Isomer-Specific Transplacental Transfer of Perfluoroalkyl Acids

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Isomer-Specific Transplacental Transfer of Perfluoroalkyl Acids: Results from a Survey of Paired Maternal, Cord Sera and Placentas Fangfang Chen, Shanshan Yin, Barry C. Kelly, and Weiping Liu Environ. Sci. Technol., Just Accepted Manuscript • Publication Date (Web): 24 Apr 2017 Downloaded from http://pubs.acs.org on April 25, 2017

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Environmental Science & Technology

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Isomer-Specific Transplacental Transfer of Perfluoroalkyl Acids: Results from a Survey of

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Paired Maternal, Cord Sera and Placentas

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Fangfang Chen1, Shanshan Yin1, Barry C. Kelly2*, Weiping Liu1*

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Ministry of Education Key Laboratory of Environmental Remediation and Ecosystem Health,

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College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058,

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China

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Department of Civil and Environmental Engineering, National University of Singapore, Singapore 117576, Singapore

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Corresponding author. * Department of Civil and Environmental Engineering, National University

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of Singapore, Block E1A, #07-03, No.1 Engineering Drive 2, Singapore 117576. Tel. (+65-6516

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3764); Fax (+65-6779-1635); Email: [email protected]

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* College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, China 310058.

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Tel. (+86-571- 8898 2341); Fax (+86-571- 8898 2341); Email: [email protected]

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1 ACS Paragon Plus Environment


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Graphical Abstract for TOC

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ABSTRACT

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Currently, information regarding isomer-specific concentrations of PFHxS, PFOS, and PFOA in

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human placenta, and corresponding placental-maternal ratios (RPM) of these compounds does not

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exist. The objective of the present study was to assess the occurrence, and distribution of

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different PFHxS, PFOS and PFOA isomers in maternal serum, umbilical cord serum and

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placenta to gain a better understanding of transplacental transport efficiency and prenatal

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exposure risks. The study involved quantitative determination of isomer-specific concentrations

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of PFHxS, PFOS and PFOA in samples of maternal serum (n = 32), cord serum (n = 32) and

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placenta (n = 32) from pregnant women in Wuhan, China. The results indicate that both linear

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and branched PFHxS, PFOS and PFOA can be efficiently transported across the placenta, with

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exposure levels ordered maternal serum > cord serum > placenta. For PFOS isomers, the

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concentration ratios between cord serum and maternal serum (RCM) were ordered n < iso < 4m

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PFHxS, which is consistent with previous studies.14, 29-31 Concentrations of PFAAs in subjects

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from the present study (Wuhan, China) were consistently lower than those previously reported in

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subjects living in northern China, including cities such as Shijiazhuang, Tianjin, and Handan.5, 14,

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those in other countries.27, 32, 33 The relatively high concentrations of PFAAs in northern China, is

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likely due to continued production of textiles utilizing PFOS. Concentrations of these studied

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PFAAs were ordered maternal sera > cord sera > placentas, (p < 0.05). In the observation of

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higher concentrations of PFAAs in maternal sera compared to cord sera is consistent with

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previous reports of PFOS and PFOA.6, 23, 27, 34 However, these findings contradicts with the

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findings by Zhang et al., which found that PFHxS and PFOS were with the concentration

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followed maternal sera > placentas > cord sera.35 It may be due to the following reasons, (i) the

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concentrations of total PFHxS and PFOS in placentas and cord sera were close in both this study

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and Zhang’s study. In addition, the range of concentration in the placentas in Zhang’s study was

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wider than that in this study, and (ii) the samples in these two studies were from the different city

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of China (Wuhan and Tianjin). Therefore their different linear and branched compositions may

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lead to different distribution in placentas and cord sera due to different transplacental transfer

However, concentrations of PFAAs in subjects from the present study are still higher than


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efficiencies. Given all that, the rank order of total PFHxS and PFOS in placentas and cord sera in

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this study may differ from that in Zhang’s study.

