Alterations in Regional Brain Regional Volume Associated with Dioxin Exposure in Men Living in the Most Dioxin-Contaminated Area in Vietnam: Magnetic Resonance Imaging (MRI) Analysis Using Voxel-Based Morphometry (VBM)

To clarify the influence of dioxin exposure on brain morphometry, the present study investigated associations between dioxin exposure at high levels and brain structural irregularities in 32 Vietnamese men. Two exposure markers were used: blood dioxin levels, as a marker of exposure in adulthood, and perinatal dioxin exposure, estimated by maternal residency in a dioxin-contaminated area during pregnancy. All subjects underwent brain magnetic resonance imaging (MRI) scans. We analyzed correlations between regional gray matter volumes and blood dioxin levels, and compared regional volumes between men with and without perinatal dioxin exposure using the voxel-based morphometry (VBM) tool from Statistical Parametric Mapping 12 (SPM12). Blood 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was associated with low volume of the medial temporal pole and fusiform gyrus. Toxic equivalency (TEQ)-PCDDs were correlated with low medial temporal pole volume. However, 1,2,3,4,7,8-HxCDD was associated with high middle frontal gyrus and cerebellum volume. In men with perinatal dioxin exposure, the left inferior frontal gyrus pars orbitalis volume was significantly lower than in those without perinatal exposure. These results suggest that dioxin exposure during the perinatal period and in adulthood may alter regional brain volume, which might lead to cognitive deficits and unusual social emotional behavior in Vietnamese men living in dioxin-contaminated areas.

Efek pemberian α-tokoferol terhadap jumlah sel spermatogenik dan sel Leydig pada tikus putih (Rattus norvegicus) yang dipapar 2,3,7,8 Tetrachlorodibenzo-p-dioxin

This research aimed to determine the effect of α-tocopherol on the count of spermatogenic and Leydig cells in rats (Rattus norvegicus) exposed to 2,3,7,8 tetrachlorodibenzo-p-dioxin (dioxin). Dioxin is an endocrine-disrupting agent that adversely affects reproductive health, while α-tocopherol maintains fertility. This research used 25 rats aged 10-12 weeks weighing 150-200 grams. Rats were divided into five groups (K, P0, P1, P2 and P3). The K (control group) was administered with corn oil 1 ml/day. P0 was exposed to 700 ng/kg/day dioxin. P1, P2 and P3 was exposed to dioxin at a dose of 700 ng/kg/day and administered with α-tocopherol at a dose of 77, 140 and 259 mg/kg/day respectively. Dioxin exposure, corn oil and α-tocopherol administration were conducted orally for 20 days. On day-21, all rats were sacrificed for histological slides preparation of testicles with hematoxylin-eosin staining. Data were analyzed with analysis of variance and continued with the Duncan test. The results indicated that exposure to dioxin caused a decrease in the number of spermatogenic and Leydig cells. The administration of α-tocopherol at a dose of 140 mg/kg/day eliminated the effect of reducing the number of spermatogenic and Leydig cells caused by exposure to dioxin. The conclusion was the administration of α-tocopherol at 140 mg/kg/day was effective in maintaining the number of spermatogenic and Leydig cells in rats (Rattus norvegicus) exposed to 2,3,7,8 tetrachlorodibenzo-p-dioxin.

Effects of Acute 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Exposure on the Circulating and Cecal Metabolome Profile

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a polyhalogenated planar hydrocarbon belonging to a group of highly toxic and persistent environmental contaminants known as “dioxins”. TCDD is an animal teratogen and carcinogen that is well characterized for causing immunosuppression through activation of aryl hydrocarbon receptor (AHR). In this study, we investigated the effect of exposure of mice to an acute dose of TCDD on the metabolic profile within the serum and cecal contents to better define the effects of TCDD on host physiology. Our findings demonstrated that within the circulating metabolome following acute TCDD exposure, there was significant dysregulation in the metabolism of bioactive lipids, amino acids, and carbohydrates when compared with the vehicle (VEH)-treated mice. These widespread changes in metabolite abundance were identified to regulate host immunity via modulating nuclear factor-kappa B (NF-κB) and extracellular signal-regulated protein kinase (ERK1/2) activity and work as biomarkers for a variety of organ injuries and dysfunctions that follow TCDD exposure. Within the cecal content of mice exposed to TCDD, we were able to detect changes in inflammatory markers that regulate NF-κB, markers of injury-related inflammation, and changes in lysine degradation, nicotinamide metabolism, and butanoate metabolism, which collectively suggested an immediate suppression of broad-scale metabolic processes in the gastrointestinal tract. Collectively, these results demonstrate that acute TCDD exposure results in immediate irregularities in the circulating and intestinal metabolome, which likely contribute to TCDD toxicity and can be used as biomarkers for the early detection of individual exposure.

