Open Access

Research Article

Materials and Methods Top

Population

Nunavik is the northern region of Québec where approximately 9,500 Inuit live in 14 communities on the coast of the Hudson and Ungava Bays. All pregnant Inuit women from the three largest communities of the Hudson Bay coast of Nunavik were invited to participate in a study that aimed to document the effects of prenatal exposure to environmental contaminants on infant development.

From November 1995 to March 2001, a research assistant contacted each potential participant after her first prenatal visit with a midwife or a nurse. All pregnant women gave informed consent for themselves and for their infants before participating in the study. The study protocol was approved by the Nunavik Nutrition and Health Committee and by ethics committees at Laval University (Québec City, Québec, Canada) and Wayne State University (Detroit, Michigan). One prenatal and two postnatal (at 1 and 6 months) interviews were conducted to obtain sociodemographic and personal information from the mothers. The participation rate for this study was 69%. Among the 248 participating mother–infant dyads, 17.8% were excluded due to the adoption of the newborn, fetal or postnatal mortality, and loss to follow-up. Biological data on TH and OC concentrations were available for 204 pregnant women. Because TH levels slowly return to non-pregnancy levels after delivery and to ensure that measured levels of TH were not related to postpartum thyroid dysfunction, which occurs between 2 and 12 months postpartum (Stagnaro-Green 2004), mothers from whom the blood sample was drawn 31 days after delivery were excluded from the statistical analysis (n = 71). Pregnant women who declared using medication for thyroid diseases were also excluded (n = 4). Biological data on TH and OC concentrations were available for 108 infants at birth and 175 infants at 7 months of age. Neonates born prematurely and/or with low birth weight were also excluded because transient neonatal hypothyroxinemia may be induced by prematurity (< 37 weeks gestation, n = 6) and low birth weight (< 2,500 g, n = 1) (Fisher 1998).

Blood sampling and laboratory procedures

A 12.5-mL blood sample was collected from participating women at delivery or within the subsequent weeks (median = 2 days). A 30-mL blood sample was collected from the umbilical cord after it was severed, and a 5-mL blood sample was obtained at 7 months postpartum (median = 6.9 months). OC, CPC, and TH levels were measured in maternal, cord, and infant plasma. Selenium and plasma lipid concentrations were also measured in samples for confounding assessment.

Blood samples were collected in vials containing EDTA as the anticoagulant and centrifuged (10 min, 5,000 rpm), and the plasma transferred into glass vials prewashed with hexane. Plasma samples were frozen at −80°C until time of analysis. We measured concentrations of the 14 most frequently detected PCB congeners in human populations [IUPAC (International Union of Pure and Applied Chemistry) nos. 28, 52, 99, 101, 105, 118, 128, 138, 153, 156, 170, 180, 183, 187] and HCB in the purified extracts using an HP-5890 series II gas chromatograph (Hewlett-Packard, Palo Alto, CA, USA) equipped with dual-capillary columns (HP Ultra and Ultra II; Hewlett-Packard) and dual Ni-63 electron capture detectors (Hewlett-Packard). Detailed laboratory procedures and quality control procedures for OCs were described previously by Rhainds et al. (1999) and Muckle et al. (2001), respectively. Limits of detection for OCs were 0.02 μg/L.

We determined concentrations of CPCs by extracting the plasma samples on an Oasis HLB (540 mg; Waters Corp., Milford, MA, USA) solid phase extraction column according to a modified method by Sandau et al. (2003). Extraction and cleanup were completed on a Zymark Rapidtrace Automated SPE workstation (Zymark Corp., Hopkinton, MA, USA). CPCs were eluted with dichloromethane:methanol (9:1) in a third fraction on a prepacked Florisil column (1 g; Alltech, Lexington, KY, USA). After evaporation, the compounds were derivatized using diazomethane in hexane according to the method of Sandau (2000). The derivatized fraction was then cleaned up on an activated silica/acidic silica column before evaporation, addition of recovery standard, and quantification by gas chromatography/high resolution mass spectrometry. HO-PCB results are presented as a sum of the 11 major HO-PCBs (4-HO-CB-107, 3-HO-CB-153, 4-HO-CB-146, 3′-HO-CB-138, 4-HO-CB-163, 4-HO-CB-187, 4-HO-CB-202, 4′-HO-CB-172, 4-HO-CB-193, 4′-HO-CB-199, and 4-HO-CB-208). The limit of detection for those compounds varied between 2 and 6 ng/L.

