Junboku Kajiwara

Maternal exposure to high levels of dioxins in relation to birth weight in women affected by Yusho disease

BACKGROUND Studies on the association of maternal exposure to polychlorinated dibenzo-p-dioxin (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) with decreased birth weight in humans have produced conflicting results. In Japan in 1968, an accidental human exposure to rice oil contaminated with PCDDs, PCDFs, and PCBs, led to the development of Yusho disease. OBJECTIVE The Yusho cohort was used to evaluate the effect of maternal exposure to PCDDs, PCDFs, and PCBs on birth weight. METHODS Blood samples, obtained from 101 Yusho women (190 births) who gave birth after exposure, were analyzed for congeners of seven PCDDs, ten PCDFs, and four non-ortho PCBs. RESULTS Total PCDD TEQ (adjusted beta=-161.9g; 95% CI, -265.3 to -58.6), total PCDF TEQ (adjusted beta=-105.9g; 95% CI, -179.5 to -32.2), and total non-ortho PCBs (adjusted beta=-178.4g; 95% CI, -318.3 to -38.5) levels were inversely associated with birth weight. Significant inverse associations with birth weight were also found for total PCDD TEQ, total PCDF TEQ, and total non-ortho PCB TEQ levels among male, but not female, infants. Significant inverse associations with birth weight were also found for nine congeners among all infants; the adjusted beta coefficients were largest for 1,2,3,6,7,8-HxCDD and smallest for 2,3,4,7,8-PeCDF. CONCLUSION In the setting of exposure to high levels of dioxins, maternal blood levels of PCDDs, PCDFs and PCBs are associated with lower birth weight in Yusho patients. The association exhibited gender-specific differences, as male infants are more susceptible than females to growth restriction induced by in utero dioxin exposures.

Blood levels of PCDDs, PCDFs, and coplanar PCBs in Yusho mothers and their descendants: Association with fetal Yusho disease

Maternal exposure to polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) may result in adverse health effects in their children. In Japan in 1968, an accidental human exposure to rice oil contaminated with PCDDs, PCDFs, and PCBs, led to the development of Yusho disease. Yusho mothers delivered descendants with low birth weights and hyperpigmented skin and mucosa, which are characteristic of fetal Yusho disease (FYD). The Yusho cohort was used to evaluate the effect of maternal exposure to PCDDs, PCDFs, and PCBs on the development of FYD. Blood samples, obtained from 64 Yusho mothers (117 descendants: 10 with FYD and 107 without FYD), were analyzed for congeners of seven PCDDs, 10 PCDFs, and four coplanar PCBs. We investigated the association between the maternal estimated blood levels of dioxins at delivery and the risk of fetal Yusho disease. We also studied the differences in dioxin blood levels in 24 mother-descendant pairs (5 with FYD and 19 without FYD). The estimated levels of total PCDD TEQ, total PCDF TEQ, total coplanar PCB TEQ, and total TEQ in the maternal blood at delivery were associated with significantly increased risk of FYD. The odds ratios, which present the risk of FYD for a 10-fold increase in blood dioxin, were largest for 1,2,3,6,7,8-HexaCDD (odds ratio=28.6, 95% confidence interval=1.67-489.9, p=0.02). The levels of 1,2,3,6,7,8-HexaCDD in both the Yusho mothers and their descendants with FYD were higher than the levels in those without FYD. These findings suggest that 1,2,3,6,7,8-HexaCDD is the most important causative congener for the development of FYD.

Comparison of the concentrations of polychlorinated biphenyls and dioxins in mothers affected by the Yusho incident and their children

