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Prenatal exposure to perfluorooctanoate and risk of overweight at 20 years of age: a prospective cohort study.

BACKGROUND: Perfluoroalkyl acids are persistent compounds used in various industrial applications. Of these compounds, perfluorooctanoate (PFOA PFOA Perfluorooctanoic Acid (suspected carcinogen used in making Teflon)
PFOA Problem Formulation and Options Assessment
PFOA Peninsula Friends of Animals (Sequim, WA) 
) is currently detected in humans worldwide. A recent study on low-dose developmental exposure to PFOA in mice reported increased weight and elevated biomarkers of adiposity adiposity /ad·i·pos·i·ty/ (ad?i-pos´i-te) obesity.

cerebral adiposity  fatness due to cerebral disease, especially of the hypothalamus.


adiposity

obesity.
 in postpubertal female offspring.

OBJECTIVE: We examined whether the findings of increased weight in postpubertal female mice could be replicated in humans.

METHODS: A prospective cohort of 665 Danish pregnant women was recruited in 1988-1989 with offspring follow-up at 20 years. PFOA was measured in serum from gestational week 30. Offspring body mass index (BMI BMI body mass index.

BMI
abbr.
body mass index


Body mass index (BMI)
A measurement that has replaced weight as the preferred determinant of obesity.
) and waist circumference were recorded at follow-up (n = 665), and biomarkers of adiposity were quantified in a subset (n = 422) of participants.

RESULTS: After adjusting for covariates, including maternal prepregnancy BMI, smoking, education, and birth weight, in utero exposure to PFOA was positively associated with anthropometry anthropometry (ănthrəpŏm`ətrē), technique of measuring the human body in terms of dimensions, proportions, and ratios such as those provided by the cephalic index.  at 20 years in female but not male offspring. Adjusted relative risks comparing the highest with lowest quartile Quartile

A statistical term describing a division of observations into four defined intervals based upon the values of the data and how they compare to the entire set of observations.

Notes:
Each quartile contains 25% of the total observations.
 (median: 5.8 vs. 2.3 ng/mL) of maternal PFOA concentration were 3.1 [95% confidence interval confidence interval,
n a statistical device used to determine the range within which an acceptable datum would fall. Confidence intervals are usually expressed in percentages, typically 95% or 99%.
 (CI): 1.4, 6.9] for overweight or obese (BMI [less than or equal to] 25 kg/[m.sup.2]) and 3.0 (95% CI: 1.3, 6.8) for waist circumference > 88 cm among female offspring. This corresponded to estimated increases of 1.6 kg/m.2 (95% CI: 0.6, 2.6) and 4.3 cm (95% CI: 1.4, 7.3) in average BMI and waist circumference, respectively. In addition, maternal PFOA concentrations were positively associated with serum insulin and leptin Leptin
A protein hormone that affects feeding behavior and hunger in humans. At present it is thought that obesity in humans may result in part from insensitivity to leptin.
 levels and inversely associated with adiponectin levels in female offspring. Similar associations were observed for males, although point estimates were less precise because of fewer observations. Maternal perfluorooctane sulfonate sul·fo·nate
n.
A salt or ester of sulfonic acid.

v.
1. To introduce one or more sulfonic acid groups into an organic compound.

2. To treat with sulfonic acid.
 (PFOS PFOS Perfluorooctane Sulfonate
PFOS Perfluorooctyl Sulfonate
PFOS Principle Field of Study
PFOS Production, Fielding, and Operational Support Life Cycle Phase
PFOS Professional Field of Study
), perfluorooctane sulfonamide sulfonamide /sul·fon·amide/ (sul-fon´ah-mid) a compound containing the sbondSO2NH2 group. The sulfonamides, or sulfa drugs, are derivatives of sulfanilamide, competitively inhibit folic acid synthesis in microorganisms, and formerly were  (PFOSA), and perfluorononanoate (PFNA PFNA Pulsed Fast-Neutron Analysis ) concentrations were not independently associated with offspring anthropometry at 20 years.

CONCLUSIONS: Our findings on the effects of low-dose developmental exposures to PFOA are in line with experimental results suggesting obesogenic effects in female offspring at 20 years of age.

KEY WORDS: offspring obesity, overweight, perfluoroalkyl compounds, PFOA, pregnancy, prenatal exposure. Environ Health Perspect 120: 668-673 (2012). http://dx.doi.org/10.1289/ehp.1104034 [Online 3 February 2012]

Because of their repellent properties and low surface tension, fluorochemicals have been used extensively for more than half a century in various commercial applications, including carpets, textiles, personal care products, leveling and wetting agents and in foodcontact materials (D'eon and Mabury 2011). Use and production of fluorochemicals has resulted in the environmental presence of perfluoroalkyl acids (PFAAs) (Giesy and Kannan 2002), which are highly persistent compounds consisting of a fully fluorinated fluorinated

material to which a fluoride has been added, e.g. water for human consumption treated as a prophylaxis against tooth decay.
 carbon chain (C4-C14) with, for example, a terminal sulfonate or carhoxylate functional group. The environmental presence of PFAAs may be a consequence of emissions during manufacturing, use, or disposal of products (direct sources) as well as transformation of other precursors to PFAAs (indirect sources) (Armitage et at 2009; D'eon and Mabury 2011). The two PFAAs most widely detected in humans are the C8-backbone derivatives perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS), with estimated elimination half-lives of around 4 and 5 years, respectively (Olsen et al.2007).

After reports of global contamination, phaseout phase·out  
n.
A gradual discontinuation.
 of C8-derivatives was initiated in the year 2000 by the major U.S. manufacturers (U.S. Environmental Protection Agency 2010). This has resulted in decreased human exposure compared with peak levels in Europe and the United Stares (Haug et al. 2009b; Olsen et al. 2011). However, recent findings from the Health and Nutrition Examination Survey (NHANES NHANES National Health and Nutrition Examination Survey (US CDC) ) indicate that PFOA levels in the United states remained relatively stable between 2003 and 2008, suggesting continued direct and indirect sources of human exposures to PFOA (Kato et al. 2011).