We determined total cholesterol, free cholesterol, and triglycerides in plasma by standard enzymatic procedures, whereas we quantified phospholipids according to Takayama et al. (1977) using a commercial kit (Wako Pure Chemical Industries, Richmond, VA, USA). Concentrations of total plasma lipids were estimated according to the formula developed by Akins et al. (1989). Blood Se concentrations were determined using inductively coupled plasma mass spectrometry (PE Elan 6000; PerkinElmer Sciex, Concord, ON, Canada). The limit of detection for blood Se was 0.1 μmol/L.

We analyzed serum throid-stimulating hormone (TSH), free T₄ (fT₄), total triiodothyronine (T₃), and thyroid-binding globulin (TBG), the major transport protein of TH, using radioimmunoassay methods. TSH, fT₄, and T₃ were measured on the Bayer Immuno 1 System (Bayer Corp., Tarrytown, NY, USA). TBG was determined on the Clinical Assays GammaDab system commercialized by DiaSorin (Stillwater, MN, USA).

Statistical analysis

Contaminant concentrations and thyroid parameters were all log-transformed to satisfy criteria of normality. We used Pearson correlations to evaluate relations between contaminants, and simple and multiple linear regression models to evaluate the relationship between environmental contaminants, TH, and TBG in plasma. A value equal to half the limit of detection of the analytical method was attributed to nondetected contaminants in biological samples. Only PCB congeners with a detection frequency of at least 70% were considered. We evaluated exposure to PCB by several approaches. First, all PCB congeners were evaluated individually. Second, congeners were grouped according to their dioxin-like activity or their capacity to induce the microsomal enzymes UDP-GT (uridine diphosphate-glucuronosyl transferase), CYP1A (cytochrome P4501A), and CYP2B as proposed by Wolff et al. (1997). For the later grouping, the enzyme-inducing congeners included were PCBs 99, 118, 153, 180, and 187. Third, because all PCB congeners were highly correlated in the study population, PCB-153 was selected as a marker of exposure to all PCBs (Muckle et al. 2001). Indeed, in maternal plasma, intercorrelations among PCB congeners varied from 0.62 to 0.96. Similarly, in cord and infant plasma, intercorrelations among PCB congeners varied from 0.73 to 0.98 and 0.81 to 0.99, respectively. Correlations between PCB-153 and the sum of PCB inducers in maternal, cord, and infant plasma were all 0.99. Because results obtained using all PCB congeners or groupings did not change significantly from those obtained with PCB-153 (data not shown), only results for PCB-153 are presented.

We performed simple regressions between potential confounding variables and thyroid parameters to determine which covariate should be included in multiple linear regression analyses. Covariates associated at a p-value ≤ 0.10 were included in multiple regression models to assess their confounding influence. Covariates modifying the regression coefficient of the contaminants by > 10% with any of the TH were included in adjusted models for all TH parameters. The following covariates were evaluated in pregnant women: age at delivery, prepregnancy body weight, socioeconomic status [Hollingshead Index of Social Status (Hollingshead AB, unpublished data)], alcohol and cigarette consumption, fish consumption during pregnancy, and plasma Se concentration. Because age at delivery and parity were highly intercorrelated, only the former was retained in the multiple models, where appropriate, because it was a better predictor of TH concentrations in pregnant women. Nine women were not included in statistical analysis because of absence of information regarding alcohol consumption. Most variables evaluated as potential confounders in newborns were also tested in the models at 7 months of age. The primary caregiver’s score for socioeconomic status, maternal alcohol and cigarette consumption, maternal fish consumption during pregnancy, sex, breast-feeding status, as well as Se level in cord blood were tested for confounding at both ages. Gestational age and birth weight were also highly intercorrelated in newborns. erefore, only the former was included in multiple regression models, where appropriate, because it was a better predictor of TH concentrations. Six newborns were excluded due to unmeasured cord selenium concentrations, and 15 infants were excluded for lack of information regarding breast-feeding status. Because breast-feeding is an important source of postnatal exposure, an interaction term between OC concentrations and breast-feeding status at 7 months of age was also tested in multiple regression models. Statistical models assessing the relationship between the lipophilic contaminants PCB-153 or HCB and thyroid parameters were further adjusted for total plasma lipid concentrations because Schisterman et al. (2005) have shown that this approach is less prone to estimate bias compared with lipid standardization. Adjustment for lipid content was not done for CPCs because they are bound to plasma proteins (Sandau et al. 2000).

