Early pregnancy exposure to endocrine disrupting chemical mixtures are associated with inflammatory changes in maternal and neonatal circulation

Angela S Kelley, Margaret Banker, Jaclyn M Goodrich, Dana C Dolinoy, Charles Burant, Steven E Domino, Yolanda R Smith, Peter X K Song, Vasantha Padmanabhan, Angela S Kelley, Margaret Banker, Jaclyn M Goodrich, Dana C Dolinoy, Charles Burant, Steven E Domino, Yolanda R Smith, Peter X K Song, Vasantha Padmanabhan

Abstract

Endocrine disrupting chemicals (EDCs) are ubiquitous, and pregnancy is a sensitive window for toxicant exposure. EDCs may disrupt the maternal immune system, which may lead to poor pregnancy outcomes. Most studies investigate single EDCs, even though "real life" exposures do not occur in isolation. We tested the hypothesis that uniquely weighted mixtures of early pregnancy exposures are associated with distinct changes in the maternal and neonatal inflammasome. First trimester urine samples were tested for 12 phthalates, 12 phenols, and 17 metals in 56 women. Twelve cytokines were measured in first trimester and term maternal plasma, and in cord blood after delivery. Spearman correlations and linear regression were used to relate individual exposures with inflammatory cytokines. Linear regression was used to relate cytokine levels with gestational age and birth weight. Principal component analysis was used to assess the effect of weighted EDC mixtures on maternal and neonatal inflammation. Our results demonstrated that maternal and cord blood cytokines were differentially associated with (1) individual EDCs and (2) EDC mixtures. Several individual cytokines were positively associated with gestational age and birth weight. These observed associations between EDC mixtures and the pregnancy inflammasome may have clinical and public health implications for women of childbearing age.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Spearman correlations between early pregnancy EDC exposures and first trimester inflammatory cytokines. Using the color spectrum, the orange color indicates a positive correlation, while the blue color indicates a negative correlation for cytokines with (a) phthalates, (b) phenols, and (c) metals. Circle size reflects the size of the correlation, with larger circles having correlations closer to 1 or −1. Shade of orange or blue also reflects the strength of the correlation coefficient. Significance is noted as follows: •••p < 0.01, ••p < 0.05, •p < 0.10.
Figure 2
Figure 2
Spearman correlations between early pregnancy EDC exposures and term inflammatory cytokines. Using the color spectrum, the orange color indicates a positive correlation, while the blue color indicates a negative correlation for cytokines with (a) phthalates, (b) phenols, and (c) metals. Circle size reflects the size of the correlation, with larger circles having correlations closer to 1 or −1. Shade of orange or blue also reflects the strength of the correlation coefficient. Significance is noted as follows: •••p < 0.01, ••p < 0.05, •p < 0.10.
Figure 3
Figure 3
Spearman correlations between early pregnancy EDC exposures and neonatal cord blood inflammatory cytokines. Using the color spectrum, the orange color indicates a positive correlation, while the blue color indicates a negative correlation for cytokines with (a) phthalates, (b) phenols, and (c) metals. Circle size reflects the size of the correlation, with larger circles having correlations closer to 1 or −1. Shade of orange or blue also reflects the strength of the correlation coefficient. Significance is noted as follows: •••p < 0.01, ••p < 0.05, •p < 0.10.
Figure 4
Figure 4
Principal component loading coefficients. This color heat map shows the loading coefficients of the exposures for each of the principal components (PC), demonstrating the relative contribution of each EDC to a specific PC group. Exposures that have a higher positive weight are darker red, whereas exposures that are negatively weighted are blue. Tables 4–6 demonstrate each of the specific PC groupings which were significantly associated with maternal first trimester, maternal term, and delivery cord blood inflammation, respectively. By analyzing the components of a significant PC, one can interpret the association results. For example, in Table 4, PC1 is shown to have positive association with IL-8 and IFN- γ. From Fig. 4, PC1 is positively weighted towards metals and phthalates (red color), suggesting that higher metal and phthalate levels may be positively associated with first trimester IL-8 and IFN-γ.

References

    1. Trasande L, et al. Burden of disease and costs of exposure to endocrine disrupting chemicals in the European Union: an updated analysis. Andrology. 2016;4:565–572.
    1. Gore AC, et al. EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals. Endocr. Rev. 2015;36:E1–E150.
    1. Silva MJ, et al. Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999-2000. Environ. Health Perspect. 2004;112:331–338.