PFAAs accumulate primarily via binding to albumin in blood (D'eon et al. 2010; Jones et al. 2003), and they are readily transported across the placenta (Monroy et al. 2008). PFAAs are found in highest concentrations in the liver (Hundley et al. 2006; Maestri et al. 2006) and low-dose human exposures to PFOA and PFOS have been associated with modest increases in liver enzymes (Lin et al.2010) and blood lipids (Nelson et al. 2010) in cross-sectional settings. The relevance of these findings is uncertain, however, because prospective studies have not been conducted.. Findings from animal studies suggest that PFAAs may act as endocrine disruptors, affecting circulating estrogens Estrogens
Hormones produced by the ovaries, the female sex glands.

Mentioned in: Acne, Polycystic Ovary Syndrome

estrogens (es´trōjenz),
n.
 levels through pathways such as aromatasc induction in the liver (Liu et al. 1996) or through altering estrogen-expressive genes (Shi et al. 2009), although findings with respect to interactions with estrogen receptors have not been consistent (Benninghoff et al. 2011; Ishibashi et al. 2007).

Experimental studies have demonstrated chat in utero exposures to certain endocrine disruptors, including xenoestrogens, may lead to permanent changes in metabolic pathways that regulate body weight (Newbold et al. 2008). A recent study using a CD-1 mouse model observed higher body weight and increased insulin and leptin levels in postpubertal female offspring after low-dose in utero exposures to PFOA (Hines et al.2009). The aim of this study was to explore these findings in environmentally exposed pregnant women with prospective offspring follow-up at 20 years of age.

Methods

The birth cohort. Between April 1988 and January 1989, 965 women with singleton pregnancies were recruited for a birth cohort study in Aarhus, Denmark (Olsen et al. 1995). This was 80% of a consecutive sample of 1,212 women attending a midwife center in the city, covering a well-defined geographical area. A face-to-face interview was conducted at a routine midwife visit in gestational week 30, covering medical history, anthropometry, diet, lifestyle, and socioeconomic factors. A blood sample was also collected, and it was immediately separated into serum, plasma, and erythrocytes and frozen at -20[degrees]C. Further information on maternal health and birth out-comes were extracted from hospital records and the Danish Medical Birth Registry.

Offspring follow-up. In 2008-2009, study mothers and offspring were contacted, and offspring were asked to fill out a Web-based questionnaire concerning their current health, lifestyle, and dietary habits and their current height and weight. In addition, a tape measure was mailed to all potential participants with instructions on how to measure their waist circumference. Offspring were also invited to participate in a 75-100-min clinical examination, which included standardized anthropometric an·thro·pom·e·try  
n.
The study of human body measurement for use in anthropological classification and comparison.



an
 measures and collection of a fasting blood sample that was immediately centrifuged and frozen at 80[degrees]C. The study was approved by the Danish Data Protection Agency Following the implementation of EU Directive 95/46/EC, regarding the protection of individuals with regards to the process of personal information and the movement of such, the Danish Data Protection Agency was created.  and the Danish Council of Ethics (reference no.20070157), and all participants gave written consent prior to inclusion into the study.

Mother-offspring pairs available for analysis. A total of 915 offspring of the 965 women with singleton pregnancies recruited in 1988-1999 were located and contacted in 2008-2009, and 692 of the offspring agreed to participate in the follow-up study.Missing values on offspring anthropometry (n = 4) and maternal blood samples (n = 23) left 665 mother offspring pairs, or 69% of the original cohort, available for analyses.Of the 665 offspring included in this study, 423 (44% of the original cohort) attended the clinical examination, and 242 completed the Web-based questionnaire only.

Maternal PFAA PFAA Professional Flight Attendants Association
PFAA Participating Field Activity
 samples. Serum samples from gestational week 30 were measured at the Department of Analytical Chemistry at the Norwegian Institute of Public Health The Norwegian Institute of Public Health (Nasjonalt folkehelseinstitutt, Folkehelseinstituttet) is a national center established in 2002 for expert knowledge of epidemiology, infectious disease control, environmental medicine, forensic toxicology and research on  in Oslo.The analytical procedure and sources of chemicals used have been described in detail elsewhere (Haug et al. 2009a). Nineteen PFAAs were analyzed, and 12 were above the limit of quantification (LOQ LOQ Limit of Quantitation
LOQ Limit Of Quantification
LOQ Loquitur (Latin: speaks)
LOQ Level of Quantification
LOQ List Of Questions
LOQ Laugh Out Quiet
LOQ Leadership Opinion Questionaire
; 0.05 ng/mL serum for all PFAAs reported in this study) in one or more samples. For quantification of PFOS, the total area of the linear and branched isomers was integrated. The quality of the analytical procedure was monitored by analyzing in-house quality control samples and human serum samples from interlaboratory comparison exercises (Institut national de sante publique Quebec 2009). For the interlaboratory comparison exercises, the coefficient of variation Coefficient of Variation

A measure of investment risk that defines risk as the standard deviation per unit of expected return.
 for PFOA was between 3% and 9%, depending on the concentration of the reference sample. No traces of PFAAs above LOQ were observed in any of the procedural blanks.

Offspring biomarkers of adiposity. In short, adiponectin was quantified by a time-resolved immunofluorometric assay based on two antibodies and recombinant human adiponectin (R&D Systems, Abingdon, United Kingdom), as previously described (Frystyk et al. 2005). Leptin was determined by a time-resolved immunofluorometric assay based on commercial reagents (R&D Systems) using recombinant human leptin as the standard; otherwise, quantification was carried out essentially as for adiponectin (Frystyk et al.2005). Plasma insulin concentrations were determined by the commercial Insulin ELISA ELISA (e-li´sah) Enzyme-Linked Immuno-Sorbent Assay; any enzyme immunoassay using an enzyme-labeled immunoreactant and an immunosorbent.

ELISA
n.
 kit (Dako, Copenhagen, Denmark).

