Inhibition, Na+/I- symporter (NIS) leads to Impairment, Learning and memory

Single NIS mutations, causing decreased thyroidal iodide uptake, may not necessarily lead to cognitive disorders. In this regard, Nicola and coworkers (Nicola et al., 2015) recently identified a new NIS mutation (V270E) in a patient (full-term girl born to healthy, non-consanguineous Jamaican parents), who resulted to be heterozygous for this NIS mutation (R124H/V270E). The presence of the mutation V270E markedly reduces iodide uptake (5.4% 24 hours after the oral administration of 100 μCi ¹²³I− (normal range, 10–40%)) via a pronounced (but not total) impairment of the protein's plasma membrane targeting. However, the retaining of a minimal iodide uptake was enough to enable sufficient TH biosynthesis and prevent cognitive impairment.

It should be noted that the van Wijk et al. 2008  study was performed with only one dose group exposed to perchlorate during development, and the behavioural assessments were performed using a limited group size of 5-8, possibly reducing the reliability of this study. In general, chronic hypothyroidism effects on development were more pronounced than the effects of perinatal hypothyroidism, suggesting that functional alterations occurring as a consequence of hypothyroidism may be partly reversible depending on developmental stage of the deficiency.

Opposite, other in vivo studies do not support associations between perinatal perchlorate exposure and neurobehavioural effects. For example, York et al. (2004) could not observe meaningful behavioral effects in rat offspring exposed as high as 10.0 mg/kg/day, as evaluated by passive avoidance, swimming water maze, motor activity, and auditory startle. In their re-evaluation of the data (York et al. 2005), authors concluded that rat pups exposed to perchlorate both during pregnancy and after 10 days of lactation, despite showing alterations of neurohistopathological features, did not show altered development of gross motor movements. Moreover, Gilbert and Sui (2008) found that adult male offspring born from rat dams exposed to 0, 30, 300, or 1,000 ppm perchlorate in drinking water from gestational day 6 until weaning, underwent reduction of T3 (10–14% reduction) and T4 (~ 9–20% reduction) reduction on postnatal day 21 (at the highest perchlorate dose), significant reductions in baseline synaptic transmission (~ 20% increase in excitatory postsynaptic potential slope amplitude), but without changes of motor activity, spatial learning, or fear conditioning.

Taylor et al. 2004 (CATS study) identified 1050 pregnant women with hypothyroidism or hypothyroxinemia; half were in the immediate T4 treatment group, and half were in the group tested and treated after pregnancy. 487 (46.4%) mother-child pairs completed psychological testing and urinary iodine and perchlorate measurements. Therefore, the 487 women-child pairs represent approximately two-thirds of those reported in the study of T4 treatment effects on cognitive outcome. Taking this into account, the absence of a direct effect of perchlorate on maternal thyroid function (Pearce et al. 2010), suggests that developmental effects of perchlorate may not necessarily be linked to maternal thyroid hormone levels, as commented in (Brent, 2014).