    1. Calafat AM, Ye X, Wong L-Y, Reidy JA, Needham LL. Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003-2004. Environ. Health Perspect. 2008;116:39–44.
    1. Vandenberg LN, et al. Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A. Environ. Health Perspect. 2010;118:1055–1070.
    1. Calafat AM, Wong L-Y, Kuklenyik Z, Reidy JA, Needham LL. Polyfluoroalkyl chemicals in the U.S. population: data from the National Health and Nutrition Examination Survey (NHANES) 2003-2004 and comparisons with NHANES 1999-2000. Environ. Health Perspect. 2007;115:1596–1602.
    1. Calafat AM, et al. Co-exposure to non-persistent organic chemicals among American pre-school aged children: A pilot study. Int. J. Hyg. Environ. Health. 2017;220:55–63.
    1. Hendryx, M. & Luo, J. Children’s environmental chemical exposures in the USA, NHANES 2003–2012. Environ. Sci. Pollut. Res. Int., 10.1007/s11356-017-0874-5 (2017).
    1. Marcoccia D, Pellegrini M, Fiocchetti M, Lorenzetti S, Marino M. Food components and contaminants as (anti)androgenic molecules. Genes Nutr. 2017;12:6.
    1. Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metal toxicity and the environment. EXS. 2012;101:133–164.
    1. Barker DJP. The origins of the developmental origins theory. J. Intern. Med. 2007;261:412–417.
    1. Barouki R, Gluckman PD, Grandjean P, Hanson M, Heindel JJ. Developmental origins of non-communicable disease: implications for research and public health. Environ. Health. 2012;11:42.
    1. Grandjean P, et al. Life-Long Implications of Developmental Exposure to Environmental Stressors: New Perspectives. Endocrinology. 2015;156:3408–3415.
    1. Arbuckle TE, et al. Exposure to free and conjugated forms of bisphenol A and triclosan among pregnant women in the MIREC cohort. Environ. Health Perspect. 2015;123:277–284.
    1. Woodruff TJ, Zota AR, Schwartz JM. Environmental chemicals in pregnant women in the United States: NHANES 2003-2004. Environ. Health Perspect. 2011;119:878–885.
    1. Rosofsky A, et al. Exposure to multiple chemicals in a cohort of reproductive-aged Danish women. Environ. Res. 2017;154:73–85.
    1. Lee W-C, Fisher M, Davis K, Arbuckle TE, Sinha SK. Identification of chemical mixtures to which Canadian pregnant women are exposed: The MIREC Study. Environ. Int. 2017;99:321–330.
    1. Philips EM, et al. Bisphenol and phthalate concentrations and its determinants among pregnant women in a population-based cohort in the Netherlands, 2004-5. Environ. Res. 2018;161:562–572.
    1. Caserta D, et al. Environment and women’s reproductive health. Hum. Reprod. Update. 2011;17:418–433.
    1. Rouillon, S. et al. Endocrine Disruptors and Pregnancy: Knowledge, Attitudes and Prevention Behaviors of French Women. Int. J. Environ. Res. Public Health14 (2017).
    1. Veiga-Lopez A, et al. Gender-Specific Effects on Gestational Length and Birth Weight by Early Pregnancy BPA Exposure. J. Clin. Endocrinol. Metab. 2015;100:E1394–403.
    1. Lauritzen HB, et al. Maternal serum levels of perfluoroalkyl substances and organochlorines and indices of fetal growth: a Scandinavian case-cohort study. Pediatr. Res. 2017;81:33–42.
    1. Bach CC, et al. Perfluoroalkyl and polyfluoroalkyl substances and human fetal growth: a systematic review. Crit. Rev. Toxicol. 2015;45:53–67.
    1. Govarts E, et al. Birth weight and prenatal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE): a meta-analysis within 12 European Birth Cohorts. Environ. Health Perspect. 2012;120:162–170.
    1. Wolff MS, et al. Prenatal phenol and phthalate exposures and birth outcomes. Environ. Health Perspect. 2008;116:1092–1097.
    1. Birks L, et al. Occupational Exposure to Endocrine-Disrupting Chemicals and Birth Weight and Length of Gestation: A European Meta-Analysis. Environ. Health Perspect. 2016;124:1785–1793.
    1. Lenters V, et al. Prenatal Phthalate, Perfluoroalkyl Acid, and Organochlorine Exposures and Term Birth Weight in Three Birth Cohorts: Multi-Pollutant Models Based on Elastic Net Regression. Environ. Health Perspect. 2016;124:365–372.