Outcome measures. Body mass index (BMI) and waist circumference measures from the clinical examination were used when available (n = 423). Self-reported measures from the Web-based questionnaire were used for the remaining 242 subjects. Although subjects tend to underestimate their weight by self-report (Tokmakidis et al. 2007), relative ranks appeared to be retained, as the correlation between measured and self-reported BMI was 0.91 for both sexes (Spearman spear·man  
n.
A man, especially a soldier, armed with a spear.
 r, n = 423). Use of self-reported measures does, however, result in underestimation of cases when dichotomizing subjects as overweight and obese (BMI[greater than or equal to] 25 kg/m2). In our data the sensitivity coefficient and specificity coefficients were 0.46 and 0.99, respectively, for identifying overweight and obese female offspring based on self-report. The corresponding numbers were 0.63 and 0.98 for male offspring, respectively.

Statistical analyses. The mean and SD were used to describe normal variables, whereas median and interquartile range (IQR IQR Interquartile Range (statistics)
IQR Internet Quick Reference
IQR Individual Qualification Record
IQR Internal Quality Review
) were used for skewed variables. Student t-tests or chi-square tests were used to test departures from the null hypothesis null hypothesis,
n theoretical assumption that a given therapy will have results not statistically different from another treatment.

null hypothesis,
n
 for normal outcomes, and the Kruskal-Wallis test was used for skewed outcomes. Linear regression Linear regression

A statistical technique for fitting a straight line to a set of data points.
 was used for continuous outcomes. For dichotomous di·chot·o·mous  
adj.
1. Divided or dividing into two parts or classifications.

2. Characterized by dichotomy.



di·chot
 outcomes, relative risk (RR) was estimated using log-Poisson regression with robust variance estimation, as implemented in PROC (language) PROC - The job control language used in the Pick operating system.

["Exploring the Pick Operating System", J.E. Sisk et al, Hayden 1986].
 GENMODE in SAS (1) (SAS Institute Inc., Cary, NC, www.sas.com) A software company that specializes in data warehousing and decision support software based on the SAS System. Founded in 1976, SAS is one of the world's largest privately held software companies. See SAS System.  (version 9.2; SAS Institute Inc., Cary, NC, USA). All analyses were performed for males and females separately. When examining association with anthropometric outcomes, maternal PFOA concentrations were divided into quartiles and a test for linear trend was performed by using the ordinal (mathematics) ordinal - An isomorphism class of well-ordered sets.  values. For the biomarker analysis, PFOA was entered as a continuous variable.

When estimating the association between in utero PFOA concentration and offspring anthropometry at 20 years of age, we adjusted for the following potential confounders identified a priori a priori

In epistemology, knowledge that is independent of all particular experiences, as opposed to a posteriori (or empirical) knowledge, which derives from experience.
: maternal age maternal age,
n the age of the mother at the period of conception.
 (continuous, no missing); maternal education (elementary schooling, high school or technical schooling, university education, higher academic education, other education, 6% missing); maternal smoking (never, < 10 and [greater than or equal to]10 cigarettes/day, 6% missing); prepregnancy BMI [restricted cubic spline In computer graphics, a smooth curve that runs through a series of given points. The term is often used to refer to any curve, because long before computers, a spline was a flat, pliable strip of wood or metal that was bent into a desired shape for drawing curves on paper. See Bezier and B-spline.  regression (Durrleman and Simon 1989), 2% missing]; parity (0, 1,[greater than or equal to]2, no missing); infant birth weight (continuous, 0.2% missing); and offspring age at follow-up (continuous, 1% missing). A total of 67 subjects (10%) had missing values for one or more of the covariates included. Maternal age and parity were included because they are known predictors of PFAA exposure (Fei et al. 2007). Maternal education and smoking were included to account for potential social and lifestyle confounding. Prepregnancy BMI and birth weight were included because they are known predictors of offspring BMI (Reynolds et al. 2010). Missing covariate values were substituted using multiple imputation IMPUTATION. The judgment by which we declare that an agent is the cause of his free action, or of the result of it, whether good or ill. Wolff, Sec. 3. , as implemented in PROC MI in SAS (SAS Institute, Inc.).

Because of skewed distributions, offspring biomarkers of adiposity were log-transformed when examining their association with maternal PFOA concentrations, and estimates were adjusted for offspring age and timing of blood sample collection.

Results

Nonsignificant non·sig·nif·i·cant  
adj.
1. Not significant.

2. Having, producing, or being a value obtained from a statistical test that lies within the limits for being of random occurrence.
 differences in maternal PFOA concentration, prepregnancy BMI, and parity were observed between mothers whose offspring did not participate in follow-up, mothers whose offspring completed the Web-based questionnaire only, and mothers whose offspring participated in the clinical examination (Table 1). However, mothers whose offspring did not participate in follow-up were more likely to smoke during pregnancy. Females who participated in clinical examination had significantly lower BMI (z 0.8 kg/m') compared with those who completed the Web-based questionnaire only, whereas nonsignificant differences were observed for waist circumference and current smoking. Male offspring who participated in the clinical examination were not significantly different from those who completed the Web-based questionnaire only with regard to BM1, waist circumference, and current smoking.

The median maternal PFOA serum concentration serum concentration Therapeutics The amount of a drug or other compound in the circulation, both bound to proteins and unbound, the latter of which generally corresponds to the theraepeutically active fraction  was 3.7 ng/mL (range: 0.1-19.8). Maternal PFOS, perfluorooctane sulfonamide (PFOSA), and perfluorononanoate (PFNA) concentrations increased across quartiles of PFOA concentration (Table 2). Eight other PFAAs were quantified but were not included in analyses because concentrations were low (median: [less than or equal to]0.4 ng/mL) and were within a narrow range (IQR < 0.2 ng/mL). Mothers in the highest quartile of PFOA concentration were less likely to he parous par·ous
adj.
Having given birth one or more times.



parous

having produced offspring.
 (32% vs. 58%) and were younger (28.7 vs. 29.8 years) than mothers in the lowest quartile of PFOA when enrolled into the original study.

