Pei-Chen Lee

Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders

IMPORTANCE Acetaminophen (paracetamol) is the most commonly used medication for pain and fever during pregnancy in many countries. Research data suggest that acetaminophen is a hormone disruptor, and abnormal hormonal exposures in pregnancy may influence fetal brain development. OBJECTIVE To evaluate whether prenatal exposure to acetaminophen increases the risk for developing attention-deficit/hyperactivity disorder (ADHD)-like behavioral problems or hyperkinetic disorders (HKDs) in children. DESIGN, SETTING, AND PARTICIPANTS We studied 64,322 live-born children and mothers enrolled in the Danish National Birth Cohort during 1996-2002. EXPOSURES Acetaminophen use during pregnancy was assessed prospectively via 3 computer-assisted telephone interviews during pregnancy and 6 months after child birth. MAIN OUTCOMES AND MEASURES To ascertain outcome information we used (1) parental reports of behavioral problems in children 7 years of age using the Strengths and Difficulties Questionnaire; (2) retrieved HKD diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry prior to 2011; and (3) identified ADHD prescriptions (mainly Ritalin) for children from the Danish Prescription Registry. We estimated hazard ratios for receiving an HKD diagnosis or using ADHD medications and risk ratios for behavioral problems in children after prenatal exposure to acetaminophen. RESULTS More than half of all mothers reported acetaminophen use while pregnant. Children whose mothers used acetaminophen during pregnancy were at higher risk for receiving a hospital diagnosis of HKD (hazard ratio = 1.37; 95% CI, 1.19-1.59), use of ADHD medications (hazard ratio = 1.29; 95% CI, 1.15-1.44), or having ADHD-like behaviors at age 7 years (risk ratio = 1.13; 95% CI, 1.01-1.27). Stronger associations were observed with use in more than 1 trimester during pregnancy, and exposure response trends were found with increasing frequency of acetaminophen use during gestation for all outcomes (ie, HKD diagnosis, ADHD medication use, and ADHD-like behaviors; P trend < .001). Results did not appear to be confounded by maternal inflammation, infection during pregnancy, the mothers mental health problems, or other potential confounders we evaluated. CONCLUSIONS AND RELEVANCE Maternal acetaminophen use during pregnancy is associated with a higher risk for HKDs and ADHD-like behaviors in children. Because the exposure and outcome are frequent, these results are of public health relevance but further investigations are needed.

Traumatic brain injury, paraquat exposure, and their relationship to Parkinson disease

ABSTRACT Objectives: Traumatic brain injury (TBI) increased risk of Parkinson disease (PD) in many but not all epidemiologic studies, giving rise to speculations about modifying factors. A recent animal study suggested that the combination of TBI with subthreshold paraquat exposure increases dopaminergic neurodegeneration. The objective of our study was to investigate PD risk due to both TBI and paraquat exposure in humans. Methods: From 2001 to 2011, we enrolled 357 incident idiopathic PD cases and 754 population controls in central California. Study participants were asked to report all head injuries with loss of consciousness for >5 minutes. Paraquat exposure was assessed via a validated geographic information system (GIS) based on records of pesticide applications to agricultural crops in California since 1974. This GIS tool assesses ambient pesticide exposure within 500 m of residences and workplaces. Results: In logistic regression analyses, we observed a 2-fold increase in risk of PD for subjects who reported a TBI (adjusted odds ratio [AOR] 2.00, 95% confidence interval [CI] 1.28–3.14) and a weaker association for paraquat exposures (AOR 1.36, 95% CI 1.02–1.81). However, the risk of developing PD was 3-fold higher (AOR 3.01, 95% CI 1.51–6.01) in study participants with a TBI and exposure to paraquat than those exposed to neither risk factor. Conclusions: While TBI and paraquat exposure each increase the risk of PD moderately, exposure to both factors almost tripled PD risk. These environmental factors seem to act together to increase PD risk in a more than additive manner.

Parkinson disease and smoking revisited Ease of quitting is an early sign of the disease

Objective: To assess whether being able to quit smoking is an early marker of Parkinson disease (PD) onset rather than tobacco being “neuroprotective,” we analyzed information about ease of quitting and nicotine substitute use. Methods: For this case-control study, we identified 1,808 patients with PD diagnosed between 1996 and 2009 from Danish registries, matched 1,876 population controls on sex and year of birth, and collected lifestyle information. We estimated odds ratios and 95% confidence intervals with logistic regression adjusting for matching factors and confounders. Results: Fewer patients with PD than controls ever established a smoking habit. Among former smokers, those with greater difficulty quitting or using nicotine substitutes were less likely to develop PD, with the risk being lowest among those reporting “extremely difficult to quit” compared with “easy to quit.” Nicotine substitute usage was strongly associated with quitting difficulty and duration of smoking, i.e., most strongly among current smokers, followed by former smokers who had used nicotine substitutes, and less strongly among former smokers who never used substitutes. Conclusions: Our data support the notion that patients with PD are able to quit smoking more easily than controls. These findings are compatible with a decreased responsiveness to nicotine during the prodromal phase of PD. We propose that ease of smoking cessation is an aspect of premanifest PD similar to olfactory dysfunction, REM sleep disorders, or constipation and suggests that the apparent “neuroprotective” effect of smoking observed in epidemiologic studies is due to reverse causation.