A bilateral p-value < 0.05 was considered statistically significant. Database management and variable transformation were performed with SPSS (version 2.0; SPSS Inc., Chicago, IL, USA) whereas statistical analyses were conducted with SAS (version 9.1; SAS Institute Inc., Cary, NC, USA).

Tables Top

Table 1.

Characteristics of included and excluded mothers and their infants.

Table 2.

Concentrations of organochlorines and chlorinated phenolic compounds in plasma from pregnant Inuit women and their infants at birth and at 7 months of age.

Table 3.

Linear regression models of thyroid hormones and TBG plasma levels with organochlorines and chlorinated phenolic compounds in plasma from pregnant Inuit women.

Table 4.

Linear regression models of thyroid hormone and TBG levels in umbilical cord with organo chlorine and chlorinated phenolic compounds in maternal and umbilical cord plasma.

Table 5.

Linear regression models of thyroid hormone and TBG plasma levels with organochlorines in plasma from 7-month-old Inuit infants.

Results Top

Table 1 lists the characteristics of included and excluded pregnant Inuit women and their infants at birth and at 7 months of age. Sociodemographic characteristics and exposure to OCs (data not shown) were similar between the pregnant women who were included and and those excluded from the study. In accordance with the exclusion criteria, newborns included in the study had a longer gestational age and were heavier. Percentages of breast-feeding at birth and at 7 months of age were significantly greater in infants included than in those excluded. ere was no significant difference in exposure to OCs between included and excluded infants at birth and at 7 months of age (data not shown).

Table 2 presents descriptive statistics for OCs and CPCs in maternal, cord, and infant plasma. PCB-153 is the most prevalent congener in this population the mean concentration of PCB-153 was higher in pregnant women, followed by infant and cord plasma levels. The correlation on a lipid basis between maternal and cord plasma PCB-153 was very high (r = 0.94), but only moderate between maternal and infant concentrations (r = 0.41) and cord and infant concentrations (r = 0.46). Mean lipid-adjusted HCB concentrations were similar for newborn, infant, and maternal plasma samples. As for PCB-153, the correlation between maternal and cord plasma HCB was high (r = 0.86), but in the moderate range between maternal and infant concentrations (r = 0.33) and cord and infant concentrations (r = 0.36). The mean wet weight concentration of HO-PCBs was higher in pregnant women than in cord plasma, and levels were highly intercorrelated (r = 0.96). Most of the HO-PCBs detected in mothers and newborns were moderately correlated with PCB-153 (r = 0.21–0.78, median: newborn r = 0.63; maternal r = 0.53) on a wet weight basis. PCP was detected in all maternal and umbilical cord plasma samples. Levels were higher in umbilical cord than in maternal plasma and were also very highly correlated (r = 0.85). Intercorrelations of contaminants in maternal, umbilical cord, and infant plasma are also presented in Table 2. In maternal and cord samples, PCB-153 concentrations were highly correlated with HO-PCBs and moderately with HCB. Also, PCP was weakly correlated with the other contaminants. Concentrations of PCB-153 and HCB were highly correlated in infant plasma.

A large proportion of the mothers had TSH values outside the TSH euthyroid reference range (0.4–2.5 mIU/L) (Demers and Spencer 2002). Sixteen percent (n = 20) had TSH concentrations below the lower limit whereas 10% (n =13) had values higher than the reference range. ere were no significant differences in OC concentrations between mothers outside and within the TSH euthyroid refence range. Most infants at birth and at 7 months of age had TSH and fT₄ levels within the normal range (Demers and Spencer 2002; Hume et al. 2004).

The associations between OCs and CPCs and the thyroid parameters documented in pregnant women at delivery are presented in Table 3. Simple regression models showed a significant positive association between HO-PCBs and T₃. Simple and multiple regressions between contaminants and TSH as well as fT₄ were not significant. Adjustment for confounding factors strengthens the positive association between HO-PCBs and T_3.

