Urinary metabolite concentrations of phthalate and plasticizers in infancy and childhood in the UNC Baby Connectome Project.

INTRODUCTION: Existing evidence suggests that exposure to phthalates is higher among younger age groups. However, limited knowledge exists on how phthalate exposure, as well as exposure to replacement plasticizers, di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) and di-2-ethylhexyl terephthalate (DEHTP), change from infancy through early childhood. METHODS: Urine samples were collected across the first 5 years of life from typically developing infants and young children enrolled between 2017 and 2020 in the longitudinal UNC Baby Connectome Project. From 438 urine samples among 187 participants, we quantified concentrations of monobutyl phthalate (MnBP), mono-3-carboxypropyl phthalate (MCPP), monoisobutyl phthalate (MiBP), monoethyl phthalate (MEP) monobenzyl phthalate (MBzP), and metabolites of di(2-ethylhexyl) phthalate (DEHP), diisonoyl phthalate (DiNP), DINCH and DEHTP. Specific gravity (SG) adjusted metabolite and molar sum concentrations were compared across age groups. Intraclass correlation coefficients (ICCs) were calculated among 122 participants with multiple urine specimens (373 samples). RESULTS: Most phthalate metabolites showed high detection frequencies (>80% of samples). Replacement plasticizers DINCH (58-60%) and DEHTP (>97%) were also commonly found. DiNP metabolites were less frequently detected (<10%). For some metabolites, SG-adjusted concentrations were inversely associated with age, with the highest concentrations found in the first year of life. ICCs revealed low to moderate reliability in metabolite measurements (ρ = 0.10-0.48) suggesting a high degree of within-individual variation in exposure among this age group. The first 6 months (compared to remaining age groups) showed an increased ratio of carboxylated metabolites of DEHP and DEHTP, compared to other common metabolites, but no clear age trends for DINCH metabolite ratios. CONCLUSION: Metabolites of phthalates and replacements plasticizers were widely detected in infancy and early childhood, with the highest concentrations observed in the first year of life for several metabolites. Higher proportions of carboxylated metabolites of DEHP and DEHTP in younger age groups indicate potential differences in metabolism during infancy.

Organophosphorus Pesticide Exposure at 17 Weeks' Gestation and Odds of Offspring Attention-Deficit/Hyperactivity Disorder Diagnosis in the Norwegian Mother, Father, and Child Cohort Study.

Prenatal organophosphorus pesticides (OPs) are ubiquitous and have been linked to adverse neurodevelopmental outcomes. However, few studies have examined prenatal OPs in relation to diagnosed attention-deficit/hyperactivity disorder (ADHD), with only two studies exploring this relationship in a population primarily exposed through diet. In this study, we used a nested case-control study to evaluate prenatal OP exposure and ADHD diagnosis in the Norwegian Mother, Father, and Child Cohort Study (MoBa). For births that occurred between 2003 and 2008, ADHD diagnoses were obtained from linkage of MoBa participants with the Norwegian Patient Registry (N = 297), and a reference population was randomly selected from the eligible population (N = 552). Maternal urine samples were collected at 17 weeks' gestation and molar sums of diethyl phosphates (ΣDEP) and dimethyl phosphates metabolites (ΣDMP) were calculated. Multivariable adjusted logistic regression models were used to estimate the association between prenatal OP metabolite exposure and child ADHD diagnosis. Additionally, multiplicative effect measure modification (EMM) by child sex was assessed. In most cases, mothers in the second and third tertiles of ΣDMP and ΣDEP exposure had slightly lower odds of having a child with ADHD, although confidence intervals were wide and included the null. EMM by child sex was not observed for either ΣDMP or ΣDEP. In summary, we did not find evidence that OPs at 17 weeks' gestation increased the odds of ADHD in this nested case-control study of ADHD in MoBa, a population primarily experiencing dietary exposure.

Prenatal organophosphorus pesticide exposure and executive function in preschool-aged children in the Norwegian Mother, Father and Child Cohort Study (MoBa).

