Faculty Bibliography

Perfluoroalkyl substances (PFAS) were shown to be immunotoxic in laboratory animals. There is some epidemiological evidence that PFAS exposure is inversely associated with vaccine-induced antibody concentration. We examined immune response to vaccination with FluMist intranasal live attenuated influenza vaccine in relation to four PFAS (perfluorooctanoate, perfluorononanoate, perfluorooctane sulfonate, perfluorohexane sulfonate) serum concentrations among 78 healthy adults vaccinated during the 2010-2011 influenza season. We measured anti-A H1N1 antibody response and cytokine and chemokine concentrations in serum pre-vaccination, 3 days post-vaccination, and 30 days post-vaccination. We measured cytokine, chemokine, and mucosal IgA concentration in nasal secretions 3 days post-vaccination and 30 days post-vaccination. Adults with higher PFAS concentrations were more likely to seroconvert after FluMist vaccination as compared to adults with lower PFAS concentrations. The associations, however, were imprecise and few participants seroconverted as measured either by hemagglutination inhibition (9%) or immunohistochemical staining (25%). We observed no readily discernable or consistent pattern between PFAS concentration and baseline cytokine, chemokine, or mucosal IgA concentration, or between PFAS concentration and change in these immune markers between baseline and FluMist-response states. The results of this study do not support a reduced immune response to FluMist vaccination among healthy adults in relation to serum PFAS concentration. Given the study's many limitations, however, it does not rule out impaired vaccine response to other vaccines or vaccine components in either children or adults.

Perfluorooctanoate (PFOA) is detectable in umbilical cord blood and amniotic fluid. Some toxicological findings suggest that perfluoroalkyl substances may be teratogenic. Using data from the C8 Health Project, a 2005-2006 survey in a Mid-Ohio Valley community exposed to PFOA through contaminated drinking water, we examined the association between estimated prenatal PFOA concentration and maternally reported birth defects (n=325) among 10,262 live singleton or multiple births from 1990 to 2006. Logistic regression models accounted for siblings using generalized estimating equations. There was generally no association between estimated PFOA concentration and birth defects, with the possible exception of brain defects, where the odds ratio adjusted for year of conception was 2.6 (95% confidence interval 1.3-5.1) for an increase in estimated PFOA exposure from the 25th to 75th percentile. This estimate, however, was based on 13 cases and may represent a chance finding. Further investigation of this potential association may be warranted.

BACKGROUND:In toxicology studies, perfluorinated compounds affect fetal growth, development, viability, and postnatal growth. There are limited epidemiologic studies on child development. METHODS:We recruited and evaluated 321 children who participated in the C8 Health Project, a 2005-06 survey in a mid-Ohio Valley community highly exposed to perfluorooctanoate (PFOA) through contaminated drinking water. We examined associations between measured childhood PFOA serum concentration and mother and teacher reports of executive function (Behaviour Rating Inventory of Executive Function), attention deficit hyperactivity disorder (ADHD)-like behaviour (Conner's ADHD Diagnostic and Statistical Manual of Mental Disorders IV Scales), and behavioural problems (Behaviour Assessment System for Children) assessed 3 to 4 years later at ages 6-12 years. RESULTS:Overall, neither reports from mothers nor teachers provided clear associations between exposure and child behaviour. Mother reports, however, did suggest favourable associations between exposure and behaviour among boys and adverse associations among girls. On the composite scale from the Behaviour Rating Inventory of Executive Function (n = 318), PFOA exposure had a favourable association among boys (highest vs. lowest quartile β = -6.39; 95% confidence interval [CI] -11.43, -1.35) and an adverse association among girls (highest vs. lowest quartile β = 4.42; 95% CI -0.03, 8.87; interaction P = 0.01). Teacher reports (n = 189) replicated some, but not all of the sex interactions observed in mothers' reports. CONCLUSIONS:Aggregate results did not suggest adverse effects of PFOA on behaviour, but sex-specific results raise the possibility of differing patterns by sex. Results are not consistent between mothers' and teachers' reports. Effect modification by sex may warrant further investigation.

BACKGROUND:Influenza virus infection is a major public health burden worldwide. Available vaccines include the inactivated intramuscular trivalent vaccine and, more recently, an intranasal live attenuated influenza vaccine (LAIV). The measure of successful vaccination with the inactivated vaccine is a systemic rise in immunoglobulin G (IgG) level, but for the LAIV no such correlate has been established. METHODS:Seventy-nine subjects were given the LAIV FluMist. Blood was collected prior to vaccination and 3 days and 30 days after vaccination. Nasal wash was collected 3 days and 30 days after vaccination. Responses were measured systemically and in mucosal secretions for cytokines, cell activation profiles, and antibody responses. RESULTS:Only 9% of subjects who received LAIV seroconverted, while 33% of patients developed at least a 2-fold increase in influenza virus-specific immunoglobulin A (IgA) antibodies in nasal wash. LAIV induced a localized inflammation, as suggested by increased expression of interferon-response genes in mucosal RNA and increased granulocyte colony-stimulating factor (G-CSF) and IP-10 in nasal wash. Interestingly, patients who seroconverted had significantly lower serum levels of G-CSF before vaccination. CONCLUSIONS:Protection by LAIV is likely provided through mucosal IgA and not by increases in systemic IgG. LAIV induces local inflammation. Seroconversion is achieved in a small fraction of subjects with a lower serum G-CSF level.

