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Background: Genetic epidemiological evidence for the kidney function traits in East Asian populations, including Japanese, remain still relatively unclarified. Especially, the number of genome-wide association studies (GWASs) for kidney traits reported still remains limited, and the sample size of each independent study is relatively small. Given the genetic variability between ancestries/ethnicities, implementation of GWAS with sufficiently large sample sizes in specific population of Japanese is considered meaningful. Methods: We conducted the GWAS meta-analyses of kidney traits by leveraging the GWAS summary data of the representative large genome cohort studies with about 200,000 Japanese participants (n = 202,406 for estimated glomerular filtration rate [eGFR] and n = 200,845 for serum creatinine [SCr]). Results: In the present GWAS meta-analysis, we identified 110 loci with 169 variants significantly associated with eGFR (on chromosomes 1–13 and 15–22; P < 5 × 10−8), whereas we also identified 112 loci with 176 variants significantly associated with SCr (on chromosomes 1–22; P < 5 × 10−8), of which one locus (more than 1 Mb distant from known loci) with one variant (CD36 rs146148222 on chromosome 7) for SCr was considered as the truly novel finding. Conclusion: The present GWAS meta-analysis of the largest genome cohort studies in Japanese subjects provided some original genomic loci associated with kidney function, which may contribute to the possible development of personalized prevention of kidney diseases based on genomic information in the near future.

Abstract Psoriasis is a chronic inflammatory disease that sometimes necessitates therapeutic intervention with biologics. Autoantibody production during treatment with tumor necrosis factor (TNF) inhibitors is a recognized phenomenon, however, the production of autoantibodies associated with antiphospholipid syndrome (APS) has not been comprehensively evaluated in patients with psoriasis. This study was conducted to assess the prevalence of APS-associated autoantibodies in patients with psoriasis treated with different biologics and to investigate the potential associations between autoantibody production and clinical or serological parameters. Patients with psoriasis undergoing biologics treatments were enrolled in this study, and were categorized based on the type of biologics administered, TNF, interleukin (IL)-17, or IL-23 inhibitors. Clinical and serological data were collected and analyzed in conjunction with data on APS autoantibodies. TNF inhibitors were associated with a higher frequency of APS autoantibodies compared to IL-17 and IL-23 inhibitors. Notably, the presence of APS autoantibodies correlated with concurrent arthritis and higher disease severity at treatment initiation in patients treated with TNF inhibitors. Elevated Psoriasis Area and Severity Index scores and anti-nuclear antibody titers higher than × 320 were predictors of APS autoantibody production. Despite the higher autoantibody rates, clinical symptoms of APS were absent in these patients. This study provides the first comprehensive evidence of an increased frequency of APS autoantibodies associated with TNF inhibitor treatment in patients with psoriasis. The observed association between APS autoantibody positivity and TNF inhibitor treatment or clinical parameters suggests a potential immunomodulatory interplay between autoimmunity and inflammation in the pathogenesis of psoriasis.

Abstract Background Natural products play a key role as potential sources of biologically active substances for the discovery of new drugs. This study aimed to identify secondary metabolites from actinomycete library extracts that are potent against the asexual stages of Plasmodium falciparum (P. falciparum). Methods Secondary metabolites from actinomycete library extracts were isolated from culture supernatants by ethyl acetate extraction. Comprehensive screening was performed to identify novel antimalarial compounds from the actinomycete library extracts (n = 28). The antimalarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and-resistant (Dd2) lines of P. falciparum. The cytotoxicity was then evaluated in primary adult mouse brain (AMB) cells. Results Out of the 28 actinomycete extracts, 17 showed parasite growth inhibition > 50% at a concentration of 50 µg/mL, nine were identified with an IC50 value

Background: Improving diets requires an awareness of the need to limit foods for which excessive consumption is a health problem. Since there are limited reports on the link between this awareness and mortality risk, we examined the association between awareness of limiting food intake (energy, fat, and sweets) and all-cause mortality in a Japanese cohort study. Methods: Participants comprised 58,772 residents (27,294 men; 31,478 women) aged 35–69 years who completed baseline surveys of the Japan Multi-Institutional Collaborative Cohort Study from 2004 to 2014. Hazard ratios (HRs) for all-cause mortality and 95% confidence intervals (CIs) were estimated by sex using a Cox proportional hazard model, with adjustment for related factors. Mediation analysis with fat intake as a mediator was also conducted. Results: The mean follow-up period was 11 years, and 2,516 people died. Estimated energy and fat intakes according to the Food Frequency Questionnaire were lower in those with awareness of limiting food intake than in those without this awareness. Women with awareness of limiting fat intake showed a significant decrease in mortality risk (HR 0.73; 95% CI, 0.55–0.94). Mediation analysis revealed that this association was due to the direct effect of the awareness of limiting fat intake and that the total effect was not mediated by actual fat intake. Awareness of limiting energy or sweets intake was not related to mortality risk reduction. Conclusion: Awareness of limiting food intake had a limited effect on reducing all-cause mortality risk.

Background: The present genome-wide association study (GWAS) aimed to reveal the genetic loci associated with folate metabolites, as well as to detect related gene–environment interactions in Japanese. Methods: We conducted the GWAS of plasma homocysteine (Hcy), folic acid (FA), and vitamin B12 (VB12) levels in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study participants who joined from 2005 to 2012, and also estimated gene–environment interactions. In the replication phase, we used data from the Yakumo Study conducted in 2009. In the discovery phase, data of 2,263 participants from four independent study sites of the J-MICC Study were analyzed. In the replication phase, data of 573 participants from the Yakumo Study were analyzed. Results: For Hcy, MTHFR locus on chr 1, NOX4 on chr 11, CHMP1A on chr 16, and DPEP1 on chr 16 reached genome-wide significance (P < 5 × 10−8). MTHFR also associated with FA, and FUT2 on chr 19 associated with VB12. We investigated gene-environment interactions in both studies and found significant interactions between MTHFR C677T and ever drinking, current drinking, and physical activity >33% on Hcy (β = 0.039, 0.038 and −0.054, P = 0.018, 0.021 and