INTRODUCTION: Prenatal exposure to organophosphorus pesticides (OPPs) has been associated with neurodevelopmental deficits in children, however evidence linking OPPs with specific cognitive mechanisms, such as executive function (EF), is limited. OBJECTIVE: This study aims to evaluate the association between prenatal exposure to OPPs with multiple measures of EF in preschool-aged children, while considering the role of variant alleles in OPP metabolism genes. METHODS: We included 262 children with preschool attention-deficit/hyperactivity disorder (ADHD), and 78 typically developing children, from the Preschool ADHD substudy of the Norwegian, Mother, Father, and Child Cohort Study. Participants who gave birth between 2004 and 2008 were invited to participate in an on-site clinical assessment when the child was approximately 3.5 years; measurements of EF included parent and teacher rating on Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P), and three performance-based assessments. We measured OPP metabolites in maternal urines collected at ∼17 weeks' gestation to calculate total dimethyl- (ΣDMP) and diethyl phosphate (ΣDEP) metabolite concentrations. We estimated multivariable adjusted ß's and 95% confidence intervals (CIs) corresponding to a change in z-score per unit increase in log-ΣDMP/DEP. We further characterized gene-OPP interactions for maternal variants in PON1 (Q192R, M55L), CYP1A2 (1548T > C), CYP1A1 (IntG > A) and CYP2A6 (-47A > C). RESULTS: Prenatal OPP metabolite concentrations were associated with worse parent and teacher ratings of emotional control, inhibition, and working memory. A one log-∑DMP increase was associated with poorer teacher ratings of EF on the BRIEF-P (e.g. emotional control domain: ß = 0.55, 95% CI: 0.35, 0.74), when weighted to account for sampling procedures. We found less consistent associations with performance-based EF assessments. We found some evidence of modification for PON1 Q192R and CYP2A6 -47A > C. Association with other variants were inconsistent. CONCLUSIONS: Biomarkers of prenatal OPP exposure were associated with more adverse teacher and parent ratings of EF in preschool-aged children.

Attributable Fractions of Nonalcoholic Fatty Liver Disease for Mortality in the United States: Results From the Third National Health and Nutrition Examination Survey With 27 Years of Follow-up.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) encompasses a range of conditions, from simple steatosis to nonalcoholic steatohepatitis. Studies in the United States have reported an increased mortality risk among individuals with NAFLD; therefore, the population attributable fractions (PAFs) for mortality were examined. APPROACH AND RESULTS: A total of 12,253 adult individuals with ultrasound assessment of NAFLD from the Third National Health and Nutrition Examination Survey and mortality follow-up through 2015 were included in the analysis. Cox proportional hazard regression was used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for NAFLD in association with all-cause and cause-specific mortality. Overall, sex- and race/ethnicity-specific PAFs and 95% CIs were estimated. In the current study, presence of NAFLD was associated with a 20% increased risk of all-cause mortality (HR, 1.20; 95% CI, 1.08, 1.34). The overall PAF for all-cause mortality associated with NAFLD was 7.5% (95% CI, 3.0, 12.0). The PAF for diabetes-specific mortality was 38.0% (95% CI, 13.1, 63.0) overall, 40.8% (95% CI, 2.1, 79.6) in men, and 36.8% (95% CI, 6.6, 67.0) in women. The PAF for liver disease (LD)-specific mortality was notably higher in men (68.3%; 95% CI, 36.3, 100.0) than women (3.5%; 95% CI, -39.7, 46.8). In the race-specific analysis, the PAFs of NAFLD for all-cause mortality (9.3%; 95% CI, 4.0, 14.6) and diabetes-specific mortality (44.4%; 95% CI, 10.8, 78.0) were significantly greater than zero only for whites. CONCLUSIONS: In the United States, approximately 8% of all-cause mortality and more than one-third of LD- and diabetes-specific deaths are associated with NAFLD. With these high percentages, efforts are needed to reduce the burden of NAFLD in the United States.

