Hostname: page-component-cd9895bd7-mkpzs Total loading time: 0 Render date: 2024-12-18T20:47:14.113Z Has data issue: false hasContentIssue false

Phthalates in neonatal health: friend or foe?

Published online by Cambridge University Press:  04 July 2016

J. D. Bowman
Affiliation:
Department of Pharmacy Practice, Texas A&M Health Science Center, Irma Lerma Rangel College of Pharmacy, Kingsville, Texas, USA
M. Choudhury*
Affiliation:
Department of Pharmaceutical Sciences, Texas A&M Health Science Center, Irma Lerma Rangel College of Pharmacy, Kingsville, Texas, USA
*
*Address for correspondence: M. Choudhury, Department of Pharmaceutical Science, Texas A&M Health Science Center, Irma Lerma Rangel College of Pharmacy, MS 131, 1010 West Ave B, Kingsville, TX 78363, USA. (Email [email protected])

Abstract

Exposure to environmental chemicals has adverse effects on the health and survival of humans. Emerging evidence supports the idea that exposure to endocrine-disrupting compounds (EDCs) can perturb an individual’s physiological set point and as a result increase his/her propensity toward several diseases. The purpose of this review is to provide an update on di-(2-ethylhexyl) phthalate, the primary plasticizer found in plastic medical devices used in neonatal intensive care units, its effects on the fetus and newborn, epidemiological studies, pharmacokinetics, toxicity and epigenetic implications. We searched the PubMed databases to identify relevant studies. Phthalates are known EDCs that primarily are used to improve the flexibility of polyvinyl chloride plastic products and are called plasticizers in lay terms. Neonates and infants are particularly vulnerable to the effects of phthalates, beginning with maternal exposure and placental transfer during gestation and during infancy following birth. In line with the developmental origins of adult disease, a focus on the effects of environmental chemicals in utero or early childhood on the genesis of adult diseases through epigenome modulation is timely and important. The epigenetic effects of phthalates have not been fully elucidated, but accumulating evidence suggests that they may be associated with adverse health effects, some of which may be heritable. Phthalate exposure during pregnancy and the perinatal period is particularly worrisome in health-care settings. Although the clinical significance of phthalate exposure has been difficult to assess with epidemiologic studies, the evidence that physiological changes occur due to exposure to phthalates is growing and points toward the need for more investigation at a molecular, specifically epigenetic level.

Type
Review
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2016 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Gluck, L. Conceptualization and Initiation of a Neonatal Intensive Care Nursery in 1960. 1992, National Institutes of Health: Bethesda, MD.Google Scholar
2. Jorgensen, A. Born in the USA – the history of neonatology in the United States: a century of caring, Abbot Nutrition Health Institute, 2010. Retrieved 8 January 2014 from http://anhi.org/articles/the-history-of-neonatology-in-the-united-states-a-century-of-caring.Google Scholar
3. Mallow, EB, Fox, MA. Phthalates and critically ill neonates: device-related exposures and non-endocrine toxic risks. J Perinatol. 2014; 34, 892897.CrossRefGoogle ScholarPubMed