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes autism, Asperger’s syndrome, and pervasive developmental disorder. Individuals with ASD may exhibit difficulties in social interactions, communication challenges, repetitive behaviors, and restricted interests. While genetic mutations in individuals with ASD can either activate or inactivate the activities of the gene product, impacting neuronal morphogenesis and causing symptoms, the underlying mechanism remains to be fully established. Herein, for the first time, we report that genetically conserved Rac1 guanine-nucleotide exchange factor (GEF) Dock5 signalosome molecules control process elongation in the N1E-115 cell line, a model line capable of achieving neuronal morphological changes. The increased elongation phenotypes observed in ASD and intellectual disability (ID)-associated Semaphorin-5A (Sema5A) Arg676-to-Cys [p.R676C] were also mediated by Dock5 signalosome molecules. Indeed, knockdown of Dock5 using clustered regularly interspaced short palindromic repeat (CRISPR)/CasRx-based guide(g)RNA specifically recovered the mutated Sema5A-induced increase in process elongation in cells. Knockdown of Elmo2, an adaptor molecule of Dock5, also exhibited similar recovery. Comparable results were obtained when transfecting the interaction region of Dock5 with Elmo2. The activation of c-Jun N-terminal kinase (JNK), one of the primary signal transduction molecules underlying process elongation, was ameliorated by either their knockdown or transfection. These results suggest that the Dock5 signalosome comprises abnormal signaling involved in the process elongation induced by ASD- and ID-associated Sema5A. These molecules could be added to the list of potential therapeutic target molecules for abnormal neuronal morphogenesis in ASD at the molecular and cellular levels.

Abstract Perfluorooctane sulfonate (PFOS) exerts adverse effects on neuronal development in young population. Limited evidences have shown that early-life PFOS exposure holds a potential risk for developing age-related neurodegenerative diseases such as Alzheimer’s disease later in life. The present study investigated the effects of lactational PFOS exposure on cognitive function using one-year-old mice. Dams were exposed to PFOS (1 mg/kg body weight) through lactation by gavage. Male offspring were used for the behavior test battery to assess cognitive function. Western blot analysis was conducted to measure the levels of proteins related to the pathogenesis of Alzheimer’s disease. PFOS-exposed mice displayed a mild deficiency in social recognition. In the hippocampus, the expression of tau protein was significantly increased. These results underline a mild effect of developing PFOS exposure on cognitive function and neurodegeneration. The present study presents the long-lasting effects of PFOS in middle-aged period and warrants a potential aftermath.

Objectives: Exploring the effects of swallowing function on sleep quality could provide valuable insights into the potential impact of reduced swallowing function on sleep. However, pertinent studies are limited. Therefore, this study aimed to investigate the relationship between dysphagia risk and sleep health in community-dwelling older adults. Methods: Data for this cross-sectional study were obtained from the Shizuoka and Daiko studies conducted as part of the Japan Multi-Institutional Collaborative Cohort Study. Information on demographics, overall lifestyle, dysphagia risk, as well as sleep quality, duration, satisfaction, and regularity, was obtained using a self-administered questionnaire. Dysphagia risk and sleep quality were assessed using the Dysphagia Risk Assessment Questionnaire for the Community-dwelling Elderly and the Japanese version of the Pittsburgh Sleep Questionnaire Index, respectively. Multivariate logistic regression, adjusted for covariates, was employed to assess the association between dysphagia risk and sleep health. Results: Among the 3058 participants (1633 males, 1425 females) aged ≥60 years, 28.0 % exhibited dysphagia risk, and 19.1 % reported poor sleep quality. Those with dysphagia risk were more likely to experience poor sleep quality than those without dysphagia risk. In male participants, dysphagia was significantly associated with poor sleep quality, unsatisfactory sleep, and sleep irregularity, but was not significantly associated with unsatisfactory or irregular sleep in female participants. The Japanese version of the Pittsburgh Sleep Questionnaire Index components—subjective sleep quality, sleep latency, sleep disturbances, and daytime dysfunction—were associated with dysphagia risk in both sexes. Conclusions: Dysphagia risk is associated with sleep quality in older individuals in Japan. Thus, preserving swallowing function may contribute to enhancing sleep quality.

Background: Although many observational studies have demonstrated significant relationships between obesity and cardiometabolic traits, the causality of these relationships in East Asians remains to be elucidated. Methods: We conducted individual-level Mendelian randomization (MR) analyses targeting 14,083 participants in the Japan Multi-Institutional Collaborative Cohort Study and two-sample MR analyses using summary statistics based on genome-wide association study data from 173,430 Japanese. Using 83 body mass index (BMI)-related loci, genetic risk scores (GRS) for BMI were calculated, and the effects of BMI on cardiometabolic traits were examined for individual-level MR analyses using the two-stage least squares estimator method. The β-coefficients and standard errors for the per-allele association of each single-nucleotide polymorphism as well as all outcomes, or odds ratios with 95% confidence intervals were calculated in the two-sample MR analyses. Results: In individual-level MR analyses, the GRS of BMI was not significantly associated with any cardiometabolic traits. In two-sample MR analyses, higher BMI was associated with increased risks of higher blood pressure, triglycerides, and uric acid, as well as lower high-density-lipoprotein cholesterol and eGFR. The associations of BMI with type 2 diabetes in two-sample MR analyses were inconsistent using different methods, including the directions. Conclusion: The results of this study suggest that, even among the Japanese, an East Asian population with low levels of obesity, higher BMI could be causally associated with the development of a variety of cardiometabolic traits. Causality in those associations should be clarified in future studies with larger populations, especially those of BMI with type 2 diabetes.

Abstract After the Fukushima nuclear accident, the Japanese government implemented extensive decontamination work in 137Cs contaminated catchments for residents’ health and local revitalization. Whether dramatic land use changes in the upstream decontaminated regions affected river suspended sediment (SS) and particulate 137Cs discharge downstream remain unknown because of the poor quantification on land cover changes and long-term river SS dynamics. We here introduce a 6-year concurrent database of the Niida River Basin, a decontaminated catchment, including the first available vector decontamination maps, satellite images in decontaminated regions with a spatial resolution of 10 m, and long-term river monitoring datasets spanning decontamination (2013–2016) and subsequent natural restoration stages (2017–2018). These datasets allow us, for the first time, to directly link the transport dynamics of river SS (particulate 137Cs) to land use changes caused by humans in real-time, which provide fundamental data for better understanding the river response of sediment to land use change. Moreover, the data obtained by interdisciplinary methods offer a template for land use change impact assessment in other river basins.