Oophorectomy and risk of non-alcoholic fatty liver disease and primary liver cancer in the Clinical Practice Research Datalink.

Incidence of non-alcoholic fatty liver disease (NAFLD) and liver cancer are 2-3 times higher in males than females. Hormonal mechanisms are hypothesized, with studies suggesting that oophorectomy may increase risk, but population-based evidence is limited. Thus, we conducted a study within the Clinical Practice Research Datalink, with controls matched to cases of NAFLD (n = 10,082 cases/40,344 controls) and liver cancer (n = 767 cases/3068 controls). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. Effect measure modification by menopausal hormone therapy (MHT) was examined, using likelihood ratio tests and relative excess risk due to interaction (RERI). Oophorectomy was associated with a 29% elevated NAFLD risk (OR = 1.29, 95% CI 1.18-1.43), which was more pronounced in women without diabetes (OR = 1.41, 95% CI 1.27-1.57) and in women who had oophorectomy prior to age 50 (OR = 1.37, 95% CI 1.22-1.52). Compared to women without oophorectomy or MHT use, oophorectomy and MHT were each associated with over 50% elevated risk of NAFLD. However, the combination of oophorectomy and MHT showed evidence of a negative interaction on the multiplicative (p = 0.003) and additive scales (RERI = - 0.28, 95% CI - 0.60 to 0.03, p = 0.08). Oophorectomy, overall, was not associated with elevated liver cancer risk (OR = 1.16, 95% CI 0.79-1.69). These findings suggest that oophorectomy may increase the risk of NAFLD, but not liver cancer.

Bacterial Translocation and Risk of Liver Cancer in a Finnish Cohort.

BACKGROUND: Elevated systemic exposure to gut-derived bacterial products has been associated with hepatic inflammation and chronic liver diseases, potentially increasing the risk of liver cancer. However, only one prior study prospectively examined exposure to bacterial products in the circulation and risk of liver cancer, with a relatively limited coverage of biomarkers. METHODS: We conducted a nested case-control study (224 liver cancer cases and 224 matched controls) in a large cohort of Finnish male smokers followed from baseline (1985-1988) to 2014. The associations between a panel of biomarkers for bacterial translocation and the risk of liver cancer were assessed using multivariable-adjusted conditional logistic regression. The biomarkers included immunoglobulin (Ig) A, IgG, and IgM against lipopolysaccharide (LPS) and flagellin, soluble CD14 (an LPS coreceptor), and the LPS-binding protein. RESULTS: Anti-flagellin IgA [odds ratios (OR), 2.79; 95% confidence intervals (CI), 1.34-5.78; P trend = 0.01] and anti-LPS IgA (2.44; 95% CI, 1.33-4.48; P trend < 0.01) were significantly associated with risk of liver cancer. When restricting the analysis to histologically classified hepatocellular carcinoma, the ORs were 4.18 (95% CI, 1.60-10.92; P trend < 0.01) and 2.48 (95% CI, 1.16-5.29; P trend < 0.01), respectively. The results were not substantially changed after excluding cases diagnosed within the first 5 years of follow-up and those with hepatitis C virus infection. CONCLUSIONS: Antibodies to flagellin and LPS were associated with increased risk of liver cancer. IMPACT: Gut-derived bacterial translocation into the circulation may play a role in the development of primary liver cancer. Our findings could contribute to the understanding of primary liver cancer etiology and further prevention efforts.

Body Mass Index, Diabetes and Intrahepatic Cholangiocarcinoma Risk: The Liver Cancer Pooling Project and Meta-analysis.

