Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease

Abstract

The etiologic pathways leading to neuropsychiatric diseases remain poorly defined. As genomic technologies have advanced over the past several decades, considerable progress has been made linking neuropsychiatric disorders to genetic underpinnings. Interest and consideration of nongenetic risk factors (e.g., lead exposure and schizophrenia) have, in contrast, lagged behind heritable frameworks of explanation. Thus, the association of neuropsychiatric illness to environmental chemical exposure, and their potential interactions with genetic susceptibility, are largely unexplored. In this review, we describe emerging approaches for considering the impact of chemical risk factors acting alone and in concert with genetic risk, and point to the potential role of epigenetics in mediating exposure effects on transcription of genes implicated in mental disorders. We highlight recent examples of research in nongenetic risk factors in psychiatric disorders that point to potential shared biological mechanisms-synaptic dysfunction, immune alterations, and gut-brain interactions. We outline new tools and resources that can be harnessed for the study of environmental factors in psychiatric disorders. These tools, combined with emerging experimental evidence, suggest that there is a need to broadly incorporate environmental exposures in psychiatric research, with the ultimate goal of identifying modifiable risk factors and informing new treatment strategies for neuropsychiatric disease.

Genetic association of FMRP targets with psychiatric disorders

“…Likewise, environmental factors influence cognitive and behavioural deficits in people with fragile X syndrome [91,92]. Consistent with genetic observations, a convergence on synaptic dysfunction is also described in studies of non-genetic and epigenetic factors contributing to psychiatric disorders [93]. However, the interaction between FMRP function and environmental exposures in the context of psychiatric disorders has not been studied.…”

Mitochondria under the spotlight: On the implications of mitochondrial dysfunction and its connectivity to neuropsychiatric disorders

“…Evidence have also pointed to a role for epigenetics in the etiology of mental illnesses, for instance in the impact of epigenetic regulation of chromatin remodeling and DNA methylation on these pathologies [5] , [6] . Further, MDD is caused by the lack of methylation at certain CpG sites in the exon 1 of BDNF gene [102] , as well as reduced response to antidepressant drugs due to the absence of methylation at CpG site in exon 4 of the same gene [103] .…”

“…The DNA methylation profile differences were also observed in another epigenetic study conducted on monozygotic twins discordant for SZ and BD, highlighting differential epigenetic dysregulations among these mental illnesses [105] . However, the identification of epigenetic profiles caused by a specific environmental chemical and their correlation with a mental illness is still limited by the lack of large scale studies on this topic [6] . Nevertheless, small scale studies are gradually pointing to a role for early-life lead exposure in the developmental, behavioral, and neuromolecular changes that are among the SZ hallmarks [106] .…”

“…This dilemma often results in misdiagnosis due to the lack of clear disease biomarkers. Although the etiology of these disorders is still poorly understood, strong evidence points out to the contribution of an assortment of factors, including genetic susceptibility, epigenetic dysregulation, and environmental stimuli to mental disease onset and/or progression [5] , [6] . Further, it remains unclear on the scope of mt pathways targeted by BD/SZ/MD psychotropic treatments, or how to strategize their administration.…”

Rationale, Relevance, and Limits of Stress-Induced Psychopathology in Rodents as Models for Psychiatry Research: An Introductory Overview

“…These issues mainly result from a lack of complete and comprehensive molecular, cellular, and circuitry understanding of psychiatric disorders pathophysiology, in which both genetics [ 14 , 15 ] — as suggested by their hereditary component [ 16 ] — and the environment plays an important role [ 17 ]. According to the Diathesis-Stress Model, diathesis or genetics are not sufficient per se to cause the majority of neuropsychiatric disorders, but it is the combination of a pre-existing genetic vulnerability with a stressor — the combination of nature and nurture — that leads to their development [ 18 ]. However, this model must be applied with a certain caution because not every patient suffering from psychopathology necessarily experienced particular stressful situations at a certain moment of his/her life.…”