Abstract This study aimed to clarify the association of daily physical activity and leisure-time exercise with the risk of dysphagia in community-dwelling Japanese older adults using a questionnaire-based survey. We analyzed 3070 participants (1657 men, 1413 women; age 66 ± 4 years [mean ± SD]) of the Shizuoka and Daiko studies within the Japanese Multi-Institutional Collaborative Cohort study. We used the Dysphagia Risk Assessment for the Community-dwelling Elderly questionnaire to assess dysphagia risk and the International Physical Activity Questionnaire to assess daily physical activity and leisure-time exercise. Logistic regression analyses were used to evaluate the independent association of the amount of physical activity and leisure-time exercise with dysphagia risk. The proportion of participants with dysphagia risk was 27.5% (n = 844) and the risk was significantly higher in women (29.8%, n = 421) than in men (25.5%, n = 423; P = 0.008). Daily physical activity was not associated with dysphagia risk. A greater amount of leisure-time exercise was associated with lower dysphagia risk (P for trend = 0.003) and individuals in the highest leisure-time exercise quartile had a significantly lower odds ratio (0.68, 95% CI 0.52–0.89) than those in the lowest quartile, even after adjusting for the covariates.

Background: Little is known about whether insufficient moderate-to-vigorous physical activity (MVPA) and longer sedentary behavior (SB) are independently associated with estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD), whether they interact with known risk factors for CKD, and the effect of replacing sedentary time with an equivalent duration of physical activity on kidney function. Methods: We examined the cross-sectional association of MVPA and SB with eGFR and CKD in 66,603 Japanese cohort study in 14 areas from 2004 to 2013. MVPA and SB were estimated using a self-reported questionnaire, and CKD was defined as eGFR

Abstract Objective: Healthy dietary patterns have been linked to lower levels of chronic inflammation. The present study aimed to investigate the associations between food group intakes and high-sensitivity C-reactive protein (hsCRP) among community-dwelling adults. Design: Cross-sectional. Setting: Three areas in Japan (Shiga, Fukuoka, or Kyushu and Okinawa). Participants: The present analysis included 13 648 participants (5126 males and 8522 females; age range, 35–69 years) who had been enrolled in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. Food group intakes were estimated using a FFQ. Multiple linear regression was used to examine associations between the quartiles of each energy-adjusted food group intake and log-transformed hsCRP. Results: The following concentration ratios of hsCRP after comparing the highest and lowest quartiles of food group intake were significant: in males, 1·12 (95 % CI 1·02, 1·22) for processed meat, 1·13 (95 % CI 1·03, 1·24) for fish and 0·83 (95 % CI 0·76, 0·90) for nuts; in females, 0·89 (95 % CI 0·81, 0·97) for bread, 1·11 (95 % CI 1·03, 1·19) for processed meat, 0·86 (95 % CI 0·80, 0·92) for vegetables, 1·19 (95 % CI 1·11, 1·29) for fruit, 0·90 (95 % CI 0·84, 0·97) for nuts and 0·88 (95 % CI 0·82, 0·95) for green tea. Conclusions: Processed meat and nut intakes were associated with higher and lower hsCRP levels, respectively, in both sexes. However, for several food groups, including fish and fruit, previous findings from dietary pattern analyses were not supported by the present analyses at the food group level.

Abstract Objective: Although small fish are an important source of micronutrients, the relationship between their intake and mortality remains unclear. This study aimed to clarify the association between intake of small fish and all-cause and cause-specific mortality. Design: We used the data from a cohort study in Japan. The frequency of the intake of small fish was assessed using a validated FFQ. The hazard ratio (HR) and 95 % confidence interval (CI) for all-cause and cause-specific mortality according to the frequency of the intake of small fish by sex were estimated using a Cox proportional hazard model with adjustments for covariates. Setting: The Japan Multi-Institutional Collaborative Cohort Study. Participants: A total of 80 802 participants (34 555 males and 46 247 females), aged 35–69 years. Results: During a mean follow-up of 9·0 years, we identified 2482 deaths including 1495 cancer-related deaths. The intake of small fish was statistically significantly and inversely associated with the risk of all-cause and cancer mortality in females. The multivariable-adjusted HR (95 % CI) in females for all-cause mortality according to the intake were 0·68 (0·55, 0·85) for intakes 1–3 times/month, 0·72 (0·57, 0·90) for 1–2 times/week and 0·69 (0·54, 0·88) for ≥ 3 times/week, compared with the rare intake. The corresponding HR (95 % CI) in females for cancer mortality were 0·72 (0·54, 0·96), 0·71 (0·53, 0·96) and 0·64 (0·46, 0·89), respectively. No statistically significant association was observed in males. Conclusions: Intake of small fish may reduce the risk of all-cause and cancer mortality in Japanese females.

Abstract Purpose Patients with inflammatory bowel disease (IBD), whether Crohn’s disease (CD) or ulcerative colitis (UC), have an increased risk of acute pancreatitis. The prognostic value of diagnosing acute idiopathic pancreatitis in patients with IBD is not well understood. Methods A retrospective review of 56 patients with IBD and acute pancreatitis was conducted in a tertiary center from 2011 to 2020. Aggressive disease course was defined as (i)biologic change, (ii)biologic dose escalation, or (iii)IBD-related surgeries occurring within 1 year of acute pancreatitis diagnosis. Logistic regression modelling identified associations between covariates and an aggressive disease course. Results Baseline characteristics between idiopathic pancreatitis and other causes of acute pancreatitis, in both CD and UC cohorts, were similar. Idiopathic pancreatitis was significantly associated with an aggressive disease course in CD (P = 0.04). No confounding factors were associated with an aggressive disease course in CD. Idiopathic pancreatitis, however, was not associated with an aggressive disease course in UC (P = 0.35). Conclusion The diagnosis of acute idiopathic pancreatitis may provide a prognostic indicator of a more severe disease course in CD. No such association appears to exist with UC. To the best of our knowledge, this is the first study that identifies an association and possible prognostic value between idiopathic pancreatitis and a more severe disease course in CD. More studies with a larger sample size are needed to validate these findings, further define idiopathic pancreatitis as an extraintestinal manifestation of IBD and elucidate a clinical strategy to optimize care in patients with aggressive CD and idiopathic pancreatitis.