4. Ferguson, KK, McElrath, TF, Meeker, JD. Environmental phthalate exposure and preterm birth. JAMA Pediatr. 2014; 168, 6167.CrossRefGoogle ScholarPubMed
5. Shen, Q, Shi, H, Zhang, Y, Cao, Y. Dietary intake and phthalates body burden in boys and girls. Arch Public Health. 2015; 73, 5.CrossRefGoogle ScholarPubMed
6. Anway, MD, Rekow, SS, Skinner, MK. Transgenerational epigenetic programming of the embryonic testis transcriptome. Genomics. 2008; 91, 3040.CrossRefGoogle ScholarPubMed
7. Perera, F, Herbstman, J. Prenatal environmental exposures, epigenetics, and disease. Reprod Toxicol. 2011; 31, 363373.CrossRefGoogle ScholarPubMed
8. Waring, RH, Harris, RM, Mitchell, SC. In utero exposure to carcinogens: epigenetics, developmental disruption and consequences in later life. Maturitas. 2016; 86, 5963.CrossRefGoogle ScholarPubMed
9. Woodruff, TJ. Making it real – the environmental burden of disease. What does it take to make people pay attention to the environment and health? J Clin Endocrinol Metab. 2015; 100, 12411244.CrossRefGoogle Scholar
10. Albert, O, Jégou, B. A critical assessment of the endocrine susceptibility of the human testis to phthalates from fetal life to adulthood. Hum Reprod Update. 2014; 20, 231249.CrossRefGoogle ScholarPubMed
11. Berge, A, Cladiere, M, Gasperi, J, et al. Meta-analysis of environmental contamination by phthalates. Environ Sci Pollut Res. 2013; 20, 80578076.CrossRefGoogle ScholarPubMed
12. Schettler, T. Human exposure to phthalates via consumer products. Int J Androl. 2006; 29, 134139, discussion 181–185.CrossRefGoogle ScholarPubMed
13. Meeker, JD, Sathyanarayana, S, Swan, SH. Phthalates and other additives in plastics: human exposure and associated health outcomes. Philos Trans R Soc Lond B Biol Sci. 2009; 364, 20972113.CrossRefGoogle ScholarPubMed
14. Latini, G, Ferri, M, Chiellini, F. Materials degradation in PVC medical devices, DEHP leaching and neonatal outcomes. Curr Med Chem. 2010; 17, 29792989.CrossRefGoogle ScholarPubMed
15. Trasande, L, Attina, TM. Association of exposure to di-2-ethylhexylphthalate replacements with increased blood pressure in children and adolescents. Hypertension. 2015; 66, 301308.CrossRefGoogle ScholarPubMed
16. Mankidy, R, Wiseman, S, Ma, H, Giesy, JP. Biological impact of phthalates. Toxicol Lett. 2013; 217, 5058.CrossRefGoogle ScholarPubMed
17. Jaeger, RJ, Rubin, RJ. Contamination of blood stored in plastic packs. Lancet. 1970; 2, 151.CrossRefGoogle ScholarPubMed
18. Mayer, FL, Stalling, DL, Johnson, JL. Phthalate esters as environmental contaminants. Nature. 1972; 238, 411413.CrossRefGoogle ScholarPubMed
19. Rozek, LS, Dolinoy, DC, Sartor, MA, Omenn, GS. Epigenetics: relevance and implications for public health. Annu Rev Public Health. 2014; 35, 105122.CrossRefGoogle ScholarPubMed
20. Singh, S, Li, SS. Epigenetic effects of environmental chemicals bisphenol a and phthalates. Int J Mol Sci. 2012; 13, 1014310153.CrossRefGoogle Scholar
21. Skinner, MK, Manikkam, M, Guerrero-Bosagna, C. Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol Metab. 2010; 21, 214222.CrossRefGoogle ScholarPubMed
22. Agency for Toxic Substances and Disease Registry. Toxicological Profile for Di(2-Ethylhexyl) Phthalate. 2002. Agency for Toxic Substances and Disease Registry: Atlanta, GA.Google Scholar
23. Tomita, I, Nakamura, Y, Yagi, Y, Tutikawa, K. Teratogenicity/fetotoxicity of DEHP in mice. Environ Health Perspect. 1982; 45, 7175.CrossRefGoogle ScholarPubMed