OBJECTIVE: Obesity and diabetes are associated with an increased liver cancer risk. However, most studies have examined all primary liver cancers or hepatocellular carcinoma, with few studies evaluating intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. Thus, we examined the association between obesity and diabetes and ICC risk in a pooled analysis and conducted a systematic review/meta-analysis of the literature. DESIGN: For the pooled analysis, we utilized the Liver Cancer Pooling Project, a consortium of 13 US-based, prospective cohort studies with data from 1,541,143 individuals (ICC cases n = 414). In our systematic review, we identified 14 additional studies. We then conducted a meta-analysis, combining the results from LCPP with results from the 5 prospective studies identified through September 2017. RESULTS: In the LCPP, obesity and diabetes were associated with a 62% [Hazard Ratio (HR) = 1.62, 95% Confidence Interval (CI): 1.24-2.12] and an 81% (HR = 1.81, 95% CI: 1.33-2.46) increased ICC risk, respectively. In the meta-analysis of prospectively ascertained cohorts and nested case-control studies, obesity was associated with a 49% increased ICC risk [Relative Risk (RR) = 1.49, 95% CI: 1.32-1.70; n = 4 studies; I2 = 0%]. Diabetes was associated with a 53% increased ICC risk (RR = 1.53, 95% CI: 1.31-1.78; n = 6 studies). While we noted heterogeneity between studies (I2 = 67%) for diabetes, results were consistent in subgroup analyses. Results from hospital-based case-control studies (n = 9) were mostly consistent, but these studies are potentially subject to reverse causation. CONCLUSIONS: These findings suggest that obesity and diabetes are associated with increased ICC risk, highlighting similar etiologies of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. However, additional prospective studies are needed to verify these associations.

Association of tooth loss with liver cancer incidence and chronic liver disease mortality in a rural Chinese population.

BACKGROUND: Tooth loss has been reported to be associated with the risk of liver cancer in several prior studies in economically advantaged countries. Whether this relationship is also evident in economically disadvantaged populations is not known. METHODS: We analyzed data from the Nutrition Intervention Trials, two randomized placebo-controlled trials of vitamin/mineral supplementation in Linxian, China. Participants who reported having lost permanent teeth were examined to determine the number of teeth remaining. In the 30-year follow-up period, 329 liver cancers were diagnosed and 368 chronic liver disease deaths occurred. Tooth loss was categorized based on loess smoothed age-specific predicted quartiles. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the two outcomes. RESULTS: Overall, persons in the highest quartile of age-specific tooth loss had an increased risk of liver cancer (HR = 1.27, 95%CI: 0.96, 1.67) which was not statistically significant. Results varied by sex and body mass index (BMI), however. Women in the highest quartile of age-specific tooth loss had a significantly increased risk (HR = 1.64, 95%CI: 1.04, 2.59), while men did not (HR = 1.08, 95%CI = 0.75, 1.57), and persons with a BMI > 23.0 kg/m2 (HR = 1.71, 95%CI: 1.00, 2.92) had a significantly increased risk, while persons with a BMI <23.0 kg/m2 did not (HR = 1.14, 95%CI: 0.82, 1.5). No relationships with chronic liver disease mortality were observed. CONCLUSIONS: In a rural, economically disadvantaged population, persons with the highest levels of age-specific tooth loss had an increased risk of liver cancer. The results, which were stronger among women and persons with greater BMI, suggest that periodontal disease may increase risk of liver cancer.

Domperidone use and risk of primary liver cancer in the Clinical Practice Research Datalink.

BACKGROUND: Pronounced sex-disparity in liver cancer suggests a role for hormones, one of which could be prolactin. Stimulation of prolactin production in mice via domperidone has been reported to decrease hepatocarcinogenesis, thus may have chemopreventive potential. To study the effect of domperidone in humans, a large medical records study was conducted. METHODS: Based in the Clinical Practice Research Datalink, 1921 liver cancer cases and 7681 controls were identified. Conditional logistic regression was employed to estimate odds ratios (OR) and 95% confidence intervals (CI). Domperidone use was analyzed overall, and by number of prescriptions and cumulative dose. RESULTS: Comparing ever- versus never-use, there was no association between domperidone and liver cancer among men (OR = 1.06, 95% CI: 0.76-1.48) or women (OR = 1.21, 95% CI: 0.82-1.76). Among men, there was no association with dose or number of prescriptions, while among women who received the highest doses (OR2700 mg vs. 0 mg = 2.52, 95% CI: 1.18-5.41, p-trend = 0.02) and greatest number of prescriptions (OR≥11 Rx vs. 0 Rx = 3.17, 95% CI: 1.07-9.40, p-trend = 0.02) there was a significantly increased risk, although there was no evidence of heterogeneity in the results by gender. CONCLUSION: Domperidone use was not associated with decreased liver cancer risk among all study participants. Among women, an increased risk at highest levels of exposure warrants further study.

Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Liver Cancer Pooling Project.

BACKGROUND: While tobacco and alcohol are established risk factors for hepatocellular carcinoma (HCC), the most common type of primary liver cancer, it is unknown whether they also increase the risk of intrahepatic cholangiocarcinoma (ICC). Thus, we examined the association between tobacco and alcohol use by primary liver cancer type. METHODS: The Liver Cancer Pooling Project is a consortium of 14 US-based prospective cohort studies that includes data from 1,518,741 individuals (HCC n = 1423, ICC n = 410). Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. RESULTS: Current smokers at baseline had an increased risk of HCC (hazard ratio (HR) = 1.86, 95% confidence interval (CI): 1.57-2.20) and ICC (HR = 1.47, 95% CI: 1.07-2.02). Among individuals who quit smoking >30 years ago, HCC risk was almost equivalent to never smokers (HR = 1.09, 95% CI: 0.74-1.61). Compared to non-drinkers, heavy alcohol consumption was associated with an 87% increased HCC risk (HR≥7 drinks/day = 1.87, 95% CI: 1.41-2.47) and a 68% increased ICC risk (HR≥5 drinks/day = 1.68, 95% CI: 0.99-2.86). However, light-to-moderate alcohol consumption of <3 drinks/day appeared to be inversely associated with HCC risk (HR>0-<0.5 drinks/day = 0.77, 95% CI: 0.67-0.89; HR>0.5-<1 drinks/day = 0.57, 95% CI: 0.44-0.73; HR1-<3 drinks/day = 0.71, 95% CI: 0.58-0.87), but not ICC. CONCLUSIONS: These findings suggest that, in this relatively healthy population, smoking cessation and light-to-moderate drinking may reduce the risk of HCC.

Skin lighteners and hair relaxers as risk factors for breast cancer: results from the Ghana breast health study.

Skin lighteners and hair relaxers, both common among women of African descent, have been suggested as possibly affecting breast cancer risk. In Accra and Kumasi, Ghana, we collected detailed information on usage patterns of both exposures among 1131 invasive breast cancer cases and 2106 population controls. Multivariate analyses estimated odds ratios (ORs) and 95% confidence intervals (CIs) after adjustment for breast cancer risk factors. Control usage was 25.8% for ever use of skin lighteners and 90.0% for use of hair relaxers for >1 year. The OR for skin lighteners was 1.10 (95% CI 0.93-1.32), with higher risks for former (1.21, 0.98-1.50) than current (0.96, 0.74-1.24) users. No significant dose-response relations were seen by duration, age at first use or frequency of use. In contrast, an OR of 1.58 (95% CI 1.15-2.18) was associated with use of hair relaxers, with higher risks for former (2.22, 1.56-3.16) than current (1.39, 1.00-1.93) users. Although numbers of burns were inconsistently related to risk, associations increased with duration of use, restricted to women who predominately used non-lye products (P for trend < 0.01). This was most pronounced among women with few children and those with smaller tumors, suggesting a possible role for other unmeasured lifestyle factors. This study does not implicate a substantial role for skin lighteners as breast cancer risk factors, but the findings regarding hair relaxers were less reassuring. The effects of skin lighteners and hair relaxers on breast cancer should continue to be monitored, especially given some biologic plausibility for their affecting risk.

The effect of 14-3-3ζ expression on tamoxifen resistance and breast cancer recurrence: a Danish population-based study.