Background: Stress coping strategies are related to health outcomes. However, there is no clear evidence for sex differences between stress-coping strategies and mortality. We investigated the relationship between all-cause mortality and stress-coping strategies, focusing on sex differences among Japanese adults. Methods: A total of 79,580 individuals aged 35–69 years participated in the Japan Multi-Institutional Collaborative Cohort Study between 2004 and 2014 and were followed up for mortality. The frequency of use of the five coping strategies was assessed using a questionnaire. Sex-specific, multivariable-adjusted hazard ratios (HRs) for using each coping strategy (“sometimes,” and “often/very often” use versus “very few” use) were computed for all-cause mortality. Furthermore, relationships were analyzed in specific follow-up periods when the proportion assumption was violated. Results: During the follow-up (median: 8.5 years), 1,861 mortalities were recorded. In women, three coping strategies were related to lower total mortality. The HRs for “sometimes” were 0.81 (95% confidence interval [CI], 0.67–0.97) for emotional expression, 0.79 (95% CI, 0.66–0.95) for emotional support-seeking, and 0.80 (95% CI, 0.66–0.98) for disengagement. Men who “sometimes” used emotional expression and sometimes or often used problem-solving and positive reappraisal had a 15–41% lower HRs for all-cause mortality. However, those relationships were dependent on the follow-up period. There was evidence that sex modified the relationships between emotional support-seeking and all-cause mortality (P for interaction = 0.03). Conclusion: In a large Japanese sample, selected coping strategies were associated with all-cause mortality. The relationship of emotional support-seeking was different between men and women.

Background: Environmental and genetic factors are suggested to exhibit factor-based association with HDL-cholesterol (HDL-C) levels. However, the population-based effects of environmental and genetic factors have not been compared clearly. We conducted a cross-sectional study using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study to evaluate the population-based impact of smoking, drinking, and genetic factors on low HDL-C. Methods: Data from 11,498 men and women aged 35–69 years were collected for a genome-wide association study (GWAS). Sixty-five HDL-C-related SNPs with genome-wide significance (P < 5 × 10−8) were selected from the GWAS catalog, of which seven representative SNPs were defined, and the population-based impact was estimated using population attributable fraction (PAF). Results: We found that smoking, drinking, daily activity, habitual exercise, egg intake, BMI, age, sex, and the SNPs CETP rs3764261, APOA5 rs662799, LIPC rs1800588, LPL rs328, ABCA1 rs2575876, LIPG rs3786247, and APOE rs429358 were associated with HDL-C levels. The gene-environmental interactions on smoking and drinking were not statistically significant. The PAF for low HDL-C was the highest in men (63.2%) and in rs3764261 (31.5%) of the genetic factors, and the PAFs of smoking and drinking were 23.1% and 41.8%, respectively. Conclusion: The present study showed that the population-based impact of genomic factor CETP rs3764261 for low HDL-C was higher than that of smoking and lower than that of drinking.

Background: Inflammation is thought to be a risk factor for kidney disease. However, whether inflammatory status is either a cause or an outcome of chronic kidney disease remains controversial. We aimed to investigate the causal relationship between high-sensitivity C-reactive protein (hs-CRP) and estimated glomerular filtration rate (eGFR) using Mendelian randomization (MR) approaches. Methods: A total of 10,521 participants of the Japan Multi-institutional Collaborative Cohort Study was analyzed in this study. We used two-sample MR approaches (the inverse-variance weighted (IVW), the weighted median (WM), and the MR-Egger method) to estimate the effect of genetically determined hs-CRP on kidney function. We selected four and three hs-CRP associated single nucleotide polymorphisms (SNPs) as two instrumental variables (IV): IVCRP and IVAsian, based on SNPs previously identified in European and Asian populations. IVCRP and IVAsian explained 3.4% and 3.9% of the variation in hs-CRP, respectively. Results: Using the IVCRP, genetically determined hs-CRP was not significantly associated with eGFR in the IVW and the WM methods (estimate per 1 unit increase in ln(hs-CRP), 0.000; 95% confidence interval [CI], −0.019 to 0.020 and −0.003; 95% CI, −0.019 to 0.014, respectively). For IVAsian, we found similar results using the IVW and the WM methods (estimate, 0.005; 95% CI, −0.020 to 0.010 and −0.004; 95% CI, −0.020 to 0.012, respectively). The MR-Egger method also showed no causal relationships between hs-CRP and eGFR (IVCRP: −0.008; 95% CI, −0.058 to 0.042; IVAsian: 0.001; 95% CI, −0.036 to 0.036). Conclusion: Our two-sample MR analyses with different IVs did not support a causal effect of hs-CRP on eGFR.

Streptomyces spp. are well-known producers of secondary metabolites with diverse biological activities. We screened the substances that regulate polyp-to-jellyfish transition, called strobilation, of the moon jellyfish (Aurelia coerulea) from the Streptomyces culture library. Among the culture extracts of the strains tested, Streptomyces albus HUT6047 inhibited the strobilation of A. coerulea. The active component in strain HUT6047 was purified. Based on structure elucidation, this component was identified as 4-methoxy-2,2′-bipyrrole-5-carbaldehyde (MBC), a possible common biosynthetic intermediate of pyrrole-containing natural products including prodigiosins and tambjamines. Synthetic MBC arrested strobilation without inducing cytotoxicity and generated abnormal tentacle-like structures in a dose-dependent manner. Synthetic MBC also exhibited a minimum activity of 6.3 µM. To our knowledge, this study provides the first example of a biological activity of MBC.

Abstract Elucidating the risk factors for chronic kidney disease is important for preventing end-stage renal disease and reducing mortality. However, little is known about the roles of psychosocial stress and stress coping behaviors in deterioration of the renal function, as measured by the estimated glomerular filtration rate (eGFR). This cross-sectional study of middle-aged and older Japanese men (n = 31,703) and women (n = 38,939) investigated whether perceived stress and coping strategies (emotional expression, emotional support seeking, positive reappraisal, problem solving, and disengagement) were related to the eGFR, with mutual interactions. In multiple linear regression analyses adjusted for age, area, lifestyle factors, and psychosocial variables, we found a significant inverse association between perceived stress and the eGFR in men (P trend = 0.02), but not women. This male-specific inverse association was slightly attenuated after adjustment for the history of hypertension and diabetes and was more evident in lower levels of emotional expression (P interaction = 0.003). Unexpectedly, problem solving in men (P trend