24. Rubin, RJ, Ness, PM. What price progress? An update on vinyl plastic bags. Transfusion (Paris). 1989; 29, 358361.CrossRefGoogle ScholarPubMed
25. Scientific Panel on Food Addities, Flavourings, Processing Aids and Materials in Contact with Food. (Packaging) EFFIa. Bis(2-ethylhexyl)phthalate (DEHP) for use in food contact materials. EFSA J. 2005; 243, 120. doi:10.2903/j.efsa.2005.243.Google Scholar
26. EPA. Basic information about di(2-ethylhexyl) phthalate in drinking water. US Environmental Protection Agency, 2014. Retrieved 23 June 2014 from http://water.epa.gov/drink/contaminants/basicinformation/di_2-ethylhexyl_phthalate.cfm.Google Scholar
27. NTP (National Toxicology Program). Report on Carcinogens, 13th edn, 2014. National Toxicology Program: Research Triangle Park, NC.Google Scholar
28. Nachman, RM, Hartle, JC, Lees, PSJ, Groopman, JD. Early life metabolism of bisphenol A: a systematic review of the literature. Curr Environ Health Rep. 2014; 1, 90100.CrossRefGoogle ScholarPubMed
29. Beko, G, Weschler, CJ, Langer, S, et al. Children’s phthalate intakes and resultant cumulative exposures estimated from urine compared with estimates from dust ingestion, inhalation and dermal absorption in their homes and daycare centers. PLoS One. 2013; 8, e62442.CrossRefGoogle ScholarPubMed
30. Koch, HM, Preuss, R, Angerer, J. Di(2-ethylhexyl)phthalate (DEHP): human metabolism and internal exposure – an update and latest results. Int J Androl. 2006; 29, 155165, discussion 181–185.CrossRefGoogle Scholar
31. Cuzzolin, L. Drug metabolizing enzymes in the perinatal and neonatal period: differences in the expression and activity. Curr Drug Metab. 2013; 14, 167173.Google ScholarPubMed
32. Dotta, A, Chukhlantseva, N. Ontogeny and drug metabolism in newborns. J Matern Fetal Neonatal Med. 2012; 25(Suppl. 4), 8384.CrossRefGoogle ScholarPubMed
33. Choi, K, Joo, H, Campbell, JL Jr, et al. In vitro metabolism of di(2-ethylhexyl) phthalate (DEHP) by various tissues and cytochrome P450s of human and rat. Toxicol In Vitro. 2012; 26, 315322.CrossRefGoogle ScholarPubMed
34. Van Overmeire, B, Touw, D, Schepens, PJ, Kearns, GL, van den Anker, JN. Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus. Clin Pharmacol Ther. 2001; 70, 336343.CrossRefGoogle ScholarPubMed
35. Sharma, PK, Garg, SK, Narang, A. Pharmacokinetics of oral ibuprofen in premature infants. J Clin Pharmacol. 2003; 43, 968973.CrossRefGoogle ScholarPubMed
36. Ito, Y, Kamijima, M, Hasegawa, C, et al. Species and inter-individual differences in metabolic capacity of di(2-ethylhexyl)phthalate (DEHP) between human and mouse livers. Environ Health Prev Med. 2014; 19, 117125.CrossRefGoogle Scholar
37. Koch, HM, Rossbach, B, Drexler, H, Angerer, J. Internal exposure of the general population to DEHP and other phthalates – determination of secondary and primary phthalate monoester metabolites in urine. Environ Res. 2003; 93, 177185.CrossRefGoogle ScholarPubMed
38. Ligi, I, Boubred, F, Grandvuillemin, I, Simeoni, U. The neonatal kidney: implications for drug metabolism and elimination. Curr Drug Metab. 2013; 14, 174177.Google Scholar
39. Chen, N, Aleksa, K, Woodland, C, Rieder, M, Koren, G. Ontogeny of drug elimination by the human kidney. Pediatr Nephrol. 2006; 21, 160168.CrossRefGoogle ScholarPubMed
40. Levey, AS, Inker, LA, Coresh, J. GFR estimation: from physiology to public health. Am J Kidney Dis. 2014; 63, 820834.CrossRefGoogle ScholarPubMed