Table 4 shows simple and multiple linear associations between thyroid parameters measured in umbilical cord blood and OCs or CPCs levels in cord and maternal plasma. In newborns at birth, no significant association was observed between cord blood contaminants and TH concentrations in univariate models. However, negative associations were found for umbilical cord and maternal PCB-153 with TBG concentrations after control for confounders. A negative association between cord fT₄ and maternal PCP, but not cord PCP, was found before and after controlling for confounders. In the subsample analysis of cord CPC, characteristics of newborns included were similar, except that those included had a higher birth weight (included: mean = 3,758 g, excluded: mean = 3,508 g, p = 0.006). Also, in the subsample analysis of maternal CPC, characteristics of mothers and newborns were similar, except that maternal and cord Se concentrations were lower (mothers included: mean = 1.09 μmol/L, excluded: mean = 1.44 μmol/L, p = 0.01; newborns included: mean = 3.11 μmol/L, excluded: mean = 3.84 μmol/L, p = 0.04). Concentrations of T₃ in cord blood were not associated with any of the contaminants under study. A significant negative association between PCB-153 and TSH was obtained in simple linear regression for infants 7 months of age (Table 5). However, the association was no longer significant after adjustment for breast-feeding status. Interaction terms between OCs and breast-feeding status were not significant. The associations were not significant after stratification for breast-feeding status (data not shown).

Discussion Top

In the present study, we investigated the potential negative effects of OCs and CPCs on the circulating concentrations of TH among Inuit women and their infants. Overall, the results show that plasma concentration of OCs and CPCs were not significant predictors of TSH and TH concentrations in this population of pregnant women and their offspring. However, maternal levels of PCP were negatively associated with fT₄ concen- trations in umbilical cord blood of neonates, suggesting that this compound may reduce the transfer of maternal T₄ across the placenta to the developing fetus.

As reported in most studies [reviewed by Maervoet et al. (2007)], an association between PCB-153 and TH concentrations was not found in Inuit neonates at birth. Similarly, no association was seen in these infants at the 7-months follow-up. Also, these data did not corroborate the relationship between PCB congeners and TSH or TH levels seen in the CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas) study (Chevrier et al. 2007), in any of the exposure matrices (maternal, cord, or infant plasma). ese associations were observed even though the maternal PCB-153 concentrations were almost 20 times lower than those in the present study. Difference in the profile of other PCB congeners in that population may provide one explanation for the discrepancy in results between the CHAMACOS study and the present study. Another possible important difference between both populations is the iodine intake. Indeed, iodine, which is essential for thyroid function, is found in high concentration in some seafood products. erefore, exposure to iodine and OCs co-occurs in individuals such as the Nunavik Inuit, who consume a large amount of marine products. Therefore, not taking into account urinary iodine concentrations in epidemiologic studies aiming to investigate this research question may partly explain the inconsistent results.

The absence of an association between HCB and umbilical cord fT₄ concentrations in this study are not consistent with a previous finding of significant positive associations in another sample of Inuit neonates and in newborns from the Lower North Shore of the St. Lawrence River (Dallaire et al. 2008). The lower statistical power of the present study as well as a difference in adjustment of confounders may account for the differential results. However, the absence of relationship between HCB and fT₄ found in the present study are in agreement with two other epidemiologic studies among neonates (Ribas-Fito et al. 2003; Takser et al. 2005).

The absence of an association between PCB-153 and thyroid parameters in pregnant Inuit women was similar to that reported in the second Faroe Islands cohort (Steuerwald et al. 2000). However, two other epidemiologic studies among pregnant women found a significant negative association of PCBs with T₃ and/or tT₄ status (Koopman-Esseboom et al. 1994; Takser et al. 2005) whereas, among Mexican-American pregnant women, three PCB congeners (44, 52, and 183) were negatively related to fT₄ concentrations (Chevrier et al. 2008). It is possible that the effects observed in these three studies were mostly attributable to the exposure to polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans, which are usually higher in urban settings than in isolated populations mostly exposed to environmental contaminants through fish and marine mammal consumption. As previously mentioned, high dietary iodine intake in fish-eating populations may also explain the lack of association between PCB-153 and thyroid hormone status in mothers (Dallaire et al. 2008).

HCB body burden was not associated with thyroid hormone profile in Inuit pregnant women at delivery. Two other studies investigated whether exposure to low background concentrations of HCB was related to TH levels during pregnancy. An inverse relationship between plasma HCB concentrations and T₃ levels was reported among Canadians (Takser et al. 2005), and negative associations between HCB concentrations and fT₄ and tT₄ levels were found in the CHAMACOS study (Chevrier et al. 2008). However, the authors were not able to determine whether effects on TH concentrations were related to PCBs or HCB plasma concentrations because these exposures were highly correlated.