Paradoxically, patients with advanced stomach cancer who are Helicobacter pylori-positive (HP+) have a higher survival rate than those who are HP-. This finding suggests that HP infection has beneficial effects for cancer treatment. The present study examines whether HP+ individuals have a lower likelihood of death from cancer than those who are HP-. Prospective cohort data (n = 4,982 subjects enrolled in the DAIKO study between 2008-2010) were used to assess whether anti-HP antibody status was associated with cancer incidence. The median age in the primary registry was 53 years-old (range 35-69 years-old). Over the 8-year observation period there were 234 (4.7%) cancer cases in the cohort and 88 (1.8%) all-cause deaths. Urine anti-HP antibody data was available for all but one participant (n = 4,981; 99.98%). The number of HP+ and HP- individuals was 1,825 (37%) and 3,156 (63%), respectively. Anti-HP antibody distribution per birth year revealed that earlier birth year was associated with higher HP+ rates. With a birth year-matched cohort (n = 3,376), all-cancer incidence was significantly higher in HP+ individuals than those who were HP- (p = 0.00328), whereas there was no significant difference in the cancer death rate between HP+ and HP- individuals (p = 0.888). Cox regression analysis for prognostic factors revealed that the hazards ratio of HP+ was 1.59-fold (95%CI 1.17-2.26) higher than HP- in all-cancer incidence. Potential systemic effects of HP+ status may contribute to reduced likelihood of death for patients after an initial diagnosis of cancer.

BackgroundThe relationship between lifestyle and obesity is a major focus of research. Personalized nutrition, which utilizes evidence from nutrigenomics, such as gene-environment interactions, has been attracting attention in recent years. However, evidence for gene-environment interactions that can inform treatment strategies is lacking, despite some reported interactions involving dietary intake or physical activity. Utilizing gene-lifestyle interactions in practice could aid in optimizing interventions according to genetic risk.MethodsThis study aimed to elucidate the effects of gene-lifestyle interactions on body mass index (BMI). Cross-sectional data from the Japan Multi-Institutional Collaborative Cohort Study were used. Interactions between a multi-locus genetic risk score (GRS), calculated from 76 ancestry-specific single nucleotide polymorphisms, and nutritional intake or physical activity were assessed using a linear mixed-effect model.ResultsThe mean (standard deviation) BMI and GRS for all participants (n = 12,918) were 22.9 (3.0) kg/m2 and -0.07 (0.16), respectively. The correlation between GRS and BMI was r(12,916) = 0.13 (95% confidence interval [CI] 0.11-0.15, P < 0.001). An interaction between GRS and saturated fatty acid intake was observed (β = -0.11, 95% CI -0.21 to -0.02). An interaction between GRS and n-3 polyunsaturated fatty acids was also observed in the females with normal-weight subgroup (β = -0.12, 95% CI -0.22 to -0.03).ConclusionOur results provide evidence of an interaction effect between GRS and nutritional intake and physical activity. This gene-lifestyle interaction provides a basis for developing prevention or treatment interventions for obesity according to individual genetic predisposition.

Single-tree detection is one of the main research topics in quantifying the structural properties of forests. Drone LiDAR systems and terrestrial laser scanning systems produce high-density point clouds that offer great promise for forest inventories in limited areas. However, most studies have focused on the upper canopy layer and neglected the lower forest structure. This paper describes an innovative tree detection method using drone LiDAR data from a new perspective of the under-canopy structure. This method relies on trunk point clouds, with under-canopy sections split into heights ranging from 1 to 7 ​m, which were processed and compared, to determine a suitable height threshold to detect trees. The method was tested in a dense cedar plantation forest in the Aichi Prefecture, Japan, which has a stem density of 1140 stems·ha−1 and an average tree age of 42 years. Dense point cloud data were generated from the drone LiDAR system and terrestrial laser scanning with an average point density of 5000 and 6500 points·m−2, respectively. Tree detection was achieved by drawing point-cloud section projections of tree trunks at different heights and calculating the center coordinates. The results show that this trunk-section-based method significantly reduces the difficulty of tree detection in dense plantation forests with high accuracy (F1−Score ​= ​0.9395). This method can be extended to different forest scenarios or conditions by changing section parameters.

Background: The Japan Multi-institutional Collaborative Cohort (J-MICC) study was launched in 2005 to examine gene–environment interactions in lifestyle-related diseases, including cancers, among the Japanese. This report describes the study design and baseline profile of the study participants. Methods: The participants of the J-MICC Study were individuals aged 35 to 69 years enrolled from respondents to study announcements in specified regions, inhabitants attending health checkup examinations provided by local governments, visitors at health checkup centers, and first-visit patients at a cancer hospital in Japan. At the time of the baseline survey, from 2005 to 2014, we obtained comprehensive information regarding demographics, education, alcohol consumption, smoking, sleeping, exercise, food intake frequency, medication and supplement use, personal and family disease history, psychological stress, and female reproductive history and collected peripheral blood samples. Results: The baseline survey included 92,610 adults (mean age: 55.2 [standard deviation, 9.4] years, 44.1% men) from 14 study regions in 12 prefectures. The participation rate was 33.5%, with participation ranging from 19.7% to 69.8% in different study regions. The largest number of participants was in the age groups of 65–69 years for men and 60–64 years for women. There were differences in body mass index, educational attainment, alcohol consumption, smoking, and sleep duration between men and women. Conclusions: The J-MICC Study collected lifestyle and clinical data and biospecimens from over 90,000 participants. This cohort is expected to be a valuable resource for the national and international scientific community in providing evidence to support longer healthy lives.

Background: Obesity is a reported risk factor for various health problems. Genome-wide association studies (GWASs) have identified numerous independent loci associated with body mass index (BMI). However, most of these have been focused on Europeans, and little evidence is available on the genetic effects across the life course of other ethnicities. Methods: We conducted a cross-sectional study to examine the associations of 282 GWAS-identified single nucleotide polymorphisms with three BMI-related traits, current BMI, BMI at 20 years old (BMI at 20), and change in BMI (BMI change), among 11,586 Japanese individuals enrolled in the Japan Multi-Institutional Collaborative Cohort study. Associations were examined using multivariable linear regression models. Results: We found a significant association (P < 0.05/282 = 1.77 × 10−4) between BMI and 11 polymorphisms in or near FTO, BDNF, TMEM18, HS6ST3, and BORCS7. The trend was similar between current BMI and BMI change, but differed from that of the BMI at 20. Among the significant variants, those on FTO were associated with all BMI traits, whereas those on TMEM18 and HS6SR3 were only associated with BMI at 20. The association of FTO loci with BMI remained, even after additional adjustment for dietary energy intake. Conclusions: Previously reported BMI-associated loci discovered in Europeans were also identified in the Japanese population. Additionally, our results suggest that the effects of each loci on BMI may vary across the life course and that this variation may be caused by the differential effects of individual genes on BMI via different pathways.