41. Lorber, M, Koch, HM, Angerer, J. A critical evaluation of the creatinine correction approach: can it underestimate intakes of phthalates? A case study with di-2-ethylhexyl phthalate. J Expo Sci Environ Epidemiol. 2011; 21, 576586.CrossRefGoogle ScholarPubMed
42. Lorber, M, Angerer, J, Koch, HM. A simple pharmacokinetic model to characterize exposure of Americans to Di-2-ethylhexyl phthalate. J Expos Sci Environ Epidemiol. 2009; 20, 3853.CrossRefGoogle ScholarPubMed
43. Enke, U, Schleussner, E, Palmke, C, Seyfarth, L, Koch, HM. Phthalate exposure in pregnant women and newborns – the urinary metabolite excretion pattern differs distinctly. Int J Hyg Environ Health. 2013; 216, 735742.CrossRefGoogle ScholarPubMed
44. Green, R, Hauser, R, Calafat, AM, et al. Use of di(2-ethylhexyl) phthalate-containing medical products and urinary levels of mono(2-ethylhexyl) phthalate in neonatal intensive care unit infants. Environ Health Perspect. 2005; 113, 12221225.CrossRefGoogle ScholarPubMed
45. Latini, G, De Felice, C, Verrotti, A. Plasticizers, infant nutrition and reproductive health. Reprod Toxicol. 2004; 19, 2733.CrossRefGoogle ScholarPubMed
46. Loff, S, Kabs, F, Subotic, U, et al. Kinetics of diethylhexyl-phthalate extraction From polyvinylchloride-infusion lines. JPEN J Parenter Enteral Nutr. 2002; 26, 305309.CrossRefGoogle ScholarPubMed
47. Rose, RJ, Priston, MJ, Rigby-Jones, AE, Sneyd, JR. The effect of temperature on di(2-ethylhexyl) phthalate leaching from PVC infusion sets exposed to lipid emulsions. Anaesthesia. 2012; 67, 514520.CrossRefGoogle Scholar
48. Bagel, S, Dessaigne, B, Bourdeaux, D, et al. Influence of lipid type on bis (2-ethylhexyl)phthalate (DEHP) leaching from infusion line sets in parenteral nutrition. JPEN J Parenter Enteral Nutr. 2011; 35, 770775.CrossRefGoogle Scholar
49. Loff, S, Subotic, U, Reinicke, F, Wischmann, H, Brade, J. Extraction of di-ethylhexyl-phthalate from perfusion lines of various material, length and brand by lipid emulsions. J Pediatr Gastroenterol Nutr. 2004; 39, 341345.Google ScholarPubMed
50. Bourdeaux, D, Sautou-Miranda, V, Bagel-Boithias, S, Boyer, A, Chopineau, J. Analysis by liquid chromatography and infrared spectrometry of di(2-ethylhexyl)phthalate released by multilayer infusion tubing. J Pharm Biomed Anal. 2004; 35, 5764.CrossRefGoogle ScholarPubMed
51. Calafat, AM, Needham, LL, Silva, MJ, Lambert, G. Exposure to di-(2-ethylhexyl) phthalate among premature neonates in a neonatal intensive care unit. Pediatrics. 2004; 113, e429e434.CrossRefGoogle Scholar
52. Centers for Disease Control. Second National Report on Human Exposure to Environmental Chemicals. 2003. Centers for Disease Control and Prevention: Atlanta, GA.Google Scholar
53. Weuve, J, Sanchez, BN, Calafat, AM, et al. Exposure to phthalates in neonatal intensive care unit infants: urinary concentrations of monoesters and oxidative metabolites. Environ Health Perspect. 2006; 114, 14241431.CrossRefGoogle ScholarPubMed
54. Frederiksen, H, Kuiri-Hanninen, T, Main, KM, Dunkel, L, Sankilampi, U. A longitudinal study of urinary phthalate excretion in 58 full-term and 67 preterm infants from birth through 14 months. Environ Health Perspect. 2014; 122, 9981005. doi:10.1289/ehp.1307569.CrossRefGoogle Scholar
55. Karle, VA, Short, BL, Martin, GR, et al. Extracorporeal membrane oxygenation exposes infants to the plasticizer, di(2-ethylhexyl)phthalate. Crit Care Med. 1997; 25, 696703.CrossRefGoogle Scholar