Sex-specific associations between type 2 diabetes incidence and exposure to dioxin and dioxin-like pollutants: a meta-analysis

The relationship between persistent organic pollutants (POPs), including dioxins and dioxin-like polychlorinated biphenyls (DL-PCBs), and diabetes incidence in adults has been extensively studied. However, significant variability exists in the reported associations both between and within studies. Emerging data from rodent studies suggest that dioxin exposure disrupts glucose homeostasis in a sex-specific manner. Thus, we performed a meta-analysis of relevant epidemiological studies to investigate whether there are sex-specific associations between dioxin or DL-PCB exposure and type 2 diabetes incidence. Articles were organized into the following subcategories: data stratified by sex (16%), unstratified data (56%), and data from only 1 sex (16% male, 12% female). We also considered whether exposure occurred either abruptly at high levels through a contamination event (“disaster exposure”) or chronically at background levels (“non-disaster exposure”). Only 8 studies compared associations between dioxin/DL-PCB exposure and diabetes risk in males versus females within the same population. When all sex-stratified or single sex studies were considered in the meta-analysis, the summary odds ratio (OR) for increased diabetes risk was similar between females and males (1.78 and 1.95, respectively) when comparing exposed to reference populations, suggesting that this relationship is not sex-specific. However, when we considered disaster-exposed populations separately, the association differed substantially between sexes, with females showing a much higher OR than males (2.86 and 1.59, respectively). Moreover, the association between dioxin/DL-PCB exposure and diabetes was stronger for females than males in disaster-exposed populations. In contrast, both sexes had significantly increased ORs in non-disaster exposure populations and the OR for females was lower than males (1.40 and 2.02, respectively). Our review emphasizes the importance of considering sex differences, as well as the mode of pollutant exposure, when exploring the relationship between pollutant exposure and diabetes in epidemiological studies.

Developmental and lifelong dioxin exposure induces measurable changes in cardiac structure and function in adulthood

Congenital heart disease (CHD) is the most common congenital abnormality. A precise etiology for CHD remains elusive, but likely results from interactions between genetic and environmental factors during development, when the heart adapts to physiological and pathophysiological conditions. Further, it has become clearer that early exposure to toxins that do not result in overt CHD may be associated with adverse cardiac outcomes that are not manifested until later life. Previously, interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, was shown to cause structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. Here, we show that continuous exposure to TCDD from fertilization throughout adulthood caused male mice to underperform at exercise tolerance tests compared to their control and female counterparts, confirming previous observations of a sexually dimorphic phenotype. Renin-angiotensin stimulation by angiotensin II (Ang II) caused measurable increases in blood pressure and left ventricle mass, along with decreased end diastolic volume and preserved ejection fraction. Interestingly, TCDD exposure caused measurable reductions in the myocardial hypertrophic effects of Ang II, suggesting that endogenous AHR signaling present in adulthood may play a role in the pathogenesis of hypertrophy. Overall, the findings reported in this pilot study highlight the complex systems underlying TCDD exposure in the development of cardiac dysfunction in later life.

Nutritional Intervention with Dried Bonito Broth for the Amelioration of Aggressive Behaviors in Children with Prenatal Exposure to Dioxins in Vietnam: A Pilot Study

Dioxins have been suggested to induce inflammation in the intestine and brain and to induce neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), partly due to deficits in parvalbumin-positive neurons in the brain that are sensitive to inflammatory stress. Previously, we reported ADHD traits with increased aggressiveness in children with prenatal exposure to dioxins in Vietnam, whereas dried bonito broth (DBB) has been reported to suppress inflammation and inhibit aggressive behavior in animal and human studies. In the present study, we investigated the association between dioxin exposure and the prevalence of children with highly aggressive behaviors (Study 1), as well as the effects of DBB on the prevalence of children with highly aggressive behaviors (Study 2). Methods: In Study 1, we investigated the effects of dioxin exposure on the prevalence of children with high aggression scores, which were assessed using the Children’s Scale of Hostility and Aggression: Reactive/Proactive (C-SHARP) in dioxin-contaminated areas. The data were analyzed using a logistic regression model after adjusting for confounding factors. In Study 2, we performed nutritional intervention by administering DBB for 60 days to ameliorate the aggressiveness of children with high scores on the C-SHARP aggression scale. The effects of DBB were assessed by comparing the prevalence of children with high C-SHARP scores between the pre- and post-intervention examinations. Results: In Study 1, only the prevalence of children with high covert aggression was significantly increased with an increase in dioxin exposure. In Study 2, in the full ingestion (>80% of goal ingestion volume) group, the prevalence of children with high covert aggression associated with dioxin exposure was significantly lower in the post-ingestion examination compared with in the pre-ingestion examination. However, in other ingestion (<20% and 20–79%) groups and a reference (no intervention) group, no difference in the prevalence of children with high covert aggression was found between the examinations before and after the same experimental period. Conclusions: The findings suggest that DBB ingestion may ameliorate children’s aggressive behavior, which is associated with perinatal dioxin exposure.