Background: While duodenal ulcer (DU) and gastric cancer (GC) are both H. pylori infection-related diseases, individuals with DU are known to have lower risk for GC. Many epidemiological studies have identified the PSCA rs2294008 T-allele as a risk factor of GC, while others have found an association between the rs2294008 C-allele and risk of DU and gastric ulcer (GU). Following these initial reports, however, few studies have since validated these associations. Here, we aimed to validate the association between variations in PSCA and the risk of DU/GU and evaluate its interaction with environmental factors in a Japanese population. Methods: Six PSCA SNPs were genotyped in 584 DU cases, 925 GU cases, and 8,105 controls from the Japan Multi-Institutional Collaborative Cohort (J-MICC). Unconditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the SNPs and risk of DU/GU. Results: PSCA rs2294008 C-allele was associated with per allele OR of 1.34 (95% CI, 1.18–1.51; P = 2.28 × 10−6) for the risk of DU. This association was independent of age, sex, study site, smoking habit, drinking habit, and H. pylori status. On the other hand, we did not observe an association between the risk of GU and PSCA SNPs. Conclusions: Our study confirms an association between the PSCA rs2294008 C-allele and the risk of DU in a Japanese population.

Multiple genetic factors related to autism spectrum disorder (ASD) have been identified, but the biological mechanisms remain obscure. Timothy syndrome (TS), associated with syndromic ASD, is caused by a gain‐of‐function mutation, G406R, in the pore‐forming subunit of L‐type Ca2+ channels, Cav1.2. In this study, a mouse model of TS, TS2‐neo, was used to enhance behavioral phenotyping and to identify developmental anomalies in inhibitory neurons. Using the IntelliCage, which enables sequential behavioral tasks without human handling and mouse isolation stress, high social competitive dominance was observed in TS2‐neo mice. Furthermore, histological analysis demonstrated inhibitory neuronal abnormalities in the neocortex, including an excess of smaller‐sized inhibitory presynaptic terminals in the somatosensory cortex of young adolescent mice and higher numbers of migrating inhibitory neurons from the medial ganglionic eminence during embryonic development. In contrast, no obvious changes in excitatory synaptic terminals were found. These novel neural abnormalities in inhibitory neurons of TS2‐neo mice may result in a disturbed excitatory/inhibitory (E/I) balance, a key feature underlying ASD.

Abstract Background Mental health has become a major public health issue worldwide. Biological and epidemiological studies suggest diet has a role in the prevention or cure of mental disorders. However, further research is required to elucidate the relationship between diet and mental health. This study aimed to investigate associations between dietary intake of nutrients (macronutrients, vitamins, calcium, and fatty acids) and food groups (fish, meat and chicken, dairy products, and vegetables) and mental health among middle-aged Japanese in cross-sectional and prospective studies. Methods In total, 9298 men and women that participated in two areas of the Japan Multi-Institutional Collaborative Cohort Study were eligible for analysis at the baseline (cross-sectional) survey. Of these, 4701 participants were followed for about 5 years and included in the follow-up (prospective) analysis. The 12-item General Health Questionnaire (GHQ) was used to assess participants’ general mental health status over the past several weeks. The average intake of 46 foods over the past year was assessed by a validated food frequency questionnaire. We also evaluated lifestyle and medical factors using a self-administered questionnaire. A cross-sectional logistic regression analysis was performed to estimate odds ratios for a GHQ score ≥ 4 (poor mental health) according to dietary intake of foods/nutrients at baseline. The prospective study used baseline dietary and lifestyle factors and GHQ scores at follow-up. Results The cross-sectional logistic regression analysis showed vegetables, protein, calcium, vitamin D, carotene and n-3 highly-polyunsaturated fatty acids were inversely associated with a GHQ score ≥ 4. On the other hand, mono-unsaturated fatty acids showed a positive association with higher GHQ score. The prospective logistic regression analysis found dairy products, calcium, vitamin B2, and saturated fatty acids were inversely correlated with a GHQ score ≥ 4. Calcium was associated with GHQ scores in both the cross-sectional and follow-up studies. In the follow-up study, the multivariable-adjusted odds ratio for a GHQ score ≥ 4 was 0.71 (95% confidence interval, 0.55–0.92) for the highest versus lowest quartiles of calorie-adjusted dietary calcium intake. Conclusion Consuming particular nutrients and foods, especially calcium and dairy products, may lead to better mental health in Japanese adults.

Few studies have investigated the interactions between HDL-C-related SNPs identified by genome-wide association (GWA) study and physical activity (PA) on HDL-C. First, we conducted a sex-stratified GWA study in a discovery sample (2,231 men and 2,431 women) and replication sample (2,599 men and 3,109 women) to identify SNPs influencing log-transformed HDL-C in Japanese participants in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. We also replicated previously reported HDL-C-related SNPs in a combined (discovery plus replication) sample (4,830 men and 5,540 women). We then analyzed the interactions of the HDL-C-related SNPs with PA on HDL-C. The sex-stratified GWA analyses identified 11 and 10 HDL-C-related SNPs in men and women as targets for an interaction analysis. Among these, only one interaction of ABCA1 rs1883025 with PA was statistically significant in men, after Bonferroni correction [P-interaction = 0.001 (α = 0.05/21 = 0.002)]. The per-major-allele (C allele) increase in log-transformed HDL-C was lost in men with low PA (β = 0.008) compared with those with medium (β = 0.032) or high PA (β = 0.034). These findings suggest that the benefit of carrying a C allele of ABCA1 rs1883025 on enhancing HDL-C may be attenuated in inactive men.