56. Sjoberg, P, Bondesson, U, Sedin, G, Gustafsson, J. Dispositions of di- and mono-(2-ethylhexyl) phthalate in newborn infants subjected to exchange transfusions. Eur J Clin Invest. 1985; 15, 430436.CrossRefGoogle ScholarPubMed
57. Sjoberg, PO, Bondesson, UG, Sedin, EG, Gustafsson, JP. Exposure of newborn infants to plasticizers. Plasma levels of di-(2-ethylhexyl) phthalate and mono-(2-ethylhexyl) phthalate during exchange transfusion. Transfusion (Paris). 1985; 25, 424428.CrossRefGoogle ScholarPubMed
58. Latini, G, Wittassek, M, Del Vecchio, A, et al. Lactational exposure to phthalates in Southern Italy. Environ Int. 2009; 35, 236239.CrossRefGoogle ScholarPubMed
59. Calafat, AM, Slakman, AR, Silva, MJ, Herbert, AR, Needham, LL. Automated solid phase extraction and quantitative analysis of human milk for 13 phthalate metabolites. J Chromatogr B Analyt Technol Biomed Life Sci. 2004; 805, 4956.CrossRefGoogle ScholarPubMed
60. Mortensen, GK, Main, KM, Andersson, AM, Leffers, H, Skakkebaek, NE. Determination of phthalate monoesters in human milk, consumer milk, and infant formula by tandem mass spectrometry (LC-MS-MS). Anal Bioanal Chem. 2005; 382, 10841092.CrossRefGoogle ScholarPubMed
61. Kelley, KE, Hernandez-Diaz, S, Chaplin, EL, Hauser, R, Mitchell, AA. Identification of phthalates in medications and dietary supplement formulations in the United States and Canada. Environ Health Perspect. 2012; 120, 379384.CrossRefGoogle Scholar
62. FDA. Guidance for industry: limiting the use of certain phthalates as excipients in CDER-regulated products. US Department of Health and Human Services, 2012. Retrieved 22 June 2014 from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM294086.pdf?source=govdelivery.Google Scholar
63. Koniecki, D, Wang, R, Moody, RP, Zhu, J. Phthalates in cosmetic and personal care products: concentrations and possible dermal exposure. Environ Res. 2011; 111, 329336.CrossRefGoogle ScholarPubMed
64. Braun, JM, Just, AC, Williams, PL, et al. Personal care product use and urinary phthalate metabolite and paraben concentrations during pregnancy among women from a fertility clinic. J Expo Sci Environ Epidemiol. 2014; 24, 459466.CrossRefGoogle ScholarPubMed
65. Sathyanarayana, S, Karr, CJ, Lozano, P, et al. Baby care products: possible sources of infant phthalate exposure. Pediatrics. 2008; 121, e260e268.CrossRefGoogle ScholarPubMed
66. Whyatt, RM, Adibi, JJ, Calafat, AM, et al. Prenatal di(2-ethylhexyl)phthalate exposure and length of gestation among an inner-city cohort. Pediatrics. 2009; 124, e1213e1220.CrossRefGoogle ScholarPubMed
67. Silva, MJ, Reidy, JA, Herbert, AR, et al. Detection of phthalate metabolites in human amniotic fluid. Bull Environ Contam Toxicol. 2004; 72, 12261231.CrossRefGoogle ScholarPubMed
68. Latini, G, De Felice, C, Presta, G, et al. In utero exposure to di-(2-ethylhexyl)phthalate and duration of human pregnancy. Environ Health Perspect. 2003; 111, 17831785.CrossRefGoogle ScholarPubMed
69. Huang, Y, Li, J, Garcia, JM, et al. Phthalate levels in cord blood are associated with preterm delivery and fetal growth parameters in Chinese women. PLoS One. 2014; 13, e87430.CrossRefGoogle Scholar
70. Tefre de Renzy-Martin, K, Frederiksen, H, Christensen, JS, et al. Current exposure of 200 pregnant Danish women to phthalates, parabens and phenols. Reproduction. 2014; 147, 443453.CrossRefGoogle ScholarPubMed
