Environmental factors in autism

Abstract

Autism is a neurodevelopmental disorders characterized by impairments in communication and social behavior, and by repetitive behaviors. Although genetic factors might be largely responsible for the occurrence of autism they cannot fully account for all cases and it is likely that in addition to a certain combination of autism-related genes, specific environmental factors might act as risk factors triggering the development of autism. Thus, the role of environmental factors in autism is an important area of research and recent data will be discussed in this review. Interestingly, the results show that many environmental risk factors are interrelated and their identification and comparison might unveil a common scheme of alterations on a contextual as well as molecular level. For example, both, disruption in the immune system and in zinc homeostasis may affect synaptic transmission in autism. Thus, here, a model is proposed that interconnects the most important and scientifically recognized environmental factors. Moreover, similarities in how these risk factors impact synapse function are discussed and a possible influence on an already well described genetic pathway leading to the development of autism via zinc homeostasis is proposed.

Keywords: ASD; Shank3; cytokines; immune system; melatonin; risk factor; zinc deficiency.

Figure 1

Interconnection of various environmental risk factors for autism. Many risk factors for autism can be related to each other. All factors are shown weighted for their interconnectedness with other factors. Zn²⁺-deficiency and immune system aberrations receive most connections and thus can be placed in the center of the network. Zn²⁺-deficiency, toxins, and the parental age may act on genetic factors providing a crosstalk between genes and environment. Zn²⁺-deficiency and melatonin deficiency in turn can also be caused by genetic alterations.

Figure 2

Modes of action of environmental risk factors for autism at excitatory synapses in the CNS. Scaffold proteins within the PSD such as proteins of the Shank family build a dense meshwork of interacting protein complexes including Homer, mGluR, AMPAR, and GKAP further connecting to PSD95 and NMDAR. These synaptic components are regulated via signaling cascades such as the p38 MAPK and ERK pathway and altogether ultimately determine the immediate and long-term response to a synaptic stimulus. Environmental factors that have been discussed in autism may influence this signaling outcome on various levels. Zn²⁺-deficiency for instance might be able to alter the PSD scaffold via Shank2 and Shank3 and additionally influences NMDAR, TrkB receptor, and GPR39 receptor signaling. Moreover, Zn²⁺ that might be released from presynaptic vesicles or postsynaptic metallothioneins can affect IGF1 signaling and gene expression via MTF1. Immune system abnormalities, including the expression of cytokines such as TNF-α, Il-1β, IL-18, and IL-6 will affect mGluR, p38 MPAK, and ERK signaling, pathways that are also activated by the receptors mentioned above.