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.

     

Evaluation of surface runoff and road dust as sources of nitrogen using nitrate isotopic composition

Stable nitrogen and oxygen isotope ratios of nitrate (δ¹⁵N-NO₃ and δ¹⁸O-NO₃) have recently been used to identify nitrogen sources in water environments. However, there have been no investigations designed to determine nitrate isotopes in non-point sources in urban areas for evaluating the impact of surface deposits on nitrogen in surface runoff. In this study, we collected rainwater, surface runoff and surface deposits (road dust, roof dust and soil) to evaluate the nitrogen sources in surface runoff using nitrate isotopes. There were no large differences in δ¹⁵N-NO₃ among rainwater (−0.3‰ to 1.5‰), surface runoff (−2.7‰ to 0.4‰), leachates from road dust (−5.8‰ to 6.2‰) and soil (−11.5‰ to 0.6‰). In contrast, the δ¹⁸O-NO₃ in surface runoff (28.5-47.9‰) was lower than that in rainwater (62.7-78.6‰), and higher than that in leachates from road dust (6.1-27.6‰) and soil (−1.1‰ to 6.6‰). δ¹⁸O-NO₃ is a useful indicator for evaluating the NO₃-N sources in surface runoff. Using this indicator, NO₃-N from road dust was estimated to account for more than half of the NO₃-N in surface runoff. This is consistent with a result based on a comparison of their loads per unit surface between rainwater and surface runoff, which also showed that most of the nitrogen in surface runoff was derived from surface deposits.     

Compound-specific isotopic and congener-specific analyses of polychlorinated biphenyl in the heat medium and rice oil of the Yusho incident

Compound-specific isotope analysis (CSIA) can be used to examine the source and transformation processes of organic pollutants in the environment. We performed a carbon stable isotope analysis of polychlorinated biphenyl (PCB) congeners in the PCB heat-transfer medium (heat medium) and the original Kanechlor-400 (KC-400, a commercial brand of PCBs) involved in the Yusho incident. The main purpose is to investigate whether isotope fractionation occurred in the rice oil deodorization process that caused the incident. The carbon isotope ratios (δ¹³C values) of the targeted PCB congeners ranged from ? 29.39 to ? 27.00‰ in the heat medium and from ? 28.77 to ? 27.05‰ in the original KC-400. No significant differences were found in the δ¹³C values, suggesting carbon isotope fractionation did not occur for the targeted PCB congeners in the heat medium when deodorization of rice oil occurred at temperatures above 200 °C. Furthermore, we also conducted a congener-specific analysis of 64 PCB congeners found in the heat medium and rice oil contaminated by it. The total PCB congener concentrations were 503 mg/g in the heat medium and 81 μg/g in the rice oil. The concentrations of the highly chlorinated congeners were significantly lower in the heat medium than in the original KC-400, and the compositional ratios of the lowly chlorinated congeners were relatively lower in the rice oil than in the heat medium. These results suggest that the PCB congener patterns gradually changed from that of the original KC-400 in the deodorization process and subsequent contamination into the rice oil. Thus, a combination of CSIA and congener-specific analysis is a new approach for investigating the changing PCB congener profiles in samples from the Yusho incident.     

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.     

Accumulation properties of polychlorinated biphenyl congeners in Yusho patients and prediction of their cytochrome P450-dependent metabolism by in silico analysis

In what has become known as the Yusho incident, thousands of people in western Japan were poisoned by the accidental ingestion of rice bran oil contaminated with polychlorinated biphenyls (PCBs) and various dioxins and dioxin-like compounds. In this study, we investigated the accumulation patterns of 69 PCB congeners in the blood of Yusho patients in comparison with those of non-exposed controls. The blood samples were collected at medical check-ups in 2004 and 2005. To compare the patterns of PCB congeners, we calculated the concentration ratio of each congener relative to the 2,2′,4,4′,5,5′-hexaCB (CB153) concentration. The concentration ratios of tetra- and penta-chlorinated congeners in the blood of Yusho patients were significantly lower than those of controls. To examine the cytochrome P450 (CYP)-dependent metabolic potential of the 2,3′,4,4′5-pentaCB (CB118), CB153, and 2,3,3′,4,4′5-hexaCB (CB156) congeners, we conducted PCB-CYP (CYP1A1, CYP1A2, CYP2A6, and CYP2B6) docking simulation by in silico analysis. The docking models showed that human CYP1A1, CYP2A6, and CYP2B6 isozymes have the potential to metabolize CB118 and CB153. On the other hand, it was inferred that CB156 is difficult to be metabolized by these four CYP isozymes. These results indicate that CYP1 and CYP2 isozymes may be involved in the characteristic accumulation patterns of PCB congeners in the blood of Yusho patients.