ObjectiveThe aim of the present study was to investigate the associations between breastfeeding and the prevalence of metabolic syndrome in community-dwelling parous women and to clarify whether the associations depend on age.MethodsThe present cross-sectional study included 11,118 women, aged 35-69 years. Participants' longest breastfeeding duration for one child and their number of breastfed children were assessed using a self-administered questionnaire, and their total breastfeeding duration was approximated as a product of the number of breastfed children and the longest breastfeeding duration. The longest and the total breastfeeding durations were categorized into none and tertiles above 0 months. Metabolic syndrome and cardiovascular risk factors (obesity, hypertension, dyslipidemia, and hyperglycemia) were defined as primary and secondary outcomes, respectively. Associations between breastfeeding history and metabolic syndrome or each cardiovascular risk factor were assessed using multivariable unconditional logistic regression analysis.ResultsAmong a total of 11,118 women, 10,432 (93.8%) had ever breastfed, and 1,236 (11.1%) had metabolic syndrome. In participants aged ConclusionsBreastfeeding history may be related to lower prevalence of metabolic syndrome in middle-aged parous women.

PurposeThe association between metabolic syndrome (MetS) and the risk of death from cancer is still a controversial issue. The purpose of this study was to examine the associations of MetS and metabolically unhealthy obesity (MUHO) with cancer mortality in a Japanese population.MethodsWe used data from the Japan Multi-Institutional Collaborative Cohort Study. The study population consisted of 28,554 eligible subjects (14,103 men and 14,451 women) aged 35-69 years. MetS was diagnosed based on the criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and the Japan Society for the Study of Obesity (JASSO), using the body mass index instead of waist circumference. The Cox proportional hazards analysis was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for total cancer mortality in relation to MetS and its components. Additionally, the associations of obesity and the metabolic health status with cancer mortality were examined.ResultsDuring an average 6.9-year follow-up, there were 192 deaths from cancer. The presence of MetS was significantly correlated with increased total cancer mortality when the JASSO criteria were used (HR = 1.51, 95% CI 1.04-2.21), but not when the NCEP-ATP III criteria were used (HR = 1.09, 95% CI 0.78-1.53). Metabolic risk factors, elevated fasting blood glucose, and MUHO were positively associated with cancer mortality (P ConclusionMetS diagnosed using the JASSO criteria and MUHO were associated with an increased risk of total cancer mortality in the Japanese population.

The purpose of the study was to investigate sex-specific associations of skipping breakfast and short sleep duration with metabolic syndrome (MetS) and their interaction. We analyzed baseline data of 14,907 men and 14,873 women aged 35–69 years, who participated in the Japan Multi-Institutional Collaborative Cohort Study from 2005. MetS was diagnosed using a modification of the National Cholesterol Education Program Adult Treatment Panel III revised definition (NCEP-R 2005), using body mass index instead of waist circumference. Breakfast consumption was classified into two categories: ≥6 days/week (consumers) or

Background This study aimed to determine the association between sedentary time and mortality with regard to leisure‐time physical activity with or without cardiometabolic diseases such as hypertension, dyslipidemia, and diabetes mellitus. Methods and Results Using data from the J‐MICC (Japan Multi‐Institutional Collaborative Cohort) Study, 64 456 participants (29 022 men, 35 434 women) were analyzed. Hazard ratios (HRs) and 95% CIs were used to characterize the relative risk of all‐cause mortality to evaluate its association with sedentary time (categorical variables:

More than 170 genetic loci have been linked to prostate cancer risk, primarily based on genome-wide association studies (GWAS) in European population. Here, the authors performed a GWAS on a Japanese cohort of prostate cancer patients, finding 12 new susceptibility loci, and identifying a polygenic risk for Japanese prostate cancer.

Abstract Background Although self-rated health (SRH) independently predicts mortality, the biological background of this association remains unexplained. This study aimed to examine the association between SRH and serum high-sensitivity C-reactive protein (hsCRP) level. Methods Subjects were 899 participants aged 35–69 years (237 men and 662 women) in the Daiko Study, part of the Japan Multi-Institutional Collaborative Cohort Study. They were enrolled from 2008 to 2010. Of the subjects, 666 participated in a second survey 5 years later. Lifestyle factors and SRH were assessed using a self-administered questionnaire. Serum hsCRP level was measured using a latex-enhanced immunonephelometric assay. The association between SRH and serum hsCRP level was evaluated using a general linear model with covariates. We further longitudinally investigated whether higher serum hsCRP level at baseline predicts poor SRH after 5 years using an unconditional logistic regression model. Results A higher serum hsCRP level was significantly associated with poor SRH at baseline after adjusting for covariates (p for trend = 0.023). The age- and sex-adjusted odds ratio and 95% confidence interval (CI) for poor SRH after 5 years was 1.45 (95% CI: 0.76–2.78) for the highest tertile compared with the lowest tertile of serum hsCRP level at baseline with a significant linear trend (p for trend = 0.033), although the risk increase disappeared after adjustment for other covariates. Conclusions The present study demonstrated that poor SRH is cross-sectionally associated with higher serum hsCRP level. However, the longitudinal data did not support the relationship between serum hsCRP level at baseline and future SRH. Further longitudinal studies that include data on mortality and multiple inflammatory markers are warranted to elucidate the possible role of low-grade inflammation in the association between SRH and mortality risk.

Recent genome-wide association studies (GWAS) on the dietary habits of the Japanese population have shown that an effect rs671 allele was inversely associated with fish consumption, whereas it was directly associated with coffee consumption. Although meat is a major source of protein and fat in the diet, whether genetic factors that influence meat-eating habits in healthy populations are unknown. This study aimed to conduct a GWAS to find genetic variations that affect meat consumption in a Japanese population. We analysed GWAS data using 14 076 participants from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study. We used a semi-quantitative food frequency questionnaire to estimate food intake that was validated previously. Association of the imputed variants with total meat consumption per 1000 kcal energy was performed by linear regression analysis with adjustments for age, sex, and principal component analysis components 1–10. We found that no genetic variant, including rs671, was associated with meat consumption. The previously reported single nucleotide polymorphisms that were associated with meat consumption in samples of European ancestry could not be replicated in our J-MICC data. In conclusion, significant genetic factors that affect meat consumption were not observed in a Japanese population.