In the present study we also documented concentrations of HO-PCBs and PCP because several in vitro studies have revealed their potency in competitively inhibiting T₄ binding to TTR (van den Berg 1990). This T₄-binding protein is implicated in the delivery of maternal T₄ to the fetus across the placenta (McKinnon et al. 2005) as well as the transport of T₄ from blood into cerebrospinal fluid during brain maturation (Southwell et al. 1993). However, experiments with TTR-null mice have shown that TTR is not essential for T₄ distribution in brain (Palha 2002). Nevertheless, as would be predicted from toxicologic data, a negative association was found between maternal PCP plasma concentrations and umbilical cord fT₄ levels, but not with umbilical cord PCP, which has two times the binding affinity of the natural ligand T₄ for TTR (van den Berg 1990). Moreover, it was the predominant CPC in the Inuit population, and concentrations were mostly higher in umbilical cord plasma than in maternal plasma. Taken together, these findings seem to indicate that PCP may impede the transfer of maternal T₄ to the fetus across the placental barrier to a certain extent by inhibiting maternal T₄ binding to TTR. is mechanism may also have favored the transport of maternal PCP to the fetal circulation, which may explain the higher concentration of this compound in cord blood compared with maternal blood. The relation between maternal PCP and neonate fT₄ concentrations was no longer evident at the later age, because there was no association between maternal or cord PCP and fT₄ levels when the infants were 7 months of age (data not shown). The rapid maturation of the hypothalamus–pituitary–thyroid axis after the severing of the umbilical cord, which leads to the complete independence of the newborn from a maternal source of fT₄, may explain such findings. However, these results should be interpreted with caution because no association was found with cord blood PCP concentrations even though they were highly correlated with maternal PCP levels (r = 0.85). Also, plasma Se concentrations of mothers and newborns included in the subsample analysis were lower than in the sample used for OCs (n = 80). Two other epidemiologic studies have looked at the association between CPC and TH concentrations in neonates. In another sample of Inuit newborns, Sandau et al. (2002) found a negative correlation between the sum of PCP and 14 HO-PCBs with cord fT₄, whereas Otake et al. (2007) reported a positive correlation between 6 HO-PCBs and neonatal blood-spot fT₄ obtained on a filter paper. Other studies are needed to ascertain the potential effects of CPCs on neonatal TH concentrations, because the small sample size in the present study limits its conclusions.

The increase of T₃ with concentrations of HO-PCBs in pregnant women may be attributable to selective or combined inhibition of sulfotransferase and type I deiodinase (D₁) activities, as these metabolites have been shown to competitively inhibit D₁ and diiodothyronine sulfotransferases actions (Schuur et al. 1998). Indeed, in adults, sulfotransferases irreversibly inactivate TH actions and facilitate D₁ deiodination for complete degradation in the liver (Visser 1996). Interestingly, in fetuses sulfated T₄ and T₃ are elevated compared with adult concentrations and have been proposed to serve as a reservoir of inactive TH for subsequent activation by sulfotransferases at specific developmental stages (Darras et al. 1999). is difference in TH metabolism between fetuses and adults, especially for sulfotransferase and deiodinase activities, may explain the absence of HO-PCB effects on cord T₃ compared with maternal T₃.

These findings suggest that the synthesis or metabolism of transport proteins may be affected by environmental contaminants. Indeed, the negative association between PCB-153 and serum TBG concentration could by mediated by a diminution of TBG synthesis by the liver. Interestingly, we already reported a similar association in a population of neonates from the Lower North Shore of the St. Lawrence River (Dallaire et al. 2008). Because commercial fT₄ immunoassays overestimate the fT₄ levels at high TBG concentration and underestimate it at low TBG concentrations (Demers and Spencer 2002), these results may indicate that contaminants affecting TBG concentrations introduce bias in the assessment of the effects of thyroid toxicants on fT₄ levels. Most toxicologic studies have focused on the competitive binding assessment of environmental contaminants with T₄, without evaluating their ability to modify transport protein synthesis. Consequently, the results cannot be corroborated on biological mechanisms because toxicologic data are unavailable. Nevertheless, such an effect remains plausible. By analogy, Richardson et al. (2008) have recently shown that polybrominated diphenyl ether congener 47 has the capacity to decrease TTR mRNA expression in the liver by an unidentified mechanism. An assessment of transport protein biosynthesis modification by environmental contaminants is needed to clarify this question.