71. Adibi, JJ, Hauser, R, Williams, PL, et al. Maternal urinary metabolites of di-(2-ethylhexyl) phthalate in relation to the timing of labor in a US multicenter pregnancy cohort study. Am J Epidemiol. 2009; 169, 10151024.CrossRefGoogle Scholar
72. Wolff, MS, Engel, SM, Berkowitz, GS, et al. Prenatal phenol and phthalate exposures and birth outcomes. Environ Health Perspect. 2008; 116, 10921097.CrossRefGoogle ScholarPubMed
73. Suzuki, Y, Niwa, M, Yoshinaga, J, et al. Prenatal exposure to phthalate esters and PAHs and birth outcomes. Environ Int. 2010; 36, 699704.CrossRefGoogle ScholarPubMed
74. Parets, SE, Bedient, CE, Menon, R, Smith, AK. Preterm birth and its long-term effects: methylation to mechanisms. Biology (Basel). 2014; 3, 498513.Google ScholarPubMed
75. Gao, F, Zhang, J, Jiang, P, et al. Marked methylation changes in intestinal genes during the perinatal period of preterm neonates. BMC Genomics. 2014; 15, 716.CrossRefGoogle ScholarPubMed
76. Meruvu, S, Zhang, J, Bedi, YS, Choudhury, M. Mono-(2-ethylhexyl) phthalate induces apoptosis through miR-16 in human first trimester placental cell line HTR-8/SVneo. Toxicol In Vitro. 2016; 31, 3542.CrossRefGoogle ScholarPubMed
77. Kay, VR, Chambers, C, Foster, WG. Reproductive and developmental effects of phthalate diesters in females. Crit Rev Toxicol. 2013; 43, 200219.CrossRefGoogle ScholarPubMed
78. Yoon, K, Kwack, SJ, Kim, HS, Lee, BM. Estrogenic endocrine-disrupting chemicals: molecular mechanisms of actions on putative human diseases. J Toxicol Environ Health B Crit Rev. 2014; 17, 127174.CrossRefGoogle ScholarPubMed
79. Culty, M, Thuillier, R, Li, W, et al. In utero exposure to di-(2-ethylhexyl) phthalate exerts both short-term and long-lasting suppressive effects on testosterone production in the rat. Biol Reprod. 2008; 78, 10181028.CrossRefGoogle ScholarPubMed
80. Bustamante-Montes, LP, Hernandez-Valero, MA, Flores-Pimentel, D, et al. Prenatal exposure to phthalates is associated with decreased anogenital distance and penile size in male newborns. J Dev Orig Health Dis. 2013; 4, 300306.CrossRefGoogle ScholarPubMed
81. Fisher, JS, Macpherson, S, Marchetti, N, Sharpe, RM. Human ‘testicular dysgenesis syndrome’: a possible model using in-utero exposure of the rat to dibutyl phthalate. Hum Reprod. 2003; 18, 13831394.CrossRefGoogle ScholarPubMed
82. Olesen, IA, Sonne, SB, Hoei-Hansen, CE, Rajpert-De Meyts, E, Skakkebaek, NE. Environment, testicular dysgenesis and carcinoma in situ testis. Best Pract Res Clin Endocrinol Metab. 2007; 21, 462478.CrossRefGoogle ScholarPubMed
83. Wu, S, Zhu, J, Li, Y, et al. Dynamic epigenetic changes involved in testicular toxicity induced by di-2-(ethylhexyl) phthalate in mice. Basic Clin Pharmacol Toxicol. 2010; 106, 118123.CrossRefGoogle ScholarPubMed
84. Wu, S, Zhu, J, Li, Y, et al. Dynamic effect of di-2-(ethylhexyl) phthalate on testicular toxicity: epigenetic changes and their impact on gene expression. Int J Toxicol. 2010; 29, 193200.CrossRefGoogle ScholarPubMed
85. Chen, J, Wu, S, Wen, S, et al. The mechanism of environmental endocrine disruptors (DEHP) induces epigenetic transgenerational inheritance of cryptorchidism. PLoS One. 2015; 10, e0126403.CrossRefGoogle ScholarPubMed
86. Swan, SH, Main, KM, Liu, F, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect. 2005; 113, 10561061.CrossRefGoogle ScholarPubMed