    1. Berends LM, Ozanne SE. Early determinants of type-2 diabetes. Best Pract. Res. Clin. Endocrinol. Metab. 2012;26:569–580.
    1. Martin, A., Connelly, A., Bland, R. M. & Reilly, J. J. Health impact of catch-up growth in low-birth weight infants: systematic review, evidence appraisal, and meta-analysis. Matern. Child Nutr. 13 (2017).
    1. Mierzynski R, et al. Intra-uterine Growth Retardation as a Risk Factor of Postnatal Metabolic Disorders. Curr. Pharm. Biotechnol. 2016;17:587–596.
    1. Casas M, et al. Exposure to Bisphenol A and Phthalates during Pregnancy and Ultrasound Measures of Fetal Growth in the INMA-Sabadell Cohort. Environ. Health Perspect. 2016;124:521–528.
    1. Marie C, Vendittelli F, Sauvant-Rochat M-P. Obstetrical outcomes and biomarkers to assess exposure to phthalates: A review. Environ. Int. 2015;83:116–136.
    1. Casals-Casas C, Desvergne B. Endocrine disruptors: from endocrine to metabolic disruption. Annu. Rev. Physiol. 2011;73:135–162.
    1. Heindel JJ, et al. Metabolism disrupting chemicals and metabolic disorders. Reprod. Toxicol. 2017;68:3–33.
    1. Vandenberg LN, et al. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr. Rev. 2012;33:378–455.
    1. MacKay, H. & Abizaid, A. A plurality of molecular targets: The receptor ecosystem for bisphenol-A (BPA). Horm. Behav., 10.1016/j.yhbeh.2017.11.001 (2017).
    1. Ribeiro, E., Ladeira, C. & Viegas, S. EDCs Mixtures: A Stealthy Hazard for Human Health? Toxics5 (2017).
    1. Feron VJ, Cassee FR, Groten JP, van Vliet PW, van Zorge JA. International issues on human health effects of exposure to chemical mixtures. Environ. Health Perspect. 2002;110(Suppl 6):893–899.
    1. Fowler PA, et al. Impact of endocrine-disrupting compounds (EDCs) on female reproductive health. Mol. Cell. Endocrinol. 2012;355:231–239.
    1. Johns LE, et al. Urinary phthalate metabolites in relation to maternal serum thyroid and sex hormone levels during pregnancy: a longitudinal analysis. Reprod. Biol. Endocrinol. 2015;13:4.
    1. Sathyanarayana S, Barrett E, Butts S, Wang C, Swan SH. Phthalate exposure and reproductive hormone concentrations in pregnancy. Reproduction. 2014;147:401–409.
    1. Dietert RR. Misregulated inflammation as an outcome of early-life exposure to endocrine-disrupting chemicals. Rev. Environ. Health. 2012;27:117–131.
    1. Ferguson KK, Loch-Caruso R, Meeker JD. Urinary phthalate metabolites in relation to biomarkers of inflammation and oxidative stress: NHANES 1999-2006. Environ. Res. 2011;111:718–726.
    1. Song H, et al. Bisphenol A induces COX-2 through the mitogen-activated protein kinase pathway and is associated with levels of inflammation-related markers in elderly populations. Environ. Res. 2017;158:490–498.
    1. Watkins DJ, et al. Associations between urinary phenol and paraben concentrations and markers of oxidative stress and inflammation among pregnant women in Puerto Rico. Int. J. Hyg. Environ. Health. 2015;218:212–219.
    1. Zota AR, et al. Association between persistent endocrine-disrupting chemicals (PBDEs, OH-PBDEs, PCBs, and PFASs) and biomarkers of inflammation and cellular aging during pregnancy and postpartum. Environ. Int. 2018;115:9–20.
    1. Cotechini T, Graham CH. Aberrant maternal inflammation as a cause of pregnancy complications: A potential therapeutic target? Placenta. 2015;36:960–966.
    1. Amaral LM, Wallace K, Owens M, LaMarca B. Pathophysiology and Current Clinical Management of Preeclampsia. Curr. Hypertens. Rep. 2017;19:61.
    1. Catalano PM, Shankar K. Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child. BMJ. 2017;356:j1.
    1. Boyle AK, Rinaldi SF, Norman JE, Stock SJ. Preterm birth: Inflammation, fetal injury and treatment strategies. J. Reprod. Immunol. 2017;119:62–66.