Particulate air pollution exposure and C-reactive protein during early pregnancy.

Background: It is not well understood how air pollution leads to adverse pregnancy outcomes. One pathway may be through C-reactive protein, a biomarker of systemic inflammation that has been reported to increase the risk of preterm delivery. We examined whether air pollution influences serum concentrations of C-reactive protein in early pregnancy. Methods: We studied 1696 pregnant women in Allegheny County, PA, from 1997 through 2001. C-reactive protein concentrations were assayed in blood collected before the 22nd week of gestation. We estimated levels of particles of less than 10 &mgr;m (PM10) and less than 2.5 &mgr;m diameter (PM2.5), carbon monoxide, nitrogen dioxide, sulfur dioxide, and ozone at the maternal zip code using Kriging interpolation for measurements obtained from ambient stations. Associations between air pollution and high C-reactive protein concentrations (≥8 ng/mL) were evaluated using logistic regression. Results: Among nonsmokers, an observed 9.2 &mgr;g/m3 increase in PM10 (averaged over 28 days prior to the blood sample) was associated with an odds ratios of 1.41 for high C-reactive protein concentrations (95% confidence interval = 0.99–2.00). Similarly, a 4.6 &mgr;g/m3 increase in PM2.5 was associated with an odds ratio of 1.47 (1.05–2.06). The odds ratio was 1.49 (0.75–2.96) per 7.9 ppb increase in ozone during summer. There were no associations in smokers or for other air pollutants, and there was no evidence for effect-measure modification by obesity. Conclusions: PM10, PM2.5, and ozone exposures were associated with increased C-reactive protein concentrations in early pregnancy, suggesting that these air pollutants contribute to inflammation and thereby possibly to adverse pregnancy outcomes.

Traffic-Related Air Pollution and Parkinson's Disease in Denmark: A Case-Control Study.

Background Very little is currently known about air pollutants’ adverse effects on neurodegenerative diseases even though recent studies have linked particulate exposures to brain pathologies associated with Parkinson’s and Alzheimer’s disease. Objective In the present study, we investigated long-term exposure to traffic-related air pollution and Parkinson’s disease. Methods In a case–control study of 1,696 Parkinson’s disease (PD) patients identified from Danish hospital registries and diagnosed 1996–2009 and 1,800 population controls matched by sex and year of birth, we assessed long-term traffic-related air pollutant exposures (represented by nitrogen dioxide; NO2) from a dispersion model, using residential addresses from 1971 to the date of diagnosis or first cardinal symptom for cases and the corresponding index date for their matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with logistic regression, adjusting for matching factors and potential confounders. Results We found ambient air pollution from traffic sources to be associated with risk of PD, with a 9% higher risk (95% CI: 3, 16.0%) per interquartile range increase (2.97 μg/m3) in modeled NO2. For participants living for ≥ 20 years in the capital city, ORs were larger (OR = 1.21; 95% CI: 1.11, 1.31) than in provincial towns (OR = 1.10; 95% CI: 0.97, 1.26), whereas there was no association among rural residents. Conclusions Our findings raise concerns about potential effects of air pollution from traffic and other sources on the risk of PD, particularly in populations with high or increasing exposures. Citation Ritz B, Lee PC, Hansen J, Funch Lassen C, Ketzel M, Sørensen M, Raaschou-Nielsen O. 2016. Traffic-related air pollution and Parkinson’s disease in Denmark: a case–control study. Environ Health Perspect 124:351–356; http://dx.doi.org/10.1289/ehp.1409313

Household organophosphorus pesticide use and Parkinson’s disease

BACKGROUND Household pesticide use is widespread in the USA. Since the 1970s, organophosphorus chemicals (OPs) have been common active ingredients in these products. Parkinsons disease (PD) has been linked to pesticide exposures but little is known about the contributions of chronic exposures to household pesticides. Here we investigate whether long-term use of household pesticides, especially those containing OPs, increases the odds of PD. METHODS In a population-based case-control study, we assessed frequency of household pesticide use for 357 cases and 807 controls, relying on the California Department of Pesticide Regulation product label database to identify ingredients in reported household pesticide products and the Pesticide Action Network pesticide database of chemical ingredients. Using logistic regression we estimated the effects of household pesticide use. RESULTS Frequent use of any household pesticide increased the odds of PD by 47% [odds ratio (OR)=1.47, (95% confidence interval (CI): 1.13, 1.92)]; frequent use of products containing OPs increased the odds of PD more strongly by 71% [OR=1.71, (95% CI: 1.21, 2.41)] and frequent organothiophosphate use almost doubled the odds of PD. Sensitivity analyses showed that estimated effects were independent of other pesticide exposures (ambient and occupational) and the largest odds ratios were estimated for frequent OP users who were carriers of the 192QQ paraoxonase genetic variant related to slower detoxification of OPs. CONCLUSIONS We provide evidence that household use of OP pesticides is associated with an increased risk of developing PD.