The prevalence of overweight or obesity (BMI [greater than or equal to] 25 kg/m2) was similar between male and female offspring (19% and 18%, respectively), but waist circumference above action level II (Lean et al. 1995) was less common in males (3.5% > 102 cm) than in females (16.2% > 88 cm) (Table 3). All males and 70% of females with waist circumference above action level II were overweight or obese. Females were more likely than males to report that they were currently on a diet (17% vs. 6%).

Maternal PFOA concentrations were positively associated (p for trend < 0.05) with BMI and waist circumference among female offspring at 20 years of age (n = 345) in both unadjusted and covariate-adjusted analyses (Table 4). In adjusted analyses, female offspring whose mothers were in the highest quartile of PFOA. concentration had 1.6 kg/[m.sup.2] [95% confidence interval (CI): 0.6, 2.6] higher BMI and 4.3 cm (95% CI: 1.4, 7.3) higher waist circumference compared with offspring whose mothers were in the lowest quartile. No statistically significant associations were observed for males (p for trend > 0.05, n = 320). Female offspring of mothers in the highest versus lowest PFOA quartile were also more likely to be overweight [RR = 3.1 (95% CI: 1.4, 6.9)1 and to have a waist circumference above action level II at 20 years of age [3.0 (95% CI: 1.3, 6.8)] (Table 5). PFOA was not associated with overweight in male offspring, and RR estimates were consistently null. Only 11 of 320 male offspring had a waist circumference above action level II; consequently, RR estimates were unstable with wide CIs.
Table 1. Maternal and offspring characteristics at baseline
and follow-up according to level of participation.

Characteristics     0ffspring   Offspring only    Offspring
                    not in      out              participating
                    follow-up   Web-based        in clinical
                                questionnaire    examination

Materal                n = 209         n = 242        n = 423

PFOA (ng/mL)(a)       3.7(1.8)        3.7(2.0)       3.7(2.0)

Prepregnancy BMI    21.8 [+ or   21.1 [+ or -]  21.4 [+ or -]
(kg/[m.sup.2])          -] 3.8             2.5            3.0

Nulliparous(%)              54              57             59

Smoking during              49              36             37
pregnancy (%)

Male offspring at                      n = 150        n = 170
follow-up

BMI (kg/[m.sup.2])               22.7 [+ or -]  22.6 [+ or -]
                                           2.9            2.9

Waist                            85.5 [+ or -]  83.5 [+ or -]
circumference                             10.6            8.9
(cm)(e)

Current smoker (%)                          19             18

Female, offspring                       n = 92        n = 253
at follow-up

BMI                              22.3 [+ or -]  21.5 [+ or -]
(kg/[m.sup.2])(e)                          3.2            3.0

Waist                            79.8 [+ or -]  78.6 [+ or -]
circumference                             10.2            9.7

(cm)(e)
Current smoker (%)                          21             17

Characteristics     p-Value
Materal

PFOA (ng/mL)(a)     0.68(b)

Prepregnancy BMI    0.06(c)
(kg/[m.sup.2])

Nulliparous(%)      0.42(d)

Smoking during      0.01(d)
pregnancy (%)

Male offspring at
follow-up

BMI (kg/[m.sup.2])  0.62(c)

Waist               0.08(c)
circumference
(cm)(e)

Current smoker (%)  0.75(d)

Female, offspring
at follow-up

BMI                 0.03(c)
(kg/[m.sup.2])(e)

Waist               0.32(c)
circumference
(cm)(e)

Current smoker (%)  0.45(d)

Based on the 874 mothers whose blood samples were analyzed for PFAAs
in the Aarhus Birth Cohort (1988-1989). Values are median (IOR) for
maternal PFOA concentration; otherwise, they are mean [+ or -] SD or %.

(a.) Maternal serum from gestational week 30.

(b.) Kruskal-Wallis test of differences among participation guoups.

(c.) F-test (type Ill) of differences among participation groups.

(d.) Chi-square test of differences among participation groups.

(e.) Comparison for offspring anthropometry is based on self-reported
values.

Table 2. Maternal characteristics during pregnancy among 665
participants from the Aarhus Birth Cohort (1988-1989).

                                 Quartiles of maternal PFOA
                                 concentration
Variables        Overall         1                      2

Serum
concentration
(ng/mL) (a)

PFOA                 3.7(2.0)       2.4(0.6)       3.3(0.4)

PFOS                21.5(9.1)      16.0(5.6)      20.2(5.7)

PFOSA                1.1(1.0)       0.7(0.5)       1.1(0.7)

PFNA                 0.3(0.2)       0.3(0.2)       0.3(0.2)

Physical
characteristic

Age (years)      29.2[+ or -]   29.8[+ or -]   29.2[+ or -]
                          4.1            3.8            4.1

Height (cm)       168[+ or -]  167.4[+ or -]  167.6[+ or -]
                          6.0            6.3            6.5

Prepregnancy     21.3[+ or -]   21.1[+ or -]   21.3[+ or -]
BMI                       2.9            2.3            3.2
(kg/[m.sup.2])

Birth weight     3.53[+ or -]   3.62[+ or -]   3.53[+ or -]
                         0.52           0.55           0.57

Smoking during             27             40             38
pregnancy (%)

Parous women               42             58             39
(%)

Maternal                   10             13             12
education (%)

Elementary                 10             13             12
schooling

High school or             23             12             19
technical
schooling

University                 39             44             36
education

Higher academic            18             25             20

Other education            10              6             13
or missing

Variables        3               4               p-value

Serum
concentration
(ng/mL) (a)

PFOA                  4.2(0.5)       5.8(1.9)

PFOS                 23.6(6.8)     28.51(2.1)  <0.0001(b)

PFOSA                 1.3(0.9)       1.5(1.1)  <0.0001(b)

PFNA                  0.4(0.2)       0.4(0.3)  <0.0001(b)

Physical
characteristic

Age (years)       28.8[ +or -]   28.7[+ or -]     0.01(c)
                           3.9            4.5

Height (cm)      167.8[+ or -]  168.0[+ or -]     0.43(c)
                           5.5            5.7

Prepregnancy      21.2[+ or -]   21.5[+ or -]     0.25(c)
BMI                        2.4           3.2
(kg/[m.sup.2])

Birth weight      3.49[+ or -]   3.47[+ or -]    0.009(c)
                          0.44           0.52

Smoking during              39             31     0.34(d)
pregnancy (%)

Parous women                38             32  <0.0001(d)
(%)

Maternal
education (%)

Elementary                   7              8   0.0002(d)
schooling

High school or              25             34
technical
schooling

University                  44             32
education

Higher academic             14             14

Other education             11             12
or missing

Values are median (IQR), mean[+or-]SD, or %

(a.) Blook (serum) samples were collected in gestational week 3;
PFOA, PFNA, PFOS, and PFOSA were detected in all samples.
(b.) Kruskal-Wallis test of differences across quartiles of maternal
PFOA concentration. (c.) Student t-test of differences across
quartiles of maternal PFOA concentration. (d.) Chi-square test of
differences across quartiles of maternal PFOA concentration.

Table 3. Characteristics of male and female offspring at 20
years of age (2008-2009), Aarhus Birth Cohort (1988-1989)

Characteristic                   Males          Females

Physical characteristic [mean        n = 320        n = 345
[+ or -] SD or n(%)]
Age (years)                    19.7 [+ or -]  19.9 [+ or -]
                                         0.4            0.4
Waist circumference (cm)       84.3 [+ or -]  79.9 [+ or -]
                                         9.3            9.4
BMI (kg/[m.sup.2])             22.8 [+ or -]  22.2 [+ or -]
                                         2 9            3.3
Waist circumference above           11 (3.5)      56 (16.2)
action level ll(a)
Overweight or obese(b)             GO (18.9)      61 (17.7)
Suftects in both al and b)          11 (3.5)      39 (11.3)
Currently on a diet                 20 (6.3)      60 (17.4)
Offspring attending clinical         n = 170        n = 252
examination [median (IQR)]
Insulin (mmol/L)                     37 (22)        42 (23)
Leptin (ng/L)                      2.2 (3.1)    13.5 (12.6)
Adiponectin ([mu]g/L)              6.8 (3.7)      9 4 (4.5)
Leptinlacliponectin ratio          0.3 (0.6)      1.5 (1.5)

(a.) Waist circumference > 102 cm for males and > 88 cm for
females (Lean et al. 1995).

(b.) BMI [greater than or equal to] 25 kg/[m.sup.2].


Among female participants who provided a blood sample at clinical examination (11 = 252), maternal PFOA concentration was positively associated with insulin, leptin, and the leptin-adiponectin ratio and inversely associated with adiponectin levels (Table 6).The associations corresponded to a 2-7% change in these biomarkers per 1-unit increase in PFOA. Point estimates were similar for male offspring but nonsignificant (n = 170).Although the precision of the estimated associations between maternal PFOA and the biomarkers was reduced because of the small sample size for this analysis (particularly in males), associations between maternal PFOA and offspring anthropometry were comparable with those for the follow-up participants as a whole, supporting the validity of these estimates. For example, estimated increases in BMI comparing highest with lowest quartile of maternal PFOA concentration were 1.8 kg/[m.sup.2] (95% CI: 0.6, 3.0) and 0.6 kg/[m.sup.2] (95% CI: 0.7, 1.9) for female and male offspring who provided a blood sample at clinical examination, compared with 1.6 kg/[m.sup.2] (95% CI: 0.6, 2.6) and 0.6 kg/[m.sup.2] (95% CI: -0.3, 1.5) for all female and male participants, respectively.

Concerning other PFAAs, we observed that PFOS, PFNA, and PFOSA (continuous variables) were in univariate analysis either borderline p for trend = 0.05 for PFOSA) or significantly (p for trend < 0.05 for PFNA, PFOS) positively associated with female offspring BMI at 20 years. However, after adjusting for PFOA, the regression coefficients became nonsignificant (p for trend [greater than or equal to] 0.56 in all cases, data not shown). We also found no evidence that the association between maternal PFOA concentration and offspring anthropometry was influenced by the presence of the other PFAAs quantified. For example, the estimated increase in female offspring BMI with a 1-ng/mL increase in maternal PFOA in. a univariate analysis was 0.43 kg/[m.sup.2] (95% CI: 0.25, 0.60) compared with 0.46 kg/m2 (95% CI: 0.21, 0.71) based on a model that included maternal PFOS, PFOSA, and PFNA as continuous terms.

Associations with offspring BMI were also stable with respect to maternal parity.For female offspring of nulliparous mothers (n = 191), we estimated a 0.46-kg/m2 (95% CI: 0.27, 0.66) increase in BMI per 1-ng/mL increase in PFOA, compared with 0.36 kg/m2 (95% CI: 0.03, 0.69) for female offspring of parous mothers (interaction p-value 0.65).

Discussion

In this cohort of environmentally exposed pregnant women, we observed a positive association between in utero exposure to PFOA and the prevalence of overweight and a high waist circumference among female offspring, but not male offspring, at 20 years of age. In addition, in utero exposure to PFOA was associated with biomarkers of adiposity among male and female offspring, although estimates for males were not significant.

Animal studies have shown that early-life exposures to xenoestrogens such as diethylstilbestrol diethylstilbestrol: see DES.  (Newbold et al. 2008) and bisphenol-A (Somm et al. 2009) can lead to permanent disruption in endocrine functions that regulate adiposity. One observation from these studies is that low-dose exposures may result in significant weight changes in the exposed animals only after adult age is reached, whereas a pattern of reduced weight in early infancy followed by rapid catch-up growth is often observed at higher doses (Newbold et al. 2008). Human studies have provided some support for these findings, including reports of rapid weight gain up to 3 years of age after in utero exposures to polychlorinated biphenyls (Verhulst et al. 2009) as well as increased overweight at 6 years of age after in utero exposure to hexachlorobenzene (Smink et al. 2008). However, metabolic pathways that might explain these findings are not well characterized, and long-term follow-up studies have not been conducted.