    1. Walker CL. Minireview: Epigenomic Plasticity and Vulnerability to EDC Exposures. Mol. Endocrinol. 2016;30:848–855.
    1. Watkins DJ, Milewski S, Domino SE, Meeker JD, Padmanabhan V. Maternal phthalate exposure during early pregnancy and at delivery in relation to gestational age and size at birth: A preliminary analysis. Reprod. Toxicol. 2016;65:59–66.
    1. Montrose L, et al. Maternal levels of endocrine disrupting chemicals in the first trimester of pregnancy are associated with infant cord blood DNA methylation. Epigenetics. 2018;13:301–309.
    1. Goodrich J. M. et al. First trimester maternal exposures to endocrine disrupting chemicals and metals and fetal size in the Michigan Mother Infant Pairs Study. J DOHaD. In press (2018).
    1. Lever J, Krzywinski M, Altman N. Principal component analysis. Nat. Methods. 2017;14:641.
    1. Morello-Frosch R, et al. Environmental Chemicals in an Urban Population of Pregnant Women and Their Newborns from San Francisco. Environ. Sci. Technol. 2016;50:12464–12472.
    1. Hauguel-de Mouzon S, Guerre-Millo M. The placenta cytokine network and inflammatory signals. Placenta. 2006;27:794–798.
    1. Redman CWG, Sargent IL. Pre-eclampsia, the placenta and the maternal systemic inflammatory response–a review. Placenta. 2003;24(Suppl A):S21–7.
    1. Ashford KB, et al. Patterns of Systemic and Cervicovaginal Fluid Inflammatory Cytokines throughout Pregnancy. Am. J. Perinatol. 2018;35:455–462.
    1. Bowen JM, Chamley L, Keelan JA, Mitchell MD. Cytokines of the placenta and extra-placental membranes: roles and regulation during human pregnancy and parturition. Placenta. 2002;23:257–273.
    1. Chow SSW, et al. Differences in amniotic fluid and maternal serum cytokine levels in early midtrimester women without evidence of infection. Cytokine. 2008;44:78–84.
    1. Ferguson KK, et al. Urinary phthalate metabolite associations with biomarkers of inflammation and oxidative stress across pregnancy in Puerto Rico. Environ. Sci. Technol. 2014;48:7018–7025.
    1. Ferguson KK, Cantonwine DE, McElrath TF, Mukherjee B, Meeker JD. Repeated measures analysis of associations between urinary bisphenol-A concentrations and biomarkers of inflammation and oxidative stress in pregnancy. Reprod. Toxicol. 2016;66:93–98.
    1. Xu LL, et al. Monocyte chemotactic protein-3 (MCP3) interacts with multiple leukocyte receptors: binding and signaling of MCP3 through shared as well as unique receptors on monocytes and neutrophils. Eur. J. Immunol. 1995;25:2612–2617.
    1. Aylward LL, et al. Relationships of chemical concentrations in maternal and cord blood: a review of available data. J. Toxicol. Environ. Health B Crit. Rev. 2014;17:175–203.
    1. Braun JM, Gennings C, Hauser R, Webster TF. What Can Epidemiological Studies Tell Us about the Impact of Chemical Mixtures on Human Health? Environ. Health Perspect. 2016;124:A6–9.
    1. Rider CV, Carlin DJ, Devito MJ, Thompson CL, Walker NJ. Mixtures research at NIEHS: an evolving program. Toxicology. 2013;313:94–102.
    1. Carpenter DO, Arcaro K, Spink DC. Understanding the human health effects of chemical mixtures. Environ. Health Perspect. 2002;110(Suppl 1):25–42.
    1. Wang A, Padula A, Sirota M, Woodruff TJ. Environmental influences on reproductive health: the importance of chemical exposures. Fertil. Steril. 2016;106:905–929.
    1. Di Renzo GC, et al. International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals. Int. J. Gynaecol. Obstet. 2015;131:219–225.
    1. Kassotis CD, Tillitt DE, Lin C-H, McElroy JA, Nagel SC. Endocrine-Disrupting Chemicals and Oil and Natural Gas Operations: Potential Environmental Contamination and Recommendations to Assess Complex Environmental Mixtures. Environ. Health Perspect. 2016;124:256–264.
    1. Evans NP, et al. Reproduction Symposium: does grazing on biosolids-treated pasture pose a pathophysiological risk associated with increased exposure to endocrine disrupting compounds? J. Anim. Sci. 2014;92:3185–3198.
