Significance Statement: Models of autosomal dominant polycystic kidney disease (ADPKD) are possible in nephron progenitor–derived human kidney organoids that form from induced pluripotent stem cells (iPSCs) that have had PKD genes deleted, enabling cyst formation. However, this has not been achieved in the ureteric bud/collecting duct lineage, despite the prevalence of collecting duct cysts in patients. Cysts formed in ureteric bud organoids derived from iPSCs with homozygous deleted PKD1, as well as in ureteric bud organoids generated from heterozygous mutant iPSCs and from a patient with ADPKD who had a heterozygous missense mutation, all upon cAMP stimulation. These PKD1 mutant organoids can model human ADPKD in the collecting duct lineage, complementing existing cell and animal models. Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease leading to renal failure, wherein multiple cysts form in renal tubules and collecting ducts derived from distinct precursors: the nephron progenitor and ureteric bud (UB), respectively. Recent progress in induced pluripotent stem cell (iPSC) biology has enabled cyst formation in nephron progenitor–derived human kidney organoids in which PKD1 or PKD2, the major causative genes for ADPKD, are deleted. However, cysts have not been generated in UB organoids, despite the prevalence of collecting duct cysts in patients with ADPKD. Methods: CRISPR-Cas9 technology deleted PKD1 in human iPSCs and the cells induced to differentiate along pathways leading to formation of either nephron progenitor or UB organoids. Cyst formation was investigated in both types of kidney organoid derived from PKD1-deleted iPSCs and in UB organoids generated from iPSCs from a patient with ADPKD who had a missense mutation. Results: Cysts formed in UB organoids with homozygous PKD1 mutations upon cAMP stimulation and, to a lesser extent, in heterozygous mutant organoids. Furthermore, UB organoids generated from iPSCs from a patient with ADPKD who had a heterozygous missense mutation developed cysts upon cAMP stimulation. Conclusions: Cysts form in PKD1 mutant UB organoids as well as in iPSCs derived from a patient with ADPKD. The organoids provide a robust model of the genesis of ADPKD.

Several scoring methods for the Mediterranean diet, which is considered as a healthy diet, are available, but studies that have compared more than one of these scores are rare. In addition, the applicability of Mediterranean diet scoring has not been sufficiently examined outside of Mediterranean regions. We collected data on the Mediterranean diet during pregnancy and the incidence of type 1 allergies in offspring from the Japan Environment and Children’s Study. Using multiple Mediterranean diet scoring methods, we analyzed the effect of adherence to the Mediterranean diet in pregnancy on the allergies of the offspring. Overall, 46,532 pairs of mothers and children were analyzed. In Japan, a high adherence to the Mediterranean diet during pregnancy was associated with a lower incidence of asthma in the offspring (odds ratio: 0.896, 95% confidence interval: 0.835, 0.962). Furthermore, we found that the selection of the Mediterranean diet scoring method and the setting of the reference value significantly altered the results. Our findings suggest that an appropriate selection of scoring methods and a reference value for food items are important to analyze the effects of adherence to the Mediterranean diet inside and outside of Mediterranean regions.

Vitamin D is essential for calcium absorption and bone homeostasis. Although short-stature children were reported to have low vitamin D concentrations, there is no clear evidence of a link between vitamin D and height growth in young children not limited to those with short stature. We collected height and weight data at 2 and 4 years of age, serum vitamin D concentrations at 4 years, and questionnaire results on sun exposure from the Japan Environment and Children’s Study (JECS). We then analyzed the relationship between vitamin D deficiency and height growth. We also analyzed the correlation between serum vitamin D concentration and sun exposure. Overall, 3624 participants from JECS were analyzed. We identified cases of subclinical vitamin D deficiency and insufficiency. We further found that definitive vitamin D deficiency (<10 ng/mL) impaired height growth by 0.6 cm per year even in young children not limited to those with short stature. Furthermore, we clarified that children with vitamin D deficiency had reduced outdoor activity, especially during winter. In children with either short or normal stature, definitive vitamin D deficiency was associated with height growth decline, and reduction in outdoor activity, especially during winter, was a risk factor for vitamin D deficiency.

Alkylphenols can originate from numerous products containing alkylphenol ethoxylates, including cleaning products, household items, and cosmetics. Some phenols, such as nonylphenol, are known to be endocrine disruptors, and exposure to them is thought to have contributed to the recent increase in allergic diseases such as asthma. However, the impacts of prenatal phenol exposure on asthma development in children are still unclear. We analyzed the association between maternal urinary phenol concentrations during early pregnancy and the development of asthma in children at the age of 4, using data from the Japan Environment and Children's Study (JECS), a large-scale nationwide birth cohort study. We recruited 3,513 pairs of mothers and children participating in the Sub-Cohort Study of JECS. We measured 24 phenols, including nitrophenol, parabens, bisphenol, octylphenol, and nonylphenol, in urine samples taken during the first trimester of pregnancy. The urinary levels of these phenols differed markedly, and some showed a broad spectrum of distribution. Methylparaben was detected at high levels in almost every participant (267.7 ng/ml, standard deviation 433.78). Logistic regression analysis revealed that the odds ratio of asthma onset for high exposure to butylparaben was 1.54 (95% confidence interval: 1.11-2.15). Additionally, logistic regression analysis by gender revealed an asthma development odds ratio of 2.09 (95% confidence interval: 1.20-3.65) for males and 0.65 (95% confidence interval: 0.25-1.70) for females born to mothers in whom 4-nonylphenol was detected, suggesting a gender difference. Our current analysis using large cohort data suggests that high exposure to butylparaben and low exposure to 4-nonylphenol during pregnancy are risk factors for asthma development in children. These findings establish a valuable foundation for formulating recommendations about prenatal phenol exposure.

Mercury pollution, including from its use during gold mining and refining, remains an important problem worldwide. In particular, methylmercury, a microbial alteration of mercury released into the environment, is a major environmental neurotoxicant. Although there has been growing concern about the health hazards of exposure to low levels of mercury, the effects of prenatal mercury exposure on neurodevelopmental outcomes in children have remained controversial. In the Japan Environment and Children's Study, a large-scale nationwide birth cohort study, we measured methylmercury and inorganic mercury concentrations in cord blood and conducted developmental scoring tests at ages 2 and 4 years. We then analyzed the associations between mercury levels in cord blood and neurodevelopmental outcomes. Measurements of cord blood obtained from 3822 participants revealed median values of 7.39 ng/ml (5th percentile: 2.95, 95th percentile: 18.1) and 0.25 ng/ml (5th percentile: 0.10, 95th percentile: 0.58) for methylmercury and inorganic mercury, respectively. Analyzing the association with fish consumption, bonito-tuna was most strongly correlated with both methylmercury and inorganic mercury in cord blood. Although the association between cord blood mercury and neurodevelopmental scores was subsequently examined in 3083 individuals, we found no significant association with either methylmercury or inorganic mercury. Further quartile group analysis based on methylmercury concentrations in cord blood revealed no concentration-dependent association between a prenatal mercury exposure and neurodevelopment in children. However, various factors influence neurodevelopment, and long-term observational studies that consider those covariates are necessary for a more definitive conclusion. Although the findings of our study provide important insights into the association between prenatal mercury exposure and neurodevelopment, further research is needed to make recommendations for safe mercury intake thresholds during pregnancy.