Current state of yusho and prospects for therapeutic strategies

The mass food poisoning incident yusho occurred in Japan in 1968. It was caused by the ingestion of rice bran oil contaminated with polychlorinated biphenyls and various dioxins and dioxin-like compounds including polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDFs). Notably, PCDFs were found to contribute to approximately 65% of the total toxicity equivalent in the blood of yusho patients. Lipophilic dioxins are retained in the body for a longer period than previously estimated. Victims suffered from characteristic skin manifestations associated with non-specific systemic symptoms, neurological symptoms, and respiratory symptoms. The severe symptoms seen in the initial phase subsequently faded, but recently, improvements have scarcely been observed. The Yusho Group has been researching treatments for this condition. Several clinical trials with chelating agents or dietary fibers aimed at accelerating the excretion of compounds. While some treatments increased dioxin excretion, none provided satisfactory symptom relief. Concurrently, various phytochemicals and herbal extracts have been found to possess biological activities that suppress dioxin-induced toxicity via aryl hydrocarbon receptor or activate the antioxidant nuclear factor-erythroid 2-related factor-2 (NRF2) signal pathway, making them promising therapeutic candidates. Here, we summarize the current status of yusho and findings of clinical trials for yusho patients and discuss the treatment prospects.

     

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 = − 161.9 g; 95% CI, −265.3 to − 58.6), total PCDF TEQ (adjusted beta = − 105.9 g; 95% CI, −179.5 to − 32.2), and total non-ortho PCBs (adjusted beta = − 178.4 g; 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.     

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.     

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.     

Concentrations of polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and polychlorinated biphenyls in blood and breast milk collected from pregnant women in Sapporo City, Japan

We measured the concentrations of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), dioxin-like polychlorinated biphenyls (PCBs), and non-dioxin-like PCBs in paired samples of blood and breast milk collected from 67 secundiparas in Sapporo City, Japan, and combined this data with those of the 30 secundiparas previously measured. The arithmetic mean total toxic equivalents (TEQ-WHO) concentrations of PCDDs, PCDFs, non-ortho PCBs, and mono-ortho PCBs in blood and breast milk of the 97 secundiparous subjects were 3.0-23 (mean: 13, median: 14) and 2.7-20 (mean: 8.6, median: 8.5) pg TEQ g⁻¹ lipid, respectively. The sums of the concentrations of 56 non-dioxin-like PCB congeners that were measured in the subjects’ blood and breast milk were 16-326 (mean: 107, median: 100) and 12-252 (mean: 73, median: 67) ng g⁻¹ lipid, respectively. The partitioning ratios of individual congeners of PCDDs, PCDFs, dioxin-like PCBs, and non-dioxin-like PCBs from blood to breast milk in secundiparas were almost the same as those of primiparas that have been recently reported, suggesting that the partitioning ratios of these compounds from maternal blood to breast milk in women is little affected by delivery. Furthermore, the partition of PCB congeners with chlorine at the 2-, 3-, 4′-, and 5-positions or the 2-, 4-, 4′-, and 5-positions of the biphenyl ring from the blood to the breast milk tended to occur at a higher level than that of other congeners. In particular, the levels of tetraCB-74 and hexaCB-146 in the breast milk for both primiparous and secundiparous mothers were slightly higher than those in the blood.