    1. Baibergenova A, Kudyakov R, Zdeb M, Carpenter DO. Low birth weight and residential proximity to PCB-contaminated waste sites. Environ. Health Perspect. 2003;111:1352–1357.
    1. Washino N, et al. Correlations between prenatal exposure to perfluorinated chemicals and reduced fetal growth. Environ. Health Perspect. 2009;117:660–667.
    1. Fei C, McLaughlin JK, Tarone RE, Olsen J. Perfluorinated chemicals and fetal growth: a study within the Danish National Birth Cohort. Environ. Health Perspect. 2007;115:1677–1682.
    1. Dadvand P, et al. Maternal exposure to particulate air pollution and term birth weight: a multi-country evaluation of effect and heterogeneity. Environ. Health Perspect. 2013;121:267–373.
    1. Padmanabhan V, et al. Maternal bisphenol-A levels at delivery: a looming problem? J. Perinatol. 2008;28:258–263.
    1. Woods MM, Lanphear BP, Braun JM, McCandless LC. Gestational exposure to endocrine disrupting chemicals in relation to infant birth weight: a Bayesian analysis of the HOME Study. Environ. Health. 2017;16:115.
    1. Alijotas-Reig J, Esteve-Valverde E, Ferrer-Oliveras R, Llurba E, Gris JM. Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review. Clin. Rev. Allergy Immunol. 2017;53:40–53.
    1. Kim CJ, Romero R, Chaemsaithong P, Kim J-S. Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance. Am. J. Obstet. Gynecol. 2015;213:S53–69.
    1. LaMarca B, et al. Identifying immune mechanisms mediating the hypertension during preeclampsia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2016;311:R1–9.
    1. Makhseed M, et al. Circulating cytokines and CD30 in normal human pregnancy and recurrent spontaneous abortions. Hum. Reprod. 2000;15:2011–2017.
    1. Peraçoli JC, Rudge MVC, Peraçoli MTS. Tumor necrosis factor-alpha in gestation and puerperium of women with gestational hypertension and pre-eclampsia. Am. J. Reprod. Immunol. 2007;57:177–185.
    1. Keelan JA, et al. Cytokines, prostaglandins and parturition–a review. Placenta. 2003;24(Suppl A):S33–46.
    1. Wei S-Q, Fraser W, Luo Z-C. Inflammatory cytokines and spontaneous preterm birth in asymptomatic women: a systematic review. Obstet. Gynecol. 2010;116:393–401.
    1. Di Renzo, G. C., Tosto, V. & Giardina, I. The biological basis and prevention of preterm birth. Best Pract. Res. Clin. Obstet. Gynaecol, 10.1016/j.bpobgyn.2018.01.022 (2018).
    1. Barker DJ, Osmond C, Golding J, Kuh D, Wadsworth ME. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ. 1989;298:564–567.
    1. Padmanabhan V, Cardoso RC, Puttabyatappa M. Developmental Programming, a Pathway to Disease. Endocrinology. 2016;157:1328–1340.
    1. Burton GJ, Fowden AL, Thornburg KL. Placental Origins of Chronic Disease. Physiol. Rev. 2016;96:1509–1565.
    1. Segovia, S. A., Vickers, M. H. & Reynolds, C. M. The impact of maternal obesity on inflammatory processes and consequences for later offspring health outcomes. J. Dev. Orig. Health Dis. 1–12 (2017).
    1. Fleming TP, et al. Origins of lifetime health around the time of conception: causes and consequences. Lancet. 2018;391:1842–1852.
    1. Agay-Shay K, et al. Exposure to Endocrine-Disrupting Chemicals during Pregnancy and Weight at 7 Years of Age: A Multi-pollutant Approach. Environ. Health Perspect. 2015;123:1030–1037.
    1. Robinson O, Vrijheid M. The Pregnancy Exposome. Curr Environ Health Rep. 2015;2:204–213.
    1. Rosenfeld CS. Sex-Specific Placental Responses in Fetal Development. Endocrinology. 2015;156:3422–3434.
    1. Chen Y-H, Ferguson KK, Meeker JD, McElrath TF, Mukherjee B. Statistical methods for modeling repeated measures of maternal environmental exposure biomarkers during pregnancy in association with preterm birth. Environ. Health. 2015;14:9.
    1. Ferguson KK, McElrath TF, Ko Y-A, Mukherjee B, Meeker JD. Variability in urinary phthalate metabolite levels across pregnancy and sensitive windows of exposure for the risk of preterm birth. Environ. Int. 2014;70:118–124.

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