87. Suzuki, Y, Yoshinaga, J, Mizumoto, Y, Serizawa, S, Shiraishi, H. Foetal exposure to phthalate esters and anogenital distance in male newborns. Int J Androl. 2012; 35, 236244.CrossRefGoogle ScholarPubMed
88. Howdeshell, KL, Furr, J, Lambright, CR, et al. Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: altered fetal steroid hormones and genes. Toxicol Sci. 2007; 99, 190202.CrossRefGoogle ScholarPubMed
89. Gaspari, L, Paris, F, Jandel, C, et al. Prenatal environmental risk factors for genital malformations in a population of 1442 French male newborns: a nested case-control study. Hum Reprod. 2011; 26, 31553162.CrossRefGoogle Scholar
90. Hart, R, Doherty, DA, Frederiksen, H, et al. The influence of antenatal exposure to phthalates on subsequent female reproductive development in adolescence: a pilot study. Reproduction. 2013; 147, 379390. doi:10.1530/REP-13-0331.CrossRefGoogle Scholar
91. Mouritsen, A, Frederiksen, H, Sorensen, K, et al. Urinary phthalates from 168 girls and boys measured twice a year during a 5-year period: associations with adrenal androgen levels and puberty. J Clin Endocrinol Metab. 2013; 98, 37553764.CrossRefGoogle ScholarPubMed
92. Martinez-Arguelles, DB, Culty, M, Zirkin, BR, Papadopoulos, V. In utero exposure to di-(2-ethylhexyl) phthalate decreases mineralocorticoid receptor expression in the adult testis. Endocrinology. 2009; 150, 55755585.CrossRefGoogle ScholarPubMed
93. Martinez-Arguelles, DB, Guichard, T, Culty, M, Zirkin, BR, Papadopoulos, V. In utero exposure to the antiandrogen di-(2-ethylhexyl) phthalate decreases adrenal aldosterone production in the adult rat. Biol Reprod. 2011; 85, 5161.CrossRefGoogle Scholar
94. Martinez-Arguelles, D, Campioli, E, Lienhart, C, et al. In utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate induces long-term changes in gene expression in the adult male adrenal gland. Endocrinology. 2014; 155, 16671678. doi:10.1210/en.2013-1921.CrossRefGoogle Scholar
95. Martinez-Arguelles, DB, Campioli, E, Culty, M, Zirkin, BR, Papadopoulos, V. Fetal origin of endocrine dysfunction in the adult: the phthalate model. J Steroid Biochem Mol Biol. 2013; 137, 517.CrossRefGoogle ScholarPubMed
96. Kang, SC, Lee, BM. DNA methylation of estrogen receptor alpha gene by phthalates. J Toxicol Environ Health A. 2005; 68, 19952003.CrossRefGoogle ScholarPubMed
97. Li, L, Zhang, T, Qin, XS, et al. Exposure to diethylhexyl phthalate (DEHP) results in a heritable modification of imprint genes DNA methylation in mouse oocytes. Molecular Biology Reports. 2014; 41, 12271235.CrossRefGoogle Scholar
98. Gupta, RK, Singh, JM, Leslie, TC, et al. Di-(2-ethylhexyl) phthalate and mono-(2-ethylhexyl) phthalate inhibit growth and reduce estradiol levels of antral follicles in vitro. Toxicol Appl Pharmacol. 2010; 242, 224230.CrossRefGoogle ScholarPubMed
99. Thomas, JA, Curto, KA, Thomas, MJ. MEHP/DEHP: gonadal toxicity and effects on rodent accessory sex organs. Environ Health Perspect. 1982; 45, 8588.CrossRefGoogle ScholarPubMed
100. Erkekoglu, P, Rachidi, W, Yuzugullu, OG, et al. Evaluation of cytotoxicity and oxidative DNA damaging effects of di(2-ethylhexyl)-phthalate (DEHP) and mono(2-ethylhexyl)-phthalate (MEHP) on MA-10 Leydig cells and protection by selenium. Toxicol Appl Pharmacol. 2010; 248, 5262.CrossRefGoogle ScholarPubMed
