need to be addressed in order to study combined human–environmental exposures using a systems-biology approach.
Paul Ebohon, M.S. is a Presidential Management Fellow (PMF) at the National Cancer Institute. He recently completed a rotation with the Knowledge Integration Team in NCI’s Epidemiology and Genomics Research Program, and he is now with the intramural Division of Cancer Epidemiology and Genomics. Before joining the NIH, Paul received a Master of Science degree in Environmental Sciences and Engineering from the University of North Carolina at Chapel Hill. Paul also completed his Bachelor of Science degree in Biology (with an Environmental concentration) at the University of North Carolina at Pembroke. Paul previously served on active duty in the U.S. Army for approximately seven years as a Preventive Medicine Specialist.