Indications that environmental exposures to PFAAs may affect cardiometabolic risk factors have, so far, been obtained from cross-sectional studies focusing on end points such as blood lipids (Nelson et al. 2010) and glucose homeostasis homeostasis

Any self-regulating process by which a biological or mechanical system maintains stability while adjusting to changing conditions. Systems in dynamic equilibrium reach a balance in which internal change continuously compensates for external change in a feedback
 (Lin et al. 2009), but in these studies, findings with respect to anthropometry have been inconsistent. Interpretation of cross-sectional findings on anthropometry is complex, however, as absorption and distribution of PFAAs depend on related factors such as lean body mass and blood volume (Ahrens et al. 2009; Fei et al. 2007).

However, our findings are consistent with a recent experimental study on CD-1 mice that reported increased body weight in postpubertal female offspring after low-dose (0.01-0.3 mg/kg body weight) in utero exposure to PFOA (Hines et al. 2009). In that study, increases in weight were most pronounced in mid-life and were accompanied by elevated levels of leptin and insulin in the exposed animals. At higher doses ([greater than or equal to] 1mg/kg), weight gain was not observed.Furthermore, exposing the offspring after weaning as opposed to in utero also had no effect on weight gain. In at least two animal studies, researchers did not observe increased body weight after in utero exposure to PFOA (Butenhoff et al. 2004; Macon et al. 2011), but one study used higher doses 1 mg/kg) (Butenhoff et al. 2004) and the other followed animals only until 12 weeks of age (Macon et al. 2011).
Table 4. Associations (a) between in utero exposure to PFOA
and the offspring BMI and waist circumference at 20 years
of age for females (n 345) and males (n = 320).

PFOA in quartiles  [DELTA]BMI [mean
                   (95% CI)]
[median (range)]b  Crude             Adjusted (c)

Females

1 2.3(O.1-28)            Referent          Referent
2 3.2(2.8-3.7)     0.2(-0.7, 1.2)    0.4(-0.6, 1.3)
3 4.2(3.7-4.8)     0.8(-0.2, 1.8)    0.9(-0.1, 1.9)
4 5.8(48-19.8)     1.6 (0.6, 2.5)     1,6(0.6, 2.6)
p-Value for trend          0.0007             0.001
(d)

Males (e)

1 2.4(1.2-18)            Referent          Referent
2 3.3(2.8-3.7)     0.5(-0.4, 1.4)    0.6(-0.3, 1.5)
3 4.2(3.7-4.8)     0.3(-0.7, 1.2)    0.2(-0.7, 1.1)
4 5.8(4.8-16.6)    O.4(-O.5, 1.3)    0.6(-0.3, 1.5)
p-Value for trend              0.47  0.30
(d)

PFOA in quartiles  [DELTA]Waist
                   circumference
                   [mean(95% CI)]
[median (range)]b  Crude           Adjusted (c)

Females

1 2.3(O.1-28)           Referent          Referent
2 3.2(2.8-3.7)     1.0(-1.7, 3.7)   1.4(-1.4, 4.2)
3 4.2(3.7-4.8)     0.9(-1.9, 3.6)   1.2(-1.7, 4.0)
4 5.8(48-19.8)     4.2 (1.5, 6.9)    4.3(1.4, 7.3)
p-Value for trend           0.005            0.006
(d)

Males (e)

1 24(1.2-18)             Referent         Referent
2 3.3(2.8-3.7)         1.3(-1.7.)  1.3 (-1.5, 4.1)
3 4.2(3.7-4.8)     1.0(-2.0, 4.0)   1.0(-1.9. 3.8)
4 5.8(4.8-16.6)    0.7(-2.2, 3.6)   1.3(-1.6, 4.1)
p-Value for trend            0.72             0.48
(d)

(a.) Linear regression with continuous outcome variables (BMI
or waist circumference) and PFOA divided into quartiles. (b.)
Nanograms per milliliter serum. (c.) Adjusted for maternal
age, maternal education, maternal preprepregnancy BMI, smoking
during pregnancy, parity, infant birth weight, and offspring
age at follow-up. (d.) Student's t-test with PFOA included in
the regression model as an ordinal variable. (e.) Waist
circumference was missing for two male offspring (n= 318).

Table 5. Associations (a) between in utero exposure to PFOA and risk
of being overweight or having waist circumference above action level
II at 20 years of age for females (n = 345) and males (n = 320).

PFOA in                                Overweight (BMI
quartiles                             [greater than or
                                           equal
                                     to]25kg/[m.sup.2])
                                       [RR (95% CI)]

[median                   Cases/no.        Crude         Adjusted(d)
(range)]
(c)

Females

1          2.3(0.1-2.8)       10/91                 1.0           1.0

2          3.3(2.8-3.7)       12/87        1.3(0.6,2.8)  1.5(0.6,3.5)

3          4.2(3.7-4.8)       15/81        1.7(0.8,3.5)  2.0(0.9,4.7)

4          5.8(4.8-19.8)      24/86        2.5(1.3,5.0)  3.1(1.4,6.9)

           p-Value for                            0.007         0.003
           trend(e)

Males(f)

1          2.3(1.2-2.8)       13/74                1.00          1.00

2          3.3(2.8-3.7)       17/81        1.2(0.6,2.3)  1.2(0.6,2.6)

3          4.3(3.7-4.8)       14/78        1.0(0.5,2.0)  1.0(0.4,2.2)

4          5.8(4.8-16.6)      16/87        1.0(0.5,2.0)  1.1(0.5,2.6)

           p-Value for                             0.97          0.89
           trend (e)

PFOA in                                High waist
quartiles                            circumference
                                          (b)
                                     [RR (95% CI)]

[median                   Cases/no.      Crude        Adjusted(d)
(range)]
(c)

Females

1          2.3(0.1-2.8)        9/91           1.00              1.0

2          3.3(2.8-3.7)       13/87   1.5(0.7,3.4)     1.7(0.7,4.1)

