Impact of Di-2-Ethylhexyl Phthalate Metabolites on Male Reproductive Function: a Systematic Review of Human Evidence
Purpose of Review
The purpose of this review is to systematically review the literature linking di-2-ethylhexyl phthalate (DEHP) exposure with effects on reproductive health in adult males.
Thirty-three papers were included of which 28 were cross-sectional. Twenty-one papers investigated semen samples, 18 investigated reproductive hormones, and three studies investigated time to pregnancy. Studies revealed some but inconsistent indications that higher urinary DEHP metabolite levels are associated with an increase in the proportion of spermatozoa with damaged DNA and to a decrease in sperm concentration and motility. A negative association between DEHP metabolites and testosterone levels was more consistent. DEHP metabolites do not seem to be associated with a delay in time to pregnancy, but data are sparse.
The studies on DEHP exposure and reproductive biomarkers in men converge to support the hypothesis that DEHP exposure is related to impaired male reproductive function. Longitudinal studies are needed to establish if the observed associations are causal.
KeywordsReview Phthalic acids Fecundity Reproduction Semen quality Gonadal steroid hormones
It is with our deepest sorrow that we inform you of the passing of our co-author, Bo A.G. Jönsson during the writing of this article.
This systematic review was part of the CLEAR collaboration funded by the European Commission 7th Framework Program FP7-ENV-2008-1 Grant no.: 226217; the Danish Research Council (10-082745); ReproHigh, the Öresund-Kattegat-Skagerrak-Program; and funded by the European Regional Development Fund. This article was furthermore a part of the ReproUnion collaborative study, co-financed by the European Union, Intereg V ÖKS.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
All reported studies with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki Declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.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(2):177–85. https://doi.org/10.1016/S0013-9351(03)00083-5.CrossRefPubMedGoogle Scholar
- 2.Kavlock R, Boekelheide K, Chapin R, Cunningham M, Faustman E, Foster P, et al. NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di-n-hexyl phthalate. Reprod Toxicol (Elmsford, NY). 2002;16(5):709–19.CrossRefGoogle Scholar
- 6.Bradley EL, Burden RA, Bentayeb K, Driffield M, Harmer N, Mortimer DN, et al. Exposure to phthalic acid, phthalate diesters and phthalate monoesters from foodstuffs: UK total diet study results. Food Addit Contam A Chem Anal Control Expo Risk Assess. 2013;30(4):735–42. https://doi.org/10.1080/19440049.2013.781684.CrossRefGoogle Scholar
- 8.Koch HM, Lorber M, Christensen KL, Palmke C, Koslitz S, Bruning T. Identifying sources of phthalate exposure with human biomonitoring: results of a 48h fasting study with urine collection and personal activity patterns. Int J Hyg Environ Health. 2013;216(6):672–81. https://doi.org/10.1016/j.ijheh.2012.12.002.CrossRefPubMedGoogle Scholar
- 11.European Chemicals Agency. Evaluation of new scientific evidence concerning the restrictions contained in annex XVII to gegulation (EC) No 1907/2006 (REACH) Review of new available information for di-‘isononyl’ phthalate (DINP) 2010.Google Scholar
- 12.• Zota AR, Calafat AM, Woodruff TJ. Temporal trends in phthalate exposures: findings from the National Health and Nutrition Examination Survey, 2001-2010. Environ Health Perspect. 2014;122(3):235–41. https://doi.org/10.1289/ehp.1306681. An interesting paper reporting time trends of human DEHP exposure in the USA.PubMedCentralPubMedGoogle Scholar
- 13.Goen T, Dobler L, Koschorreck J, Muller J, Wiesmuller GA, Drexler H, et al. Trends of the internal phthalate exposure of young adults in Germany—follow-up of a retrospective human biomonitoring study. Int J Hyg Environ Health. 2011;215(1):36–45. https://doi.org/10.1016/j.ijheh.2011.07.011. PubMedGoogle Scholar
- 15.European Chemicals Agency. Bis(2-ethylhexyl) phthalate. 2017. https://echa.europa.eu/brief-profile/-/briefprofile/100.003.829#collapseSeven. Accessed August 03 2017.
- 17.Noriega NC, Howdeshell KL, Furr J, Lambright CR, Wilson VS, Gray LE Jr. Pubertal administration of DEHP delays puberty, suppresses testosterone production, and inhibits reproductive tract development in male Sprague-Dawley and Long-Evans rats. Toxicol Sci 2009;111(1):163–178. doi: https://doi.org/10.1093/toxsci/kfp129., 1
- 19.Erkekoglu P, Rachidi W, Yