Dopamine receptor D2 gene polymorphism, urine fluoride, and intelligence impairment of children in China: A school-based cross-sectional study.

OBJECTIVE: We aimed to study the association of urine fluoride with intelligence quotient (IQ) in children with a careful consideration of up to 30 potential confounding factors as well as possible heterogeneity of the relation between urine fluoride levels and IQ scores across children with different dopamine receptor-2 (DRD2) Taq 1A genotypes (CC, CT, and TT). METHODS: A school-based cross-sectional study design was applied. A total of 323 children (2014-2015, 7-12 years old) were enrolled from four schools in both historical endemic and non-endemic areas of fluorosis in Tianjin of China using a cluster sampling method. Urine fluoride levels and age-specific IQ scores in children were measured at the enrollment. Polymerase chain reaction-restriction fragment length polymorphism methods were used to genotype DRD2 Taq 1A polymorphism with genomic DNA isolated from whole blood collected at the enrollment. Multiple linear regression models were applied to evaluate the relationship between urine fluoride levels and IQ scores overall and within the DRD2 Taq 1A SNP = CC/CT and TT subgroups. Model robustness was tested through bootstrap, sensitivity analysis, and cross-validation techniques. A safety threshold of urine fluoride levels for IQ impairment was determined in the subgroup TT. RESULTS: In overall participants, the DRD2 Taq 1A polymorphism itself was not related to IQ scores in children who had a high level of urine fluoride. In the CC/CT subgroup, urine fluoride levels and IQ scores in children were unrelated (adjusted ß (95% confidence interval (CI)) = - 1.59 (- 4.24, 1.05), p = 0.236). Among the participants carrying the TT genotype, there was a strong and robust negative linear relationship between log-urine fluoride and IQ scores in children (adjusted ß (95% CI) = - 12.31 (- 18.69, - 5.94), p < 0.001). Urine fluoride levels had a stronger association with IQ in children carrying the TT genotype (adjusted ß = - 12.31, bootstrapped standard error (SE) = 1.28), compared to that in overall participants (adjusted ß = - 2.47, bootstrapped SE = 3.75) (Z = 2.483 and bootstrapped p = 0.007). The safety threshold of urine fluoride levels in the subgroup TT was 1.73 mg/L (95% CI = (1.51, 1.97) (mg/L)). CONCLUSIONS: There is heterogeneity in the relation between urine fluoride and IQ across children carrying different DRD2 Taq 1A genotypes. Large-scale epidemiological studies are needed to confirm our findings.

Long-term repetitive exposure to excess iodine induces mitochondrial apoptosis, and alters monoamine neurotransmitters in hippocampus of rats of different genders.

The influence of excess iodine on human health has been paid more and more attention. Although numerous studies have reported that excess iodine may cause deleterious effects, the mental damage and its mechanism is yet to be identified. Using Sprague-Dawley rats exposed to excess iodine from pregnancy to 6 months post-delivery as in vivo model, this study explored the impacts of long-term repetitive excess iodine administration on the hippocampus of offspring rats, focusing on mitochondrial apoptosis pathway, with changes in monoamine neurotransmitters. The results showed that excess iodine could increase urinary iodine and brain organ coefficient in offspring of both genders, change the hippocampal cell structure, and damage the spatial learning and memory capacities. Poly ADP-ribose polymerase (PARP), P53, Cleaved Caspase-3, and cytochrome C proteins expression increased and Bcl2 protein expression decreased in hippocampus of excess iodine-treated offspring, indicating that excess iodine could activate the mitochondrial apoptosis pathway. Besides, excess iodine showed different effects on monoamine neurotransmitter in different gender. Collectively, our experimental data indicated that the learning and memory impairment induced by excess iodine may be mediated via mitochondrial apoptotic pathway. Long-term repetitive excess iodine exposure affected monoamine neurotransmitters in hippocampus of offspring rats.

Excessive apoptosis and disordered autophagy flux contribute to the neurotoxicity induced by high iodine in Sprague-Dawley rat.

In recent years, the detrimental effects of high iodine on intelligence are gaining tons of attention, but the relationship between high iodine and neurotoxicity is controversial. This study aimed to explore whether high iodine intake may impair intelligence and the roles of apoptosis and autophagy in high iodine-induced neurotoxicity. The results showed that high iodine exposure reduced brain coefficient and intelligence of rats, and caused histopathological abnormalities in hippocampus. Moreover, high iodine increased hippocampal apoptosis, as confirmed by elevation of apoptotic proteins and TUNEL-positive incidence. Further study showed that high iodine impaired mitochondrial ultrastructure and caused elevation of Bax, cytochrome c and decline of Bcl2, indicating the participation of mitochondrial apoptotic pathway. Simultaneously, high iodine also increased the number of autophagosomes. Intriguingly, the expression of autophagosomes formation protein Atg7, Beclin1 and autophagic substrate p62 were elevated, suggesting that the accumulated autophagosomes is not only due to the enhancement of formation but also the decline of clearance. These, together with the numerous damaged organelles observed in hippocampal ultrastructure, reveal the crucial role of disordered autophagy flux in high iodine-elicited neurotoxicity. Collectively, these findings suggest that excessive apoptosis and disordered autophagy flux contribute to high iodine-elicited neurotoxicity.

Autophagy regulates high concentrations of iodide-induced apoptosis in SH-SY5Y cells.

To date, there are many people residing in areas with high levels of iodide in water. Our previous epidemiological study showed that exposure to high iodine in drinking water significantly reduced the intelligence of children although the mechanisms remain unclear. To explore whether high concentrations of iodide may cause cytotoxic effect and the role of autophagy in the high iodide-induced apoptosis, human neuroblastoma cells (SH-SY5Y cells) were exposed to high concentrations of iodide. Morphological phenotypes, cell viability, Hoechst 33258 staining, the expression levels of apoptosis and autophagy-related proteins were detected. A possible effect of an inhibitor (3-methyladenine, 3-MA) or an inducer (rapamycin) of autophagy on high iodide-induced apoptosis also was examined. Results indicated that high iodide changed cellular morphology, decreased cell viability and increased the protein's expression level of apoptosis and autophagy. In addition, high iodide-induced apoptosis was enhanced by inhibition of autophagy and inhibited by activation of autophagy in SH-SY5Y cells. Collectively, high concentrations of iodide are toxic to SH-SY5Y cells, as well as induce apoptosis and autophagy. Furthermore, autophagy plays a regulatory role in high concentrations of iodide-induced apoptosis in SH-SY5Y cells.

Role of endoplasmic reticulum stress-induced apoptosis in rat thyroid toxicity caused by excess fluoride and/or iodide.

Excess fluoride and iodide coexist in drinking water in many regions, but few studies have investigated the single or interactive effects on thyroid in vivo. In our study, Wistar rats were exposed to excess fluoride and/or iodide through drinking water for 2 or 8 months. The structure and function of the thyroid, cells apoptosis and the expression of inositol-requiring enzyme 1 (IRE1) pathway-related factors were analyzed. Results demonstrated that excess fluoride and/or iodide could change thyroid follicular morphology and alter thyroid hormone levels in rats. After 8 months treatment, both single and co-exposure of the two microelements could raise the thyroid cells apoptosis. However, the expressions of IRE1-related factors were only increased in fluoride-alone and the combined groups. In conclusion, thyroid structure and thyroid function were both affected by excess fluoride and/or iodide. IRE1-induced apoptosis were involved in this cytotoxic process caused by fluoride or the combination of two microelements.

[Association between adverse experiences in childhood and risk of chronic diseases in adulthood].

OBJECTIVE: To analyze the prevalence and characteristics of childhood adverse experiences among adults aged 18-59 years and understand the association between childhood adverse experiences and risk of chronic diseases in adulthood. METHODS: A cross-sectional study was conducted with a questionnaire among adults aged 18-59 years selected through cluster random sampling from 3 communities in Macheng, Hubei province. Uinivariate and multivariate logistic regression analyses were conducted to evaluate the association between adverse experiences in childhood and the risk of chronic diseases in adulthood. RESULTS: A total of 1 767 adults aged 18-59 years were surveyed and 1 501 valid questionnaires were returned. The average age was (36.32± 10.20) years for males and (35.72±9.08) years for females. The prevalence rate of childhood adverse experiences was 66.22%. The risk of chronic disease in adults increased with the increase of the score indicating childhood adverse experiences (Z=-5.902 1, P<0.000 1). Multivariate logistic regression analysis showed that being physically abused (OR=1.93, 95% CI: 1.41-2.64), substance abuse in family (OR=2.82, 95% CI: 1.16-6.80), being bullied (OR=2.59, 95% CI: 1.39-4.80) and parents separation/divorce (OR=1.51, 95% CI: 1.09-2.09) were significantly associated with risk of chronic diseases in adulthood. CONCLUSION: The prevalence of adverse childhood experiences was high in adults aged 18-59 years, which was significantly associated with the risk of chronic diseases in adulthood. Early prevention of chronic diseases should be conducted in childhood.