3          4.2(3.7-4.8)       10/81   1.2(0.5,2.9)     1.3(0.5,3.2)

4          5.8(4.8-19.8)      24/86   2.8(1.4,5.7)     3.0(1.3,6.8)

           p-Value for                       0.008             0.01
           trend(e)

Males(f)

1          2.3(1.2-2.8)        1/74           1.00             1.00

2          3.3(2.8-3.7)        4/81            3.7  6.1 (0.4, 90.0)
                                        (0.4,32.0)

3          4.3(3.7-4.8)        3/77  2.9(0.3,27.1)   7.3(0.4,121.4)

4          5.8(4.8-16.6)       3/86            2.6  13.3(0.4,298.9)
                                        (0.3,24.3)

           p-Value for                        0.60             0.11
           trend (e)

(a.) Log-Poisson regression with robust variance estimation, as
implemented in PROC GENMODE in SAS. (b.) Waist circ
umference > 88 cm for females and > 102 cm for males (Lean et al.
1995). (c.) Nanograms per milliliter serum. (d.) Adjusted for maternal
age, maternal education, maternal preprepregnancy BMI, smoking during
pregnancy, parity, infant birth weight, and offspring age at follow-up.
(e.) Chi-square test (Type III) with PFOA included in the regression
model as an ordinal variable. (f.) Waist circumference was missing
for two male offspring (n = 318).

Table 6. Association(a) between in utero exposure to PFOA and
offspring serum biomarkers of adiposity at 20 years of  age.

                    Females (n =                      Males (n =
                        252)                               170)
Biomarker              Percent       95% CI   p-Value    Percent
                    change(b),(c)                       change(c)

Insulin                       4.5    1.8,7.2    0.001         2.2

Leptin                        4.8    0.5,9.4     0.03         4.5

Adiponectin                  -2.3  -4.5,-0.2     0.03        -1.7

Leptin/adiponectin            7.2   2.2,12.5    0.004         6.3
ratio

Biomarker             95% CI   p-Value

Insulin             -0.8, 5.3     0.15

Leptin              -2.6,12.1     0.21

Adiponectin          -4.6,1.2     0.25

Leptin/adiponectin  -1.5,14.6     0.11
ratio

The associations are limited to the subgroup of participants
(n = 422) that provided blood samples at clinical  examination
(a.) Linear regression using log-transformation for the dependent
variable (continuous).The results are adjusted for time of blood
sample collection (e.g.,08:00-12:30)and offspring age at follow-up.
(b.) Blood sample was  missing for one female subject who attended
clinical examination. (c.) Percent change in the outcome measure
for 1- ng/mL change in serum PFOA.


Similar to the findings of Hines et al.(2009), we observed significant associations between maternal PFOA and insulin and leptin in addition to adiponectin levels among female offspring. Changes in these biomarkers were modest, however, and corresponded to what could be expected from the observed increase in offspring BMI. The results from our biomarker analysis provide valuable insight, as elevared insulin levels predict central fat in both normal weight and overweight women (Carey et al. 1996). Therefore, these results provide added weight to our findings, as BMI and waist circumference are relatively crude measures of body composition.

The absence of an association between in utero PFOA exposure and weight gain among male offspring is noteworthy but not unexpected. Sex-specific differences with respect to weight gain have been observed for xenoestrogens, where female offspring appear to be more affected (Newbold et al. 2008; Somm et al. 2009). Results for male offspring were not reported in the CD-I mouse study (Hines et al. 2009), and experimental studies have suggested that reproductive development, but not weight gain, may be a more sensitive end point for males with respect to developmental exposures to PFAAs (Shi et al. 2007).Despite these observations, results for male offspring in our study should be interpreted cautiously, as many study participants were still in their late adolescence, and relatively few males had high waist circumference compared with females. Because girls gain more fa mass and boys gain more fat-free mass during adolescent age (Ahmed a al. 1999), weight gain in male offspring at a later age when accumulation of far mass increases cannot be excluded.

Concerning mechanism, there are at least three potential pathways by which in utero exposure to PFOA might affect offspring weight. First, PFOA may interfere with ovary ovary, ductless gland of the female in which the ova (female reproductive cells) are produced. In vertebrate animals the ovary also secretes the sex hormones estrogen and progesterone, which control the development of the sexual organs and the secondary sexual  development in utero, leading to impaired estrogen synthesis among female offspring.This mechanism is supported by the observation that in utero PFOA exposure did nor affect weight gain in the previously mentioned study on CD-1 mice when ovariectomy ovariectomy /ovar·i·ec·to·my/ (o-var?e-ek´tah-me) oophorectomy.

o·var·i·ec·to·my
n.
The surgical removal of one ovary or both ovaries. Also called oophorectomy.
 was performed in exposed offspring after delivery (Hines et al. 2009). Second, PFAAs may interact with the peroxisome Peroxisome

An intracellular organelle found in all eukaryotes except the archezoa (original lifeforms). In electron micrographs, peroxisomes appear round with a diameter of 0.1–1.
 proliferator-activated receptors (PPAR PPAR Peroxisome Proliferator Activated Receptor
PPAR Physical Partitions
) PPARa and PPART PPART Plutonium Processing Automation Review Team , which are involved in lipid metabolism in adipocytes (Hines et al. 2009). Whether such an interaction can lead to sex-specific differences in weight gain remains unclear. Third, thyroid hormones might play some role: The results of one cross-sectional study suggested that PFOA exposure may lead to an increased risk of thyroid disease thyroid disease Thyroid disorder Endocrinology Any benign or malignant condition that affects the structure or function of the thyroid gland. See Anaplastic carcinoma of thyroid, Chronic thyroiditis–Hashimoto's disease, Hyperthyroidism, Hypoparathyroidism,  (Meizer et al. 2010), which is more common in females than males. A recent study from the C8 Health project also observed a modest positive association of PFOA with serum thyroxine and an inverse association with T3 uptake (Knox et al. 2011). The overall evidence linking PFAAs to thyroid function is still weak (Steenland et al. 2010), particularly as prospective studies have not been con ducted, and no clear effect on thyroid function has been observed in occupationally exposed individuals (Olsen and Zobel 2007).

