Is lead exposure in early life an environmental risk factor for Schizophrenia? Neurobiological connections and testable hypotheses

Abstract

Schizophrenia is a devastating neuropsychiatric disorder of unknown etiology. There is general agreement in the scientific community that schizophrenia is a disorder of neurodevelopmental origin in which both genes and environmental factors come together to produce a schizophrenia phenotype later in life. The challenging questions have been which genes and what environmental factors? Although there is evidence that different chromosome loci and several genes impart susceptibility for schizophrenia; and epidemiological studies point to broad aspects of the environment, only recently there has been an interest in studying gene × environment interactions. Recent evidence of a potential association between prenatal lead (Pb2+) exposure and schizophrenia precipitated the search for plausible neurobiological connections. The most promising connection is that in schizophrenia and in developmental Pb2+ exposure there is strong evidence for hypoactivity of the N-methyl-d-aspartate (NMDA) subtype of excitatory amino acid receptors as an underlying neurobiological mechanism in both conditions. A hypofunction of the NMDA receptor (NMDAR) complex during critical periods of development may alter neurobiological processes that are essential for brain growth and wiring, synaptic plasticity and cognitive and behavioral outcomes associated with schizophrenia. We also describe on-going proof of concept gene-environment interaction studies of early life Pb2+ exposure in mice expressing the human mutant form of the disrupted in schizophrenia 1 (DISC-1) gene, a gene that is strongly associated with schizophrenia and allied mental disorders.

Mechanisms of lead and manganese neurotoxicity

“…86,88 Pb exposure has also been suggested to enhance susceptibility to schizophrenia through a gene–environment interaction with a mutant form of the disrupted-in-schizophrenia 1 (DISC1) gene. 89 …”

Developmental exposure to manganese induces lasting motor and cognitive impairment in rats

“…During these vulnerable periods, which may encompass either in utero or early postnatal phases, particular toxicants, even at low doses that do not affect adults, may cause significant detrimental effects Landrigan, 2006, 2014). It has been proposed that environmental exposure to toxic agents during early periods of neural development may increase susceptibility to additional exposure of the CNS or increase the risk of neurological diseases such as Parkinson's disease and schizophrenia (CorySlechta et al, 2005;Guilarte et al, 2012;Grandjean and Landrigan, 2014). Mn has been identified as a developmental neurotoxicant associated with hyperactivity, lower intellectual function, impaired motor skills and reduced olfactory function in children (Zoni and Lucchini, 2013;Grandjean and Landrigan, 2014).…”

Clinical, Haematological, and Neurocognitive Findings in Lead-Exposed Workers of a Battery Plant in Iran

“…Workers in these factories can be exposed to lead dusts or fumes, and if protective tools are not properly used, exposure may result in serious health disorders (2)(3)(4)(5). Neurocognitive and neurobehavioral disorders that are associated with high blood lead level (BLL) include (6, 7) attention and intelligence impairment in children (8,9), neurobehavioral problems (10), neurobiological defects such as schizophrenia (11), or Alzheimer's disease (12). The aim of this study was to establish neurocognitive impairment and its association with lead-related haematological fi ndings and clinical symptoms in workers of a battery plant in Iran.…”