Background: Although beneficial associations have been reported between moderate alcohol intake and the serum lipid profile, it is unclear whether polymorphisms in alcohol-metabolizing enzymes can modify these associations. Here, we assessed the effects of ADH1B His48Arg (rs1229984), ALDH2 Glu504Lys (rs671), and their combination on these associations. Furthermore, we examined if the findings for ALDH2 could be replicated. Methods: We categorized 889 male participants in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study into two groups based on presence or absence of minor allele(s) or four groups based on genotype combinations. We performed regression analyses of serum lipid concentrations on alcohol intake, with multivariable adjustment. The replication study was conducted among 2,562 men in the Shizuoka part of the J-MICC Study. Results: The ALDH2 Glu/Lys or Lys/Lys groups showed significant decreases in serum low-density lipoprotein (LDL) cholesterol with increasing alcohol consumption; the coefficient per intake increase of 10 g/day was −2.49 mg/dL (95% confidence interval [CI], −3.85 to −1.13), and a significant interaction with the polymorphism was confirmed (P for interaction = 0.006). This inverse correlation was more evident among the ADH1B His/His + ALDH2 Glu/Lys or Lys/Lys groups (−3.24 mg/dL, 95% CI, −5.03 to −1.45). Serum triglycerides were positively associated with alcohol consumption in the ADH1B His/His group (P for interaction = 0.020). The stronger association between serum LDL cholesterol and alcohol consumption in the ALDH2 Glu/Lys or Lys/Lys groups was replicated. Conclusions: The ALDH2 Glu504Lys polymorphism can modify the association between alcohol intake and serum LDL cholesterol in Japanese men.

Background: Renal hypouricemia (RHUC) is characterized by a low serum uric acid (SUA) level and high fractional excretion of uric acid (FEUA). Further studies on FEUA in hypouricemic individuals are needed for a more accurate diagnosis of RHUC. Methods: In 30,685 Japanese health-examination participants, we genotyped the two most common nonfunctional variants of URAT1 (NFV-URAT1), W258X (rs121907892) and R90H (rs121907896), in 1040 hypouricemic individuals (SUA ≤ 3.0 mg/dL) and 2240 individuals with FEUA data. The effects of NFV-URAT1 on FEUA and SUA were also investigated using linear and multiple regression analyses. Results: Frequency of hypouricemic individuals (SUA ≤ 3.0 mg/dL) was 0.97% (male) and 6.94% (female) among 30,685 participants. High frequencies of those having at least one allele of NFV-URAT1 were observed in 1040 hypouricemic individuals. Furthermore, NFV-URAT1 significantly increased FEUA and decreased SUA, enabling FEUA and SUA levels to be estimated. Conversely, FEUA and SUA data of hypouricemic individuals are revealed to be useful to predict the number of NFV-URAT1. Conclusions: Our findings reveal that specific patterns of FEUA and SUA data assist with predicting the number of nonfunctional variants of causative genes for RHUC, and can also be useful for practical diagnosis of RHUC even before genetic tests.

Abstract Despite recent advances in chemotherapy for gastrointestinal cancer, a crucial factor related to poor prognosis is reduced tolerance to chemotherapy induced by cancer cachexia. Fish oil (FO)-derived eicosapentaenoic acid (EPA) modulates inflammation in patients with various malignancies; however, the impact of FO-enriched nutrition as a combined modality therapy on clinical outcomes remains controversial. We systemically analysed chronological changes in biochemical and physiological status using bioelectrical impedance analysis in 128 gastrointestinal cancer patients provided with or without FO-enriched nutrition during chemotherapy. Furthermore, we evaluated the clinical significance of FO-enriched nutrition and clarified appropriate patient groups that receive prognostic benefits from FO-enriched nutrition during treatment of gastrointestinal cancer. The control group showed significant up-regulation of serum CRP) levels and no significant difference in both skeletal muscle mass and lean body mass. In contrast, the FO-enriched nutrition group showed no changes in serum CRP concentration and significantly increased skeletal muscle mass and lean body mass over time. Furthermore, high CRP levels significantly correlated with reduced tolerance to chemotherapy, and FO-enriched nutrition improved chemotherapy tolerance and prognosis, particularly in gastrointestinal cancer patients with a modified Glasgow prognostic score (mGPS) of 1 or 2. We conclude that FO-enriched nutrition may improve the prognosis of patients with cancer cachexia and systemic inflammation (i.e., those with a mGPS of 1 or 2).

The association between dietary acid load and metabolic syndrome (MetS) has not been fully investigated. A cross-sectional study was performed on 14,042 men and 14,105 women (aged 35–69 years) who participated in a baseline survey of the Japan Multi-Institutional Collaborative Cohort study. Dietary acid load was assessed using the net-endogenous-acid-production (NEAP) score that is closely correlated with the rate of renal net acid excretion. MetS was diagnosed according to the Joint Interim Statement Criteria of 2009 using body-mass index instead of waist circumference. After adjusting for potential confounders, higher NEAP scores were associated with a significantly increased odds ratio (OR) of MetS, obesity, high blood pressure, and high fasting blood glucose. These associations remained significant after further adjustment for carbohydrate intake or two nutrient-pattern scores significantly associated with MetS. After adjustment for fiber, iron, potassium, and vitamin pattern scores, the OR of MetS for the highest quartile of NEAP scores, relative to the lowest quartile, was 1.25 (95% confidence interval 1.12–1.39). There was no significant interaction between sex, age, or body-mass index and NEAP. Higher dietary acid load was associated with a higher prevalence of MetS and several of its components, independently of carbohydrate intake or nutrient patterns.

Thyroid hormones (THs) play crucial roles in general and brain development. Even if the hypothyroidism is mild, it may alter brain function, resulting in irreversible behavioral alterations. Although various behavioral analyses have been conducted, the effects of propylthiouracil (PTU) treatment during in utero and postnatal periods on maternal behavior have not yet been studied. The present study examined in mice whether THs insufficiency during development induce behavioral changes. Pregnant C57BL/6j mice were divided into three groups, and each group was administered different dosages of PTU (0, 5, or 50 ppm) in drinking water during in utero and postnatal periods (from gestational day 14 to postnatal day 21). First, locomotor activity and cognitive function were assessed in the offspring at 10 weeks. Next, female offspring were mated with normal mice and they and their offspring were used to assess several aspects of maternal behavior (identifying first pup, returning all pups to nest, time spent nursing, and licking pups). As expected, locomotor and cognitive functions in these mice were disrupted in a PTU dose-dependent manner. On postpartum day 2, dams who had been exposed 50 ppm PTU during in utero and postnatal periods displayed a significantly longer time identifying the first pup and returning all three pups back to the nest, less time nursing, and decreased licking behavior. The decrease in maternal behavior was significantly correlated with a decrease in cognition. These results indicate that insufficiency of THs during in utero and postnatal periods impairs maternal behavior, which may be partly induced by impaired cognitive function.