PURPOSE: Overexpression of 14-3-3ζ has been linked to breast cancer recurrence in several studies, including studies assessing its effect on tamoxifen resistance. The study was performed to estimate the effect of 14-3-3ζ and differentiate potential prognostic or predictive utility. METHODS: A case-control study, nested in a population of 11,251 females residing on the Jutland Peninsula of Denmark, was performed. Participants were aged 35-69, diagnosed with stage I, II, or III breast cancer between 1985 and 2001, and registered with the Danish Breast Cancer Cooperative Group. We identified 541 recurrent breast cancer cases with estrogen receptor-positive disease treated with tamoxifen for at least 1 year (ER+/TAM+) and 300 cases with estrogen receptor-negative disease never treated with tamoxifen (ER-/TAM-). We matched cases to controls on ER/TAM status, date of surgery, menopausal status, stage, and county. 14-3-3ζ expression was assessed using immunohistochemistry on tissue microarrays. We computed the odds ratio (OR) associating 14-3-3ζ expression with breast cancer recurrence adjusting for confounding using logistic regression. A quantitative bias analysis was performed to account for bias due to expression assay methods. RESULTS: Associations for cytoplasmic and nuclear 14-3-3ζ staining above the 50th percentile were near null in both ER+/TAM+ and ER-/TAM- patients. When examining combined 14-3-3ζ staining, the association increased in the ER+/TAM+ group (adjusted OR 1.44, 95% confidence interval (CI) 1.05, 1.99). A nearly twofold increase in odds of recurrence was observed in above the 75th percentile staining of combined 14-3-3ζ, both for ER+/TAM+ patients (adjusted OR 1.93, 95% CI 1.15, 3.24) and ER-/TAM- patients (adjusted OR 1.93, 95% CI 1.03, 3.62), indicating potential prognostic utility. CONCLUSION: Evidence is lacking to conclude that 14-3-3ζ is a useful marker of tamoxifen resistance; however, 14-3-3ζ expression is a potentially useful prognostic marker of breast cancer recurrence. Independent utility beyond established prognostic markers needs to be determined.

Epidemiology of vulvar neoplasia in the NIH-AARP Study.

OBJECTIVE: To clarify risk factors for rare vulvar neoplasms. METHODS: Within the NIH-AARP Study, among 201,469 women interviewed in 1995-1996 and followed for a mean of 13.8years, there were 370 diagnoses of incident vulvar neoplasms, including 170 invasive and 198 vulvar intraepithelial neoplasms grade 3 (VIN3). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated via multivariate logistic regression for various demographic, reproductive and lifestyle factors, with separate consideration of relations according to invasiveness, histology and age at diagnosis. RESULTS: Consistent with descriptive data, we found non-white women at lower risks of vulvar neoplasia than white women (HR=0.59, 95% CI 0.36-0.95). Significant risk factors for VIN3 included being divorced/separated (HR vs. currently married=1.77, 95% CI 1.24-2.51), a current cigarette smoker (3.88, 95% CI 2.64-5.72), a user of oral contraceptives (1.46, 95% CI 1.06-2.01), or a current user of menopausal hormones (1.73, 95% CI 1.24-2.41). Significant risk factors for invasive cancers were being obese (HR for BMI ≥30 vs. <25=1.62, 95% CI 1.10-2.40) or a current smoker (1.86, 95% CI 1.21-2.87). Cigarette smoking was a risk factor mainly for neoplasms shown in other investigations to be HPV-related, namely VIN3 and invasive squamous cell cancers (SCCs) occurring in the younger stratum of cases. In contrast, obesity was primarily associated with the development of invasive SCCs. CONCLUSIONS: Our results support that vulvar neoplasia is a heterogeneous disease. VIN3 demonstrated risk factors consistent with an HPV-related etiology, while invasive cancers were additionally affected by obesity, suggesting that further attention should focus on the role of chronic inflammatory conditions.