101. Rose, ML, Rivera, CA, Bradford, BU, et al. Kupffer cell oxidant production is central to the mechanism of peroxisome proliferators. Carcinogenesis. 1999; 20, 2733.CrossRefGoogle Scholar
102. Wan, X, Zhu, Y, Ma, X, et al. Effect of DEHP and its metabolite MEHP on in vitro rat follicular development. Wei Sheng Yan Jiu. 2010; 39, 268270, 274.Google ScholarPubMed
103. Sjoberg, P, Bondesson, U, Gray, TJ, Ploen, L. Effects of di-(2-ethylhexyl) phthalate and five of its metabolites on rat testis in vivo and in in vitro. Acta Pharmacol Toxicol (Copenh). 1986; 58, 225233.CrossRefGoogle ScholarPubMed
104. Naville, D, Labaronne, E, Vega, N, et al. Metabolic outcome of female mice exposed to a mixture of low-dose pollutants in a diet-induced obesity model. PLoS One. 2015; 10, e0124015.CrossRefGoogle Scholar
105. Manikkam, M, Tracey, R, Guerrero-Bosagna, C, Skinner, MK. Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PLoS One. 2013; 8, e55387.CrossRefGoogle ScholarPubMed
106. Newbold, RR. Prenatal exposure to diethylstilbestrol and long-term impact on the breast and reproductive tract in humans and mice. J Dev Orig Health Dis. 2012; 3, 7382.CrossRefGoogle ScholarPubMed
107. Kavlock, R, Barr, D, Boekelheide, K, et al. NTP-CERHR expert panel update on the reproductive and developmental toxicity of di(2-ethylhexyl) phthalate. Reprod Toxicol. 2006; 22, 291399.Google Scholar
108. Braun, JM, Sathyanarayana, S, Hauser, R. Phthalate exposure and children’s health. Curr Opin Pediatr. 2013; 25, 247254.CrossRefGoogle ScholarPubMed
109. Health Care Without Harm. Alternatives to polyvinyl chloride (PVC) medical devices for the Neonatal Intensive Care Unit (NICU), Reston, VA, 2006. Health Care Without Harm. Retrieved 1 July 2014 from https://noharm-uscanada.org/documents/alternatives-polyvinyl-chloride-pvc-medical-devices-neonatal-intensive-care-unit-nicu.Google Scholar
110. Health Care Without Harm. Alternatives to polyvinyl chloride (PVC) and di(2-ethylhexyl) phthalate (DEHP) medical devices, Reston, VA, 2008. Health Care Without Harm. Retrieved 1 July 2014 from https://noharm-uscanada.org/documents/alternatives-polyvinyl-chloride-pvc-and-di2-ethylhexyl-phthalate-dehp-medical-devices.Google Scholar
111. Pediatric Environmental Health Specialty Units. Resources for health professionals. Pediatric Environmental Health Specialty Units, Washington, DC, March 2014. Retrieved 2 July 2014 from http://www.pehsu.net/_Phthalates_and_Bisphenol_A_Advisory.html Google Scholar
112. The Scientific Committee on medicinal products and medical devices. Opinion on medical devices containing DEHP plasticised PVC; neonates and other groups possibly at risk from DEHP toxicity, 2002. Retrieved 17 September 2014 from http://ec.europa.eu/health/ph_risk/committees/scmp/documents/out43_en.pdf.Google Scholar
113. Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR). Preliminary report on the safety of medical devices containing DEHP-plasticized PVC or other plasticizers on neonates and other groups possibly at risk. Scientific Committee on Emerging and Newly Identified Health Risks, European Commission, Brussels and Luxembourg, 2013. Retrieved 18 June 2014 from http://ec.europa.eu/health/scientific_committees/consultations/public_consultations/scenihr_cons_05_en.htm.Google Scholar
114. Goodman, M, Lakind, JS, Mattison, DR. Do phthalates act as obesogens in humans? A systematic review of the epidemiological literature. Crit Rev Toxicol. 2014; 44, 151175.CrossRefGoogle ScholarPubMed