Conclusion Top

In summary, in this study we did not find similar effects of potential thyroid toxicants on TH homeostasis in mother and infant. Differential TH and contaminant metabolizing capacity between fetuses and adults may account for this discrepancy. There were also no associations between concentrations of PCB-153 and TH levels in Nunavik Inuit mothers and infants. However, a significant inverse relationship was found between maternal PCP levels and fT₄ umbilical cord concentrations. This finding is in agreement with the hypothesis regarding the capacity of CPCs to competitively inhibit T₄ binding to TTR in humans. However, this result must be interpreted with caution because it was found in a subsample of the neonate population and consequently needs to be corroborated in larger studies. Nevertheless, epidemiologic studies of pregnant women suffering from hypothyroxinemia (low fT₄) have shown that reduced transfer of maternal fT₄ during fetal brain maturation can negatively affect the neurocognitive function in infants (Pop et al. 1999,, 2003). Results from the neurodevelopment assessment of the participating infants in this cohort will allow us to determine whether a reduction of fT₄ concentrations during fetal development, perhaps mediated by PCP, may induce deficits similar to those observed in the offspring of hypothyroxinemic pregnant women.

References Top

1. Akins JR, Waldrep K, Bernert JT Jr. 1989. The estimation of total serum lipids by a completely enzymatic “summation” method Clin Chim Acta 184(3):219–226. Find this article online
2. Brouwer A, Ahlborg UG, Van den Berg M, Birnbaum LS, Boersma ER, Bosveld B, et al. 1995. Functional aspects of developmental toxicity of polyhalogenated aromatic hydrocarbons in experimental animals and human infants Eur J Pharmacol 293(1):1–40. Find this article online
3. Brouwer A, Morse DC, Lans MC, Schuur AG, Murk AJ, Klasson-Wehler E, et al. 1998. Interactions of persistent environmental organohalogens with the thyroid hormone system: mechanisms and possible consequences for animal and human health Toxicol Ind Health 14(1–2):59–84. Find this article online
4. Calvo RM, Jauniaux E, Gulbis B, Asuncion M, Gervy C, Contempre B, et al. 2002. Fetal tissues are exposed to biologically relevant free thyroxine concentrations during early phases of development J Clin Endocrinol Metab 87(4):1768–1777. Find this article online
5. Chevrier J, Eskenazi B, Bradman A, Fenster L, Barr DB. 2007. Associations between prenatal exposure to polychlorinated biphenyls and neonatal thyroid-stimulating hormone levels in a Mexican-American population, Salinas Valley, California Environ Health Perspect 115:1490–1416. Find this article online
6. Chevrier J, Eskenazi B, Holland N, Bradman A, Barr DB. 2008. Effects of exposure to polychlorinated biphenyls and organochlorine pesticides on thyroid function during pregnancy Am J Epidemiol 168(3):298–310. Find this article online
7. Dallaire R, Dewailly É, Ayotte P, Muckle G, Laliberte C, Bruneau S. 2008. Effects of prenatal exposure to organochlorines on thyroid hormone status in newborns from two remoate coastal regions in Québec, Canada Environ Res 108(3):387–392. Find this article online
8. Darras VM, Hume R, Visser TJ. 1999. Regulation of thyroid hormone metabolism during fetal development Mol Cell Endocrinol 151(1–2):37–47. Find this article online
9. Demers LM, Spencer CA 2002. Laboratory Medicine Practice Guidelines. Laboratory Support for The Diagnosis and Monitoring of Thyroid Disease. Washington, DC: National Academy of Clinical Biochemistry.
10. Dowling AL, Zoeller RT. 2000. Thyroid hormone of maternal origin regulates the expression of RC3/neurogranin mRNA in the fetal rat brain Brain Res Mol Brain Res 82(1–2):126–132. Find this article online
11. Fisher DA. 1998. Thyroid function in premature infants. The hypothyroxinemia of prematurity Clin Perinatol 25(4):999–1014. Find this article online
12. Goldey ES, Kehn LS, Lau C, Rehnberg GL, Crofton KM. 1995. Developmental exposure to polychlorinated biphenyls (Aroclor 1254) reduces circulating thyroid hormone concentrations and causes hearing deficits in rats Toxicol Appl Pharmacol 135(1):77–88. Find this article online
13. Hume R, Simpson J, Delahunty C, van Toor H, Wu SY, Williams FL, et al. 2004. Human fetal and cord serum thyroid hormones: developmental trends and interrelationships J Clin Endocrinol Metab 89(8):4097–4103. Find this article online
14. Jacobson JL, Jacobson SW. 1996. Intellectual impairment in children exposed to polychlorinated biphenyls in utero N Engl J Med 335(11):783–789. Find this article online
15. Koopman-Esseboom C, Morse DC, Weisglas-Kuperus N, Lutkeschipholt IJ, Van der Paauw CG, Tuinstra LG, et al. 1994. Effects of dioxins and polychlorinated biphenyls on thyroid hormone status of pregnant women and their infants Pediatr Res 36(4):468–473. Find this article online
16. Maervoet J, Vermeir G, Covaci A, Van Larebeke N, Koppen G, Schoeters G, et al. 2007. Association of thyroid hormone concentrations with levels of organochlorine compounds in cord blood of neonates Environ Health Perspect 115:1780–1786. Find this article online
17. McKinnon B, Li H, Richard K, Mortimer R. 2005. Synthesis of thyroid hormone binding proteins transthyretin and albumin by human trophoblast J Clin Endocrinol Metab 90(12):6714–6720. Find this article online
18. Morreale de Escobar G, Obregon MJ, Escobar del Rey F. 2000. Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 85(11):3975–3987. Find this article online
19. Morse DC, Wehler EK, Wesseling W, Koeman JH, Brouwer A. 1996. Alterations in rat brain thyroid hormone status following pre- and postnatal exposure to polychlorinated biphenyls (Aroclor 1254) Toxicol Appl Pharmacol 136(2):269–279. Find this article online
20. Muckle G, Ayotte P, Dewailly É, Jacobson SW, Jacobson JL. 2001. Prenatal exposure of the northern Quebec Inuit infants to environmental contaminants Environ Health Perspect 109:1291–1299. Find this article online
21. Otake T, Yoshinaga J, Enomoto T, Matsuda M, Wakimoto T, Ikegami M, et al. 2007. Thyroid hormone status of newborns in relation to in utero exposure to PCBs and hydroxylated PCB metabolites Environ Res 105(2):240–246. Find this article online
22. Palha JA. 2002. Transthyretin as a thyroid hormone carrier: function revisited Clin Chem Lab Med 40(12):1292–1300. Find this article online
23. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ. 2003. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study Clin Endocrinol (Oxf) 59(3):282–288. Find this article online
24. Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, et al. 1999. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy Clin Endocrinol (Oxf) 50(2):149–155. Find this article online
25. Porterfield SP, Hendrich CE. 1993. The role of thyroid hormones in prenatal and neonatal neurological development —current perspectives Endocr Rev 14(1):94–106. Find this article online
26. Rhainds M, Levallois P, Dewailly É, Ayotte P. 1999. Lead, mercury, and organochlorine compound levels in cord blood in Quebec, Canada Arch Environ Health 54(1):40–47. Find this article online
27. Ribas-Fito N, Sala M, Cardo E, Mazon C, De Muga ME, Verdu A, et al. 2003. Organochlorine compounds and concentrations of thyroid stimulating hormone in newborns Occup Environ Med 60(4):301–303. Find this article online
28. Richardson VM, Staskal DF, Ross DG, Diliberto JJ, DeVito MJ, Birnbaum LS. 2008. Possible mechanisms of thyroid hormone disruption in mice by BDE 47, a major polybrominated diphenyl ether congener Toxicol Appl Pharmacol 226(3):244–250. Find this article online
29. Sandau CD 2000. Analytical Chemistry of Hydroxylated Metabolites of PCBs and Other Halogenated Phenolic Compounds in Blood and Their Relationship to Thyroid Hormone and Retinol Homeostasis in Humans and Polar Bears. PhD thesis. Carleton, Ontario, Canada: Carleton University.
30. Sandau CD, Ayotte P, Dewailly É, Duffe J, Norstrom RJ. 2000. Analysis of hydroxylated metabolites of PCBs (OH-PCBs) and other chlorinated phenolic compounds in whole blood from Canadian Inuit Environ Health Perspect 108:611–616. Find this article online