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Table S5 of the SI shows the isomer-specific PFHxS, PFOS and PFOA concentrations in

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matched maternal sera, cord sera and placentas. Linear and branched PFHxS and PFOS were

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detected in all of the maternal sera, cord sera, and placentas. Branched PFOA was detected less

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frequently in maternal sera, cord sera and placentas, with detection frequencies of 0% for 5m-,

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4m- and tb-PFOA. Branched PFOS isomers contributed approximately 17% (median) of total

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PFOS in maternal sera, 24% in cord sera and 29% in placentas (Figure 2). The proportion of

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linear PFOS in human sera of previous studies was generally lower than that in historical ECF

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PFOS standards (i.e 70%), such as Sweden (68.1%), Australia (58.7%), Norway (57%–70%),

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Canada (64%), and China (48.1%).6, 15, 29, 36 While our result with the proportion of n-PFOS

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(83%) was not consistent with these studies. One previous study conducted in Vietnam similarly

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reported a relatively high n-PFOS contribution (83%).37 The reason for these differences is not

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clear. The exposure source, metabolism of its precursors (PreFOS), or pharmacokinetics in the

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human body may contribute to the observed differences. It has been reported that linear PFOS

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and PFOA are more bioaccumulative and exhibit lower urinary excretion rates compared to

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branched PFOS and PFOA.12, 14, 15 Branched PFOA isomers contributed 9% (median) of total

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PFOA in maternal sera, 11% in cord sera and 8% in placentas. The proportion of linear PFOA

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was significantly higher than in historical ECF PFOA (78%), which is consistent with previous

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studies.6, 15, 29, 36 The branched compositions of total PFOS and PFOA were consistently and

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significantly (p < 0.001) lower in maternal sera than in corresponding cord sera (Figure 2), which

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is consistent with previous studies.6, 23 This indicates branched isomers of PFOS and PFOA were

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transported more efficiently than their linear isomers. Branched PFHxS isomers contributed 14% 11 ACS Paragon Plus Environment


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(median) of total PFHxS in maternal sera, 3% in cord sera and 23% in placentas indicating lower

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transplacental efficiency of branched PFHxS compared to linear PFHxS. The reason for higher

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transplacental efficiency of branched PFHxS is unclear, which requires further investigation.

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Placental transfer. The occurrence of linear and branched PFAA residues in cord serum and

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placenta indicates that these chemicals can be transported through the placenta into the umbilical

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cord blood, with retention in the placenta. Previous studies have demonstrated that shorter-chain

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perfluoroalkyl sulfonic acids (PFSAs) cross the placenta more efficiently than longer-chain

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PFSAs.20, 26, 27 For example, these previous studies reported RCM values of total PFHxS (C6) was

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greater than that of total PFOS (C8), which is consistent with our findings. Specifically, Figure 3

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shows RCM values were consistently higher than RPM for total PFHxS, PFOS, and PFOA in the

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present study.

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The median RCM (0.392-0.963, Table S6 of the SI) of different branched PFOS isomers

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were greater than those of linear isomer (0.370), indicating that all the branched isomers of

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PFOS were transferred more efficiently than the linear isomer (Figure 4-A). In particular, RCM

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values decreased as the branching point moved away from the sulfonate moiety among the

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perfluoromethyl PFOS branched isomers: iso < 4m < (3+5)m < 1m. This is similar to the

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structure–activity relationship reported by Beesoon et al. (2011).6 In the present study, the RCM of

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Σm2-PFOS was still higher than 1m-PFOS, which is different with the result of Beesoon et al.

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(2011).6 However, similar to results of Beesoon et al. (2011),6 1m-, (3+5)m-, 4m-, and

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particularly Σm2-PFOS, the concentrations in cord sera were sometimes higher than in maternal

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sera (i.e. RCM values > 1.0). For RPM, a similar trend was observed for branched PFOS isomers:

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iso < 4m ≈ (3+5)m < 1m (Figure 4-B), which has not been observed previously. No obvious

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structure-activity relationship of RCM and RPM was observed for PFOA isomers (Figure 4), 12 ACS Paragon Plus Environment

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consistent with results of Beesoon et al. (2011).6 RCM and RPM of n-PFHxS were greater than

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those of br-PFHxS (Figure 4). Sometimes, the RPM is slightly different with the RCM for above

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compounds. The variation of physiology and pathology of individual placenta might have

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contributed to the placental differences.38 For example, the difference in the fat weight, the size

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of the placenta,39 or inflammation during the delivery was reported to be an important factor of

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the transplacental transport.40

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It has been reported that passive diffusion often governs transport mechanism for drugs

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crossing the placental barrier.41 Generally, more hydrophobic compounds exhibit higher

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placental transfer efficiency compared to more hydrophilic compounds.42 However, branched

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isomers of PFHxS, PFOS and PFOA are less hydrophobic than their linear isomers, based on

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their elution orders in reversed-phase chromatography. Further, Sastry claimed that compounds