BACKGROUND:In animal studies, perfluorinated compounds affect fetal growth, development, viability, and postnatal growth. The limited epidemiologic findings on child neurobehavioral development are mixed. METHODS:We recruited and evaluated 320 children who participated in the C8 Health Project, a 2005-2006 survey in a Mid-Ohio Valley community highly exposed to perfluorooctanoate (PFOA) through contaminated drinking water. We examined associations among estimated in utero PFOA exposure, measured childhood PFOA serum concentration, and subsequent performance on neuropsychological tests 3-4 years later at ages 6-12 years. We assessed Intelligence Quotient (IQ) reading and math skills, language, memory and learning, visual-spatial processing, and attention. All multivariable linear regression models were adjusted for age, sex, home environment, test examiner, and maternal IQ. Models with measured childhood PFOA were additionally adjusted for child body mass index. RESULTS:Children in the highest as compared with lowest quartile of estimated in utero PFOA had increases in Full Scale IQ (β 4.6, 95% confidence interval [CI] = 0.7-8.5) and decreases in characteristics of attention deficit/hyperactivity disorder as measured by the Clinical Confidence Index of Connors' Continuous Performance Test-II (β -8.5, 95% CI = -16.1 to -0.8). There were negligible associations between PFOA and reading or math skills or neuropsychological functioning. CONCLUSION/CONCLUSIONS:These results do not suggest an adverse association between the levels of PFOA exposure experienced by children in this cohort and their performance on neuropsychological tests.

BACKGROUND:Previous research suggests perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) may be associated with adverse pregnancy outcomes. OBJECTIVE:We conducted a population-based study of PFOA and PFOS and birth outcomes from 2005 through 2010 in a Mid-Ohio Valley community exposed to high levels of PFOA through drinking-water contamination. METHODS:Women provided serum for PFOA and PFOS measurement in 2005-2006 and reported reproductive histories in subsequent follow-up interviews. Reported singleton live births among 1,330 women after 1 January 2005 were linked to birth records (n = 1,630) to identify the outcomes of preterm birth (< 37 weeks gestation), pregnancy-induced hypertension, low birth weight (< 2,500 g), and birth weight (grams) among full-term infants. RESULTS:We observed little or no evidence of association between maternal serum PFOA or PFOS and preterm birth (n = 158) or low birth weight (n = 88). Serum PFOA and PFOS were both positively associated with pregnancy-induced hypertension (n = 106), with adjusted odds ratios (ORs) per log unit increase in PFOA and PFOS of 1.27 (95% CI: 1.05, 1.55) and 1.47 (95% CI: 1.06, 2.04), respectively, but associations did not increase monotonically when categorized by quintiles. Results of subanalyses restricted to pregnancies conceived after blood collection were consistent with the main analyses. There was suggestion of a modest negative association between PFOS and birth weight in full-term infants (-29 g per log unit increase; 95% CI: -66, 7), which became stronger when restricted to births conceived after the blood sample collection (-49 g per log unit increase; 95% CI: -90, -8). CONCLUSION/CONCLUSIONS:Results provide some evidence of positive associations between measured serum perfluorinated compounds and pregnancy-induced hypertension and a negative association between PFOS and birth weight among full-term infants.

BACKGROUND:Perfluorooctanoic acid (PFOA) is a potential cause of adverse pregnancy outcomes, but previous studies have been limited by low exposures and small study size. OBJECTIVES/OBJECTIVE:Using birth certificate information, we examined the relation between estimated PFOA exposure and birth outcomes in an area of West Virginia and Ohio whose drinking water was contaminated by a chemical plant. METHODS:Births in the study area from 1990 through 2004 were examined to generate case groups of stillbirth (n = 106), pregnancy-induced hypertension (n = 224), preterm birth (n = 3,613), term low birth weight (n = 918), term small-for-gestational-age (SGA) (n = 353), and a continuous measure of birth weight among a sample of term births (n = 4,534). A 10% sample of term births ≥ 2,500 g were selected as a source of controls (n = 3,616). Historical estimates of serum PFOA were derived from a previously developed fate and transport model. In a second study, we examined 4,547 area births linked to a survey with residential history data. RESULTS:In the analysis based only on birth records, we found no consistent evidence of an association between estimated PFOA exposure and stillbirth, pregnancy-induced hypertension, preterm birth, or indices of fetal growth. In the analysis of birth records linked to the survey, PFOA was unrelated to pregnancy-induced hypertension or preterm birth but showed some suggestion of an association with early preterm birth. Measures of growth restriction showed weak and inconsistent associations with PFOA. CONCLUSIONS:Based on the analysis using the health survey, these results provide little support for an effect of PFOA exposure on most pregnancy outcomes, except for early preterm birth and possibly fetal growth restriction.

