Autism: Transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents.

 

Roman, G., 2007.

Journal of the Neurological Sciences 262 :15‚ 26

Abstract

The incidence and prevalence of autism have increased during the past two decades. Despite comprehensive genetic studies the cause of autism remains unknown. This review emphasizes the potential importance of environmental factors in its causation. Alterations of cortical neuronal migration and cerebellar Purkinje cells have been observed in autism. Neuronal migration, via reelin regulation, requires triiodothyronine (T3) produced by deiodination of thyroxine (T4) by fetal brain deiodinases. Experimental animal models have shown that transient intrauterine deficits of thyroid hormones (as brief as 3 days) result in permanent alterations of cerebral cortical architecture reminiscent of those observed in brains of patients with autism. I postulate that early maternal hypothyroxinemia resulting in low T3 in the fetal brain during the period of neuronal cell migration (weeks 8‚ 12 of pregnancy) may produce morphological brain changes leading to autism. Insufficient dietary iodine intake and a number of environmental antithyroid and goitrogenic agents can affect maternal thyroid function during pregnancy. The most common causes could include inhibition of deiodinases D2 or D3 from maternal ingestion of dietary flavonoids or from antithyroid environmental contaminants. Some plant isoflavonoids have profound effects on thyroid hormones and on the hypothalamus‚ pituitary axis. Genistein and daidzein from soy (Glycine max) inhibit thyroperoxidase that catalyzes iodination and thyroid hormone biosynthesis. Other plants with hypothyroid effects include pearl millet (Pennisetum glaucum) and fonio millet (Digitaria exilis); thiocyanate is found in Brassicae plants including cabbage, cauliflower, kale, rutabaga, and kohlrabi, as well as in tropical plants such as cassava, lima beans, linseed, bamboo shoots, and sweet potatoes. Tobacco smoke is also a source of thiocyanate. Environmental contaminants interfere with thyroid function including 60% of all herbicides, in particular 2,4-dichlorophenoxyacetic acid (2,4-D), acetochlor, aminotriazole, amitrole, bromoxynil, pendamethalin, mancozeb, and thioureas. Other antithyroid agents include polychlorinated biphenyls (PCBs), perchlorates, mercury, and coal derivatives such as resorcinol, phthalates, and anthracenes. A leading ecological study in Texas has correlated higher rates of autism in school districts affected by large environmental releases of mercury from industrial sources. Mercury is a well known antithyroid substance causing inhibition of deiodinases and thyroid peroxidase. The current surge of autism could be related to transient maternal hypothyroxinemia resulting from dietary and/or environmental exposure to antithyroid agents. Additional multidisciplinary epidemiological studies will be required to confirm this environmental hypothesis of autism.

Environmental chemicals with antithyroid effects Howdeshell [103] and Colborn [104,105] have recently reviewed the potential effects of environmental chemical agents on endocrine function‚ causing in particularly thyroid disruption and abnormal brain development. Low doses of toxins could become deleterious in cases of low maternal iodine [104] . Table 2 [103] provides a comprehensive list of chemical agents with effects at several levels of thyroid metabolism. More than 60% of herbicides are endocrine disruptors [104] in particular the widely used 2,4-dichlorophenoxyacetic acid (2,4-D), mancozeb, acetochlor, aminotriazole, amitrole, bromoxynil, pendamethalin, and the thioureas. Contamination of drinking water from areas rich in coal and shale by naturally occurring powerful antithyroid products such as resorcinol (1,3-dihydroxybenzene dihydroxybenzene) and the substituted resorcinol 2,4- dihydroxyacetophenone, methoxy-anthracene, phthalate esters and phthalic acid, can produce endemic goiter and hypothyroidism [106]. The developmental neurotoxicity of polychlorinated biphenyls (PCBs) and dioxins has been known since the 1990s [107,108] . Neurobehavioral alterations have been observed in newborn children exposed to PCBs including motor immaturity, hyporreflexia, and lower psychomotor scores between 6 months and 2 years of age; along with decrease in dopamine in basal ganglia and prefrontal cortex [107] . Similar dopamine alterations have been reported in children with autism [109] . These abnormalities could be mediated by disruption of thyroid hormones by competitive binding of PCBs (structurally similar to thyroid hormones) to serum transport proteins [110] and by alterations in thyroid hormone-responsive genes in the developing brain [103‚ 105,110‚ 112] . Recently, Kimura-Kuroda et al. [113] demonstrated that several hydroxy- PCBs are capable of inhibiting the thyroid-hormone-dependent development of dendrites in cerebellar Purkinje cells and suggested that PCBs could be a cause of autism and other developmental disorders.

Although many authors have suggested that environmental pollutants‚ such as those affecting thyroid hormones‚ may play a role in autism [85,103‚ 105,112,113,125] only recently Palmer and colleagues [126], from the University of Texas at San Antonio, reported an ecological association between autism and environmental mercury pollution. This study was based on quantitative data on mercury released in the Texas environment, provided by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The authors correlated environmentally released mercury (per 1000 lb) with rates of autism in Texas using county (N=254) and school district (N=1184) information by means of a multilevel Poisson regression model adjusted for racial composition, socioeconomic level and urbanicity. They concluded that the risk for autism increased 6.15% per each 100 lb of environmentally released mercury (RR=1.614, 95% CI 1.487‚ 1.752); the highest increase in relative rates of autism in school districts was for urban relative to rural (RR=4.726, 95% CI 3.8‚ 5.9) and for suburban vs. rural districts (RR=2.547, 95% CI 2.1‚ 3.2). Autism accounted for the increase in special education rate whereby each 100 lb of mercury released increased 4.3% the rate of special education students (RR=1.433, 95% CI 1.35‚ 1.52) [126]. This study from our institution is one of the first to demonstrate an association between environmental pollution and autism.