Accumulated maternal dioxins are passed onto the fetus and neonate via the placenta and maternal milk. In Japan in 1968, an accidental human exposure to rice oil contaminated with polychlorinated biphenyls (PCBs) and other dioxin-related compounds, such as polychlorinated dibenzofurans (PCDFs), led to development of Yusho oil disease. We investigated differences in blood dioxin concentrations in mother-children pairs affected by the Yusho incident. From 2002 to 2008, blood samples were collected from 26 pairs of Yusho mothers and their children (19 mothers, 26 children). Specific congeners of seven polychlorinated dibenzo-p-dioxins (PCDDs), ten PCDFs, and four non-ortho PCBs were analyzed. The children had significantly lower TEQ concentrations of PCDDs, PCDFs, and coplanar PCBs compared to their mothers. The mother-child difference in blood concentrations varied with the congeners; the largest for 2,3,4,7,8-pentaCDF and the smallest for 1,2,3,4,6,7,8-heptaCDD. The level for 2,3,4,7,8-pentaCDF, which characterizes Yusho oil disease, was approximately 17-30 times higher in the mothers than in the general population, whereas there were no significant differences between children in the formula-fed group and the general population. In contrast, the mean level for 2,3,4,7,8-pentaCDF in the breast-fed group was approximately 1.5 times, (range 0.5-6.5 times) higher than that in the general population. Over 30 years after the Yusho incident, the mean blood dioxin levels in the offspring were only a fraction of the levels in their mothers. This is more consistent with exposure via breast milk than via transplacental transfer in the Yusho incident.

Reduction of CC-chemokine ligand 5 by aryl hydrocarbon receptor ligands

BACKGROUND The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that recognizes a large number of xenobiotics, such as polycyclic aromatic hydrocarbons (PAHs), dioxins, and some endogenous ligands. Despite numerous investigations targeting AhR ligands, the precise physiological role of AhR remains unknown. OBJECTIVE We explored novel AhR target genes, especially focused on inflammatory chemokine. METHODS We treated (1) HaCaT, a human keratinocyte cell line, (2) normal human epidermal keratinocytes (NHEKs), and (3) mouse primary keratinocytes with AhR ligands, such as 6-formylindolo[3,2-b]carbazole (FICZ; endogenous ligand) and benzo[a]pyrene (BaP; exogenous ligand). Then, we detected mRNA and protein of chemokine using quantitative RT-PCR and ELISA. We next clarified the relationship between AhR and chemokine expression using AhR siRNA. In addition, we measured serum chemokine levels in patients with Yusho disease (oil disease), who were accidentally exposed to dioxins in the past. RESULTS We identified CC-chemokine ligand 5 (CCL5), a key mediator in the development of inflammatory responses, as the AhR target gene. AhR ligands (FICZ and BaP) significantly reduced CCL5 mRNA and protein expression in HaCaT cells. These effects were observed in NHEKs and mouse primary keratinocytes. AhR knockdown with siRNA restored CCL5 inhibition by AhR ligands. In addition, AhR ligands exhibited a dose-dependent suppression of CCL5 production induced by Th1-derived cytokines. Finally, serum levels of CCL5 in patients with Yusho disease, were significantly lower than in controls. CONCLUSION Our findings indicate that CCL5 is a target gene for AhR, and might be associated with the pathology of dioxin exposure.

Sex-specific differences in effect of prenatal exposure to dioxin-like compounds on neurodevelopment in Japanese children: Sapporo cohort study

Background: Consistent reports are not available on the effects of dioxin‐like polychlorinated biphenyls (PCBs) and polychlorinated dibenzo‐p‐dioxins (PCDD)/ polychlorinated dibenzofurans (PCDF) (dioxin‐like compounds [DLCs]) on child neurodevelopment. Further, the effect of background‐level exposure to individual DLC isomers is not known. Objectives: We carried out the Sapporo cohort study to evaluate the effect of prenatal exposure to each DLC isomer on child neurodevelopment at 6 and 18 months of age, and assessed sex‐specific differences in these effects. Methods: The levels of all and each individual DLC isomers were estimated in maternal peripheral blood. Neurodevelopment was evaluated using the Bayley Scales of Infant Development‐2nd Edition for 6‐month‐old infants (n = 190) and 18‐month‐old children (n = 121). Results: In male children, levels of 10 DLC isomers were significantly negatively associated with the Psychomotor Developmental Index (PDI) at 6 months of age after adjustment for potential confounding variables. However, at 18 months of age, these associations were absent. In female children, the level of only one DLC isomer was significantly negatively associated with PDI at 6 months of age. However, in contrast to the male children, the levels of six DLC isomers in 18‐month‐old female children were significantly positively associated with the Mental Developmental Index. Conclusions: These findings indicate that adverse neurodevelopmental effects of prenatal background‐level exposure to DLCs may be stronger in male children. HighlightsAdverse developmental effects of prenatal exposure to DLCs may be stronger in male.A significant negative association to development of DLCs was absent at 18 m of age.Some of DLCs were positively associated with MDI at 18 m of age in female.