31. Sandau CD, Ayotte P, Dewailly É, Duffe J, Norstrom RJ. 2002. Pentachlorophenol and hydroxylated polychlorinated biphenyl metabolites in umbilical cord plasma of neonates from coastal populations in Quebec Environ Health Perspect 110:411–417. Find this article online
32. Sandau CD, Sjodin A, Davis MD, Barr JR, Maggio VL, Waterman AL, et al. 2003. Comprehensive solid-phase extraction method for persistent organic pollutants. Validation and application to the analysis of persistent chlorinated pesticides Anal Chem 75(1):71–77. Find this article online
33. Schantz SL, Seo BW, Wong PW, Pessah IN. 1997. Long-term effects of developmental exposure to 2,2′,3,5′,6-pentachlorobiphenyl (PCB 95) on locomotor activity, spatial learning and memory and brain ryanodine binding Neurotoxicology 18(2):457–467. Find this article online
34. Schantz SL, Widholm JJ. 2001. Cognitive effects of endocrine-disrupting chemicals in animals Environ Health Perspect 109:1197–1206. Find this article online
35. Schisterman EF, Whitcomb BW, Louis GM, Louis TA. 2005. Lipid adjustment in the analysis of environmental contaminants and human health risks Environ Health Perspect 113:853–857. Find this article online
36. Schreiber G, Southwell BR, Richardson SJ. 1995. Hormone delivery systems to the brain-transthyretin Exp Clin Endocrinol Diabetes 103(2):75–80. Find this article online
37. Schuur AG, Legger FF, van Meeteren ME, Moonen MJ, van Leeuwen-Bol I, Bergman A, et al. 1998. In vitro inhibition of thyroid hormone sulfation by hydroxylated metabolites of halogenated aromatic hydrocarbons Chem Res Toxicol 11(9):1075–1081. Find this article online
38. Southwell BR, Duan W, Alcorn D, Brack C, Richardson SJ, Kohrle J, et al. 1993. Thyroxine transport to the brain: role of protein synthesis by the choroid plexus Endocrinology 133(5):2116–2126. Find this article online
39. Stagnaro-Green A. 2004. Postpartum thyroiditis Best Pract Res Clin Endocrinol Metab 18(2):303–316. Find this article online
40. Steuerwald U, Weihe P, Jorgensen PJ, Bjerve K, Brock J, Heinzow B, et al. 2000. Maternal seafood diet, methylmercury exposure, and neonatal neurologic function J Pediatr 136(5):599–605. Find this article online
41. Stewart P, Lonky E, Reihman J, Pagano J, Gump B, Darvill T. 2008. The relationship between prenatal PCB exposure and intelligence (IQ) in 9-year-old children Environ Health Perspect 116:1416–1422. Find this article online
42. Takayama M, Itoh S, Nagasaki T, Tanimizu I. 1977. A new enzymatic method for determination of serum choline-containing phospholipids Clin Chim Acta 79(1):93–98. Find this article online
43. Takser L, Mergler D, Baldwin M, de Grosbois S, Smargiassi A, Lafond J. 2005. Thyroid hormones in pregnancy in relation to environmental exposure to organochlorine compounds and mercury Environ Health Perspect 113:1039–1045. Find this article online
44. van den Berg KJ. 1990. Interaction of chlorinated phenols with thyroxine binding sites of human transthyretin, albumin and thyroid binding globulin Chem Biol Interact 76(1):63–75. Find this article online
45. van Raaij JA, Frijters CM, van den Berg KJ. 1993. Hexachlorobenzene-induced hypothyroidism. Involvement of different mechanisms by parent compound and metabolite Biochem Pharmacol 46(8):1385–1391. Find this article online
46. van Raaij JA, Frijters CM, Kong LW, van den Berg KJ, Notten WR. 1994. Reduction of thyroxine uptake into cerebrospinal fluid and rat brain by hexachlorobenzene and pentachlorophenol Toxicology 94(1–3):197–208. Find this article online
47. Visser TJ. 1996. Pathways of thyroid hormone metabolism Acta Med Austriaca 23(1–2):10–16. Find this article online
48. Vulsma T, Gons MH, de Vijlder JJ. 1989. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis N Engl J Med 321(1):13–16. Find this article online
49. Wolff MS, Camann D, Gammon M, Stellman SD. 1997. Proposed PCB congener groupings for epidemiological studies Environ Health Perspect 105:13–14. Find this article online