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with a more “rounded” molecular shape may have lower transplacental efficiency due to steric

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effects.43 Therefore, branched isomers of PFHxS, PFOS and PFOA are anticipated to have lower

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transplacental efficiencies compared to linear isomers based on passive diffusion. However, the

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findings from the present study show that only PFHxS followed this notion. Transport of

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chemicals across placenta can also be influenced by the degree of binding to plasma protein.6, 44

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Beesoon et al. (2015) reported that binding affinity of linear PFOS and PFOA to human serum

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albumin were much stronger than branched isomers,45 which may explain the higher

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transplacental efficiency of the branched isomers of PFOS and compared to linear isomers.

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Moreover, according to Beesoon et al. (2015), the rank order of protein binding affinities for the

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different PFOS isomers was 3m- < 4m- < 1m- < 5m- < iso- < n-PFOS.45 The findings in the

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present study are generally consistent with this rank order, with the exception of 1m-PFOS. The



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fact that binding affinity of n-PFOS was much stronger than n-PFOA may explain the reason

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RCM of n-PFOA was greater than that of n-PFOS in the present study (Figure 4).45

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In addition to passive diffusion, active transport may also play an important role in placental

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transport. In human placenta, multiple transporter proteins are expressed on both sides of the

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placental cells, which may elicit advective chemical transport across the placenta.46 These

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transporters are capable of either increasing or decreasing the chemical concentration in placental

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cells, given the characteristic and location of these transporters and the specificity of their

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substrates.47, 48 Organic anion transporter (OAT) proteins were identified as the principal

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transporter of PFOS located on the basal side (the fetal-facing basolateral membrane) of the

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placenta.36, 37 Kummu et al. have reported that the expressions of OAT4 in the placenta were

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negatively correlated with transplacental efficiencies of PFOS and PFOA, indicating these active

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transporter proteins may ultimately lower prenatal exposure to these compounds.49 Further, Pan

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et al. (2017) have observed lower transfer efficiency of PFAAs with higher glomerular filtration

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rate (GFR).50 GFR is the clearance rate when any solute is freely filtered and is neither

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reabsorbed nor secreted by the kidneys.51 GFR was also suggested to be associated with the

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transfer efficiency of the PFAAs.52 Specifically, the OAT 4 expressed on both sides of the

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kidney, OAT4 could either take up organic anions from the primary urine (“influx mode”) or

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release organic anions from the cell into the tubule lumen (“efflux mode”) depends on its

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different location expressed in the kidney.53 Further studies of advective transport mechanism via

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specific transporter proteins in the placenta or kidney are warranted, as they may help to better

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understand placental transport mechanism of these and other organic contaminants.

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Mother-Placenta-fetus Distribution. Significant correlations were observed between linear and

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branched PFAA concentrations in maternal serum, cord serum, and placenta samples (r > 0.7, p 14 ACS Paragon Plus Environment

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< 0.001). Strong linear relationships of log-transformed concentrations of linear and branched

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PFAAs between the maternal-cord sera and maternal-placentas were observed (Table 1). These

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empirical relationships may help to assess prenatal exposure by predicting concentrations in cord

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sera based on maternal concentrations. Conversely, it may be possible to estimate linear and

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branched PFAAs concentrations in maternal sera using the concentrations in the cord sera, which

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is a relatively more less-invasive approach. Zhang et al. (2013) reported that levels of PFAAs in

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human urine were positively correlated with levels in human blood, indicating urine

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concentration can be a good surrogate measure of internal exposure. Non-invasive screening can

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be used for epidemiological and biomonitoring studies.14

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The occurrence of PFAAs in cord sera reveals the potential for neonatal exposure.

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Fetuses are more sensitive to chemical exposure during embryonic and fetal development, where

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even low dose exposure may lead to risks of irreversible damage or diseases in their later life.17,

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accumulate in fetal cord blood.

Our findings clearly demonstrated that many PFAAs can effectively cross the placenta and

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The association between isomer-specific PFAA concentrations in maternal sera, cord sera,

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placentas and demographic characteristics of mothers and fetuses was also investigated in the

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present study. Maternal /fetal characteristics included maternal age, parity, pregnancy weight

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gain, as well as gender and gestational age of fetuses etc. (see Table S1). No correlations were

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observed between PFAA concentrations and these maternal /fetal characteristics. This may be

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due to the limited sample size of this study.

