Exposome effects on the brain

The unique combination of environmental exposures that we each encounter throughout our lives—known as our exposome—strongly influences our health span and risk of disease. Pervasive and harmful stressors ranging from industrial products that pollute our soil to heavy metals that contaminate our water to wildfires that reduce the quality of our air all have an impact on how our cells and tissues develop, function, and age. We are especially susceptible to environmental toxicants in utero when critical organ systems are under construction. In the fetal brain, for example, the neural progenitors that act as the building blocks of the cortex can be disrupted by the dozens of different chemicals commonly found in maternal blood. The cascading effects of these prenatal insults ultimately impacts the ways we think, behave, and socialize.

Our exposome is expansive and ever growing. There are 85,000 chemicals currently produced in the United States, and ~1,500 novel compounds are created each year. Roughly 200 are neurotoxic agents, though a vast majority have not been tested for their effects on human health, let alone fetal brain development. Safety assessments have not matched the pace of industrial chemical proliferation, and it often takes decades—and countless individuals with neurodevelopmental damage—before dangerous compounds are banned. We are being bombarded by more pollutants than ever before and lack the necessary information to protect ourselves from this threat.

How do our genetics influence sensitivity to environmental exposures?

Our diversity might provide some answers, and maybe even some solutions. Some people are more resistant to the effects of harmful exposures than others in ways that are in part genetically encoded. In theory, if we could discover the natural mechanisms protecting these individuals, we could develop preventative or therapeutic drugs based on this information. Unfortunately, this knowledge has remained elusive using conventional research methods because the human genome is immensely complex and because it is nearly impossible to accurately measure all the exposures someone has experienced throughout their entire lives.

We use cell villages to overcome these barriers to better understand the relationships between the human genome and exposome. To do so, we challenge 100+ donor neural cell villages with specific concentrations of different toxicants and ask a simple question—who lives, and who dies? We then scan the genome to determine if there are any associations between specific genetic variants and where someone sits on the resistance-vulnerability spectrum. We take a similar approach to determine if genetic variation influences toxicant-induced molecular changes that can alter neurodevelopmental processes later in life.

Thus far, we have leveraged this system to identify risk biomarkers for Zika virus infection and lead-induced cell death, and we are currently probing other common fetal exposures like pesticides, bisphenol-A (BPA), PFAS (aka “forever chemicals”), and maternal stress.