Prenatal Air Pollution Exposure and Ultrasound Measures of Fetal Growth in Los Angeles, California

BACKGROUND Few previous studies examined the impact of prenatal air pollution exposures on fetal development based on ultrasound measures during pregnancy. METHODS In a prospective birth cohort of more than 500 women followed during 1993-1996 in Los Angeles, California, we examined how air pollution impacts fetal growth during pregnancy. Exposure to traffic related air pollution was estimated using CALINE4 air dispersion modeling for nitrogen oxides (NOx) and a land use regression (LUR) model for nitrogen monoxide (NO), nitrogen dioxide (NO2) and NOx. Exposures to carbon monoxide (CO), NO2, ozone (O3) and particles <10μm in aerodynamic diameter (PM10) were estimated using government monitoring data. We employed a linear mixed effects model to estimate changes in fetal size at approximately 19, 29 and 37 weeks gestation based on ultrasound. RESULTS Exposure to traffic-derived air pollution during 29 to 37 weeks was negatively associated with biparietal diameter at 37 weeks gestation. For each interquartile range (IQR) increase in LUR-based estimates of NO, NO2 and NOx, or freeway CALINE4 NOx we estimated a reduction in biparietal diameter of 0.2-0.3mm. For women residing within 5km of a monitoring station, we estimated biparietal diameter reductions of 0.9-1.0mm per IQR increase in CO and NO2. Effect estimates were robust to adjustment for a number of potential confounders. We did not observe consistent patterns for other growth endpoints we examined. CONCLUSIONS Prenatal exposure to traffic-derived pollution was negatively associated with fetal head size measured as biparietal diameter in late pregnancy.

Gene-environment interactions linking air pollution and inflammation in Parkinson's disease

Both air pollution exposure and systemic inflammation have been linked to Parkinsons disease (PD). In the PASIDA study, 408 incident cases of PD diagnosed in 2006-2009 and their 495 population controls were interviewed and provided DNA samples. Markers of long term traffic related air pollution measures were derived from geographic information systems (GIS)-based modeling. Furthermore, we genotyped functional polymorphisms in genes encoding proinflammatory cytokines, namely rs1800629 in TNFα (tumor necrosis factor alpha) and rs16944 in IL1B (interleukin-1β). In logistic regression models, long-term exposure to NO2 increased PD risk overall (odds ratio (OR)=1.06 per 2.94μg/m3 increase, 95% CI=1.00-1.13). The OR for PD in individuals with high NO2 exposure (≧75th percentile) and the AA genotype of IL1B rs16944 was 3.10 (95% CI=1.14-8.38) compared with individuals with lower NO2 exposure (<75th percentile) and the GG genotype. The interaction term was nominally significant on the multiplicative scale (p=0.01). We did not find significant gene-environment interactions with TNF rs1800629. Our finds may provide suggestive evidence that a combination of traffic-related air pollution and genetic variation in the proinflammatory cytokine gene IL1B contribute to risk of developing PD. However, as statistical evidence was only modest in this large sample we cannot rule out that these results represent a chance finding, and additional replication efforts are warranted.

Head injury and risk for Parkinson disease: results from a Danish case-control study.

Objective: To examine the association between head injuries throughout life and the risk for Parkinson disease (PD) in an interview-based case-control study. Methods: We identified 1,705 patients diagnosed with PD at 10 neurologic centers in Denmark in 1996–2009 and verified their diagnoses in medical records. Patients were matched to 1,785 controls randomly selected from the Danish Central Population Register on sex and year of birth. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Results: We observed no association between any head injury before first cardinal symptom and PD (OR 1.02; 95% CI 0.88, 1.19). Examination of number of head injuries (1: OR 1.02; 95% CI 0.87, 1.20; ≥2: OR 1.03; 95% CI 0.72, 1.47) or hospitalization for a head injury (OR 0.89; 95% CI 0.70, 1.12) did not show an association with PD. For 954 study subjects with at least one head injury, there was no evidence of an association between loss of consciousness (OR 0.89; 95% CI 0.67, 1.17), duration of loss of consciousness (≤1 minute: OR 0.93; 95% CI 0.58, 1.49; 1–5 minutes: OR 0.74; 95% CI 0.51, 1.08; ≥5 minutes: OR 0.81; 95% CI 0.53, 1.24), or amnesia (OR 1.31; 95% CI 0.88, 1.95) and risk for PD. Application of a lag time of 10 years between head injury and first cardinal symptom resulted in similar risk estimates. Conclusions: The results do not support the hypothesis that head injury increases the risk for PD.

Head injury, α-synuclein genetic variability and Parkinson's disease.

Head injury has been linked to Parkinsons disease (PD) in some but not all studies. Differences in the genetic and environmental susceptibility to PD between populations might be one explanation. The joint effects of head injuries and SNCA genetic variants were investigated.