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Implications for human health risk assessment. To our knowledge, this is the first study to

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report the occurrence of isomer-specific PFAAs in placenta and placental-maternal serum



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transfer efficiency in humans. The occurrence of n- and br-PFHxS in umbilical cord serum and

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placenta was also studied for the first time. The findings help to further understand the governing

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mechanisms related to the placental transfer of PFAA isomers.

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While the sample size in the present study is relatively small (32 maternal-fetal pairs), the

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results provide insights into the exposure source and placental transfer efficiency of linear and

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branched PFAAs. Based on these findings, more comprehensive studies encompassing a larger

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sample size would be useful. Different transporter proteins (e.g., serum albumin, OATs) and

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phospholipids in maternal /cord serum and placenta may influence the placental transport rates

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and distribution of these chemicals.4, 54, 55 Thus, future studies of protein binding and

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phospholipid partitioning behavior of PFAAs in serum and tissues may provide further insights

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into placental transfer and prenatal exposure risks of these important contaminants of concern.

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ASSOCIATED CONTENT

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Supporting Information. Additional information including supplemental tables (Tables S1-S6)

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and supplemental figure (Figure S1) is available free of charge via the Internet at

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http://pubs.acs.org.

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Acknowledgments. This work was supported by the National Natural Science Foundation of

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China (Key Program Grant No. 21427815 and International Cooperation Grant No.

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21320102007) and the China Postdoctoral Science Foundation (Grant No. 2015M580514). We

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thank the medical staffs at the Wuhan No.1 Hospital for collecting the serum and placenta

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samples.


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Figure Captions Figure 1. Box chart of total PFHxS, PFOS and PFOA concentrations in matched maternal serum (ng/mL), cord serum (ng/mL) and placenta (ng/g). The boxes mark the 25th, 50th and 75th percentiles, respectively. Squares within the boxes indicate the mean values. The whiskers represent 5th and 95th percentiles. The crosses below or above the whiskers indicate outlier values. Figure 2. Isomer compositions of PFHxS, PFOS and PFOA in maternal serum, cord serum and placenta (%, median). Figure 3. Box chart of cord-maternal (RCM, dimensionless) and placental-maternal (RPM, dimensionless) ratios for total PFHxS, PFOS and PFOA. The boxes mark the 25th, 50th and 75th percentiles, respectively. Squares within the boxes indicate the mean values. The whiskers represent 5th and 95th percentiles. The crosses below or above the whiskers indicate outlier values. Figure 4. Box chart of isomer-specific (A) cord-maternal (RCM, dimensionless) and (B) placental-maternal (RPM, dimensionless) ratios for PFHxS, PFOS and PFOA. The boxes mark the 25th, 50th and 75th percentiles, respectively. Squares within the boxes indicate the mean values. The whiskers represent 5th and 95th percentiles. The crosses below or above the whiskers indicate outlier values.



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Table 1. Linear regression equations between logC-logMa and logP-logMa for linear and branched PFAAs. Compound Equation (C-M) R2 Equation (P-M) n-PFHxS logC = 1.19 logM +0.05 0.75 logP = 1.13 logM -0.12 ΣPFHxS logC = 1.34 logM -0.15 0.77 logP = 0.91 logM -0.42 n-PFOS logC = 1.10 logM -0.52 0.77 logP = 1.08 logM -0.53 iso-PFOS logC = 1.12 logM -0.38 0.81 logP = 1.00 logM -0.53 (3+5)m-PFOS logC = 1.42 logM +0.77 0.59 logP = 1.04 logM -0.09 4m-PFOS logC = 1.42 logM +0.26 0.49 logP = 1.02 logM -0.05 1m-PFOS logC = 1.36 logM +0.41 0.68 logP = 1.14 logM +0.13 Σm2-PFOS logC = 1.12 logM +0.23 0.59 NAb ΣPFOS logC = 0.97 logM -0.36 0.77 logP = 1.08 logM -0.58 n-PFOA logC = 0.89 logM -0.10 0.45 logP = 0.89 logM -0.51 ΣPFOA logC = 0.89 logM -0.11 0.53 logP = 0.87 logM -0.49 a C: cord serum concentration; M: maternal serum concentration; P: placenta concentration b NA: not available

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R2 0.80 0.79 0.86 0.82 0.70 0.61 0.83 NA 0.86 0.66 0.66

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Figure 1.

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Figure 2.

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Figure 3.

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Figure 4.


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Isomer-Specific Transplacental Transfer of Perfluoroalkyl Acids

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