After the emergence of pandemic influenza viruses in 1957, 1968, and 2009, existing seasonal viruses were observed to be replaced in the human population by the novel pandemic strains. We have previously hypothesized that the replacement of seasonal strains was mediated, in part, by a population-scale boost in antibodies specific for conserved regions of the hemagglutinin stalk and the viral neuraminidase. Numerous recent studies have shown the role of stalk-specific antibodies in neutralization of influenza viruses; the finding that stalk antibodies can effectively neutralize virus alters the existing dogma that influenza virus neutralization is mediated solely by antibodies that react with the globular head of the viral hemagglutinin. The present study explores the possibility that stalk-specific antibodies were boosted by infection with the 2009 H1N1 pandemic virus and that those antibodies could have contributed to the disappearance of existing seasonal H1N1 influenza virus strains. To study stalk-specific antibodies, we have developed chimeric hemagglutinin constructs that enable the measurement of antibodies that bind the hemagglutinin protein and neutralize virus but do not have hemagglutination inhibition activity. Using these chimeric hemagglutinin reagents, we show that infection with the 2009 pandemic H1N1 virus elicited a boost in titer of virus-neutralizing antibodies directed against the hemagglutinin stalk. In addition, we describe assays that can be used to measure influenza virus-neutralizing antibodies that are not detected in the traditional hemagglutination inhibition assay.

BACKGROUND:We assessed the association between perfluorooctanoic acid (PFOA) and pregnancy outcome in an area with elevated exposure to PFOA from drinking water contaminated by chemical plant releases. METHODS:Serum PFOA was measured, and reproductive and residential histories were obtained during 2005-2006. We estimated serum PFOA levels at the time of pregnancy for 11,737 pregnancies occurring between 1990 and 2006, based on historical information on PFOA releases, environmental distribution, pharmacokinetic modeling, and residential histories. We assessed the association between PFOA and the odds of miscarriage, stillbirth, preeclampsia, preterm birth, term low birthweight, and birth defects, controlling for calendar time, age, parity, education, and smoking. PFOA exposure was evaluated as a continuous measure (with and without log transformation) and in quintiles, combining the lowest 2 quintiles (< 6.8 ng/mL) as the referent. RESULTS:Measures of association between PFOA and miscarriage, preterm birth, term low birthweight, and birth defects were close to the null. Odds of stillbirth were elevated in the fourth quintile only. For preeclampsia, the odds ratio was 1.13 (95% confidence interval = 1.00-1.28) for an interquartile shift in log-transformed PFOA, and the odds ratios were 1.1-1.2 across the upper 3 quintiles of exposure. CONCLUSIONS:In this large, population-based study in a region with markedly elevated PFOA exposure, we found no associations between estimated serum PFOA levels and adverse pregnancy outcomes other than possibly preeclampsia. Conclusions are tempered by inherent limitations in exposure reconstruction and self-reported pregnancy outcome information.

Studies on ethnic differences in the risk of pre-eclampsia are limited. We linked birth records for 902,460 singleton births for the period 1995-2003 in New York City with hospital discharge data to evaluate the association between ethnicity and the risk of pre-eclampsia and compare risks between US-born and foreign-born women. Logistic regression models adjusted for maternal age, maternal education, parity, self-reported pre-pregnancy maternal weight, smoking during pregnancy and year of delivery were used to compare each ethnic group with non-Hispanic White women. The prevalence of pre-eclampsia in this study population was 3.2%. Among the major ethnic groups considered in our study, East Asian women had the lowest risk of pre-eclampsia (1.4%) and Mexican women had the highest risk (5.0%). Compared with non-Hispanic White women, there was a slightly decreased risk for East Asian women (adjusted OR = 0.8, [95% CI 0.7, 0.8]), similar risk for North African women (adjusted OR = 1.1, [95% CI 0.9, 1.3]), and increased risk for all other major ethnic groups (adjusted ORs: 1.3, 2.9), with the highest risk for Mexican women (adjusted OR = 2.9, [95% CI 2.7, 3.1]). No difference in risks was observed for US- vs. foreign-born women with the exception that foreign-born South-East Asian and Pacific Islanders had an increased risk of pre-eclampsia (adjusted OR = 1.8, [95% CI 1.0, 3.1]) relative to those born in the US. We concluded that there was ethnic heterogeneity in the development of pre-eclampsia among women in New York City and that Asian subgroups should be examined separately in future studies on ethnicity. Our results should contribute to screening for pre-eclampsia taking ethnic variation into account, and may help to suggest leads for the study of the aetiology of the condition.