A unique strength of our study is the long-term prospective follow-up with outcome assessment at an age where weight changes due to linear growth have leveled off, and it was possible to adjust for several prenatal factors including maternal BMI, smoking, and education. We were also able to support our findings on offspring anthropometry with assessment on serum biomarkers of adiposity in a subset of study participants. Furthermore, quantification of a total of 12 PFAAs made it possible to conclude that PFAAs other than PFOA were unlikely to play an important role in our study population, either because of a low concentration or a lack of association after adjusting for PFOA.

Concerning limitations, we acknowledge that uncertainties regarding routes of human exposure to PFAAs may have resulted in a failure to identify important confounders. We also acknowledge that maternal PFOA concentrations in late gestation may be influenced by factors such as blood volume expansion, decreased albumin concentration, and fetal uptake (Fei et al. 2007; Frederiksen 2001), and these factors may predict fetal outcomes such as birth weight (Savitz 2007). However, with a temporal separation of 20 years, our findings should be less prone to such influence. Furthermore, PFOA concentrations in samples collected at around gestational weeks 6-12 and 24 (Olsen et al. 2001) and in cord blood cord blood
n.
Blood present in the umbilical vessels at the time of delivery.
 have been observed to be highly correlated (r [approximately equal to] 0.8-0.9) (Fei et al. 2007).

Finally, as with all longitudinal studies, losses during follow-up are inevitable, and this is perhaps the main limitation of our study.Having quantified maternal PFOA concentrations in 874 (or 72%) of 1,212 women who were originally invited to participate, it is reasswing that exposure levels were nondifferential with respect to level of participation in the follow-up study. A higher prevalence of smoking among mothers whose offspring did not participate suggests that losses due to follow-up were related to some extent to maternal life-style. There were relatively modest differences in anthropometry between offspring who participated in the clinical examination and those who completed the Web-based questionnaire only. Nonetheless, our secondary analyses of offspring biomarkers of adiposity may be compromised because of the low participation rate, particularly among males.

Conclusion

In a cohort of environmentally exposed pregnant women, a positive association between in utero exposure to PFOA and the prevalence of overweight and high waist circumference was observed in female offspring at 20 years of age. Our findings are in line with recent experimental findings (Hines et at 2009) and provide added support for the hypothesis that early-life exposure to certain endocrine disruptors, even at low concentrations, may play a role in the current obesity epidemic. Given the widespread detection of PFOA in humans and wildlife and observed increase in related perfluorinated compounds of similar biological potential (Harada et al. 2011; Haug et al. 2009b), it is of considerable public health importance to understand and eliminate pathways of human exposures to PFAAs.

Address correspondence to T.I. Halldorsson, Center for Fetal Programming, Department of Epidemiology Research, Statens Serum Institut Statens Serum Institut (English: the State Serum Institute), or SSI for short, is a Danish sector research institute located on the island of Amager in Copenhagen. , Orestads Boulevard 5, Building 206, 2300 Copenhagen, Denmark. Telephone: 4532688692. Fax: 4532683165. E-mail: Iur@ssi.dk

Funding for this study was provided by the Danish Agency for Science, Technology and Innovation (DSP (1) (Digital Signal Processor) A special-purpose CPU used for digital signal processing applications (see definition #2 below). It provides ultra-fast instruction sequences, such as shift and add, and multiply and add, which are commonly used in math-intensive : 09-067124, DSE 1. DSE - Display Screen Equipment. See Visual Display Unit.
2. DSE - Data Structure Editor.
: 09-063072, DES: 2101-060005; ESS: 09-065631).

The authors declare they have no actual or potential competing financial interests.

Received 3 June 2011; accepted 3 February 2012.

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Verhulst SL, Nelen V, Florid florid /flor·id/ (flor´id)
1. in full bloom; occurring in fully developed form.

2. having a bright red color.


flor·id
adj.
Of a bright red or ruddy color.
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in·tra·u·ter·ine
adj.
Within the uterus.


Intrauterine
Situated or occuring in the uterus.
 exposure to environmental pollutants and body mass index during the first 3 years of life. Environ Health Perspect 117:122-126.

Thorhallur I. Halldorsson, (1), (2), (3) Done Rytter, (4) Line Smastuen Haug, (5) Bodil Hammer Bech, (4) Inge Danielsen, (1) Georg Becher, (5), (6) Tine Brink Henriksen, (7) and Sjurdur F. Olsen (1), (8)

(1.) Center for Fetal Programming, Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark; (2.) Faculty of Food Science and Nutrition, University of Iceland (body, education) University of Iceland - The Home of Fjolnir.

Háskóli Íslands.

http://rhi.hi.is/.
, Reykjavik, Iceland; (3.) Unit for Nutrition Research, Landspitali University Hospital, Reykjavik, Iceland; (4.) Department of Public Health, Section for Epidemiology, Aarhus University, Denmark; (5.) Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo, Norway; (6.) Department of Analytical Chemistry, University of Oslo The University of Oslo (Norwegian: Universitetet i Oslo, Latin: Universitas Osloensis) was founded in 1811 as Universitas Regia Fredericiana (the Royal Frederick University , Oslo, Norway; (7.) Department of Paediatrics, Aarhus University Hospital, Skejby, Denmark; (8.) Department of Nutrition, Harvard School of Public Health The Harvard School of Public Health is (colloquially, HSPH) is one of the professional graduate schools of Harvard University. Located in Longwood Area of the Boston, Massachusetts neighborhood of Mission Hill, next to Harvard Medical School and Cambridge, Massachusetts, , Boston, Massachusetts, USA
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Title Annotation:Research
Author:Halldorsson, Thorhallur I.; Rytter, Dorte; Haug, Line Smastuen; Bech, Bodil Hammer; Danielsen, Inge;
Publication:Environmental Health Perspectives
Article Type:Report
Geographic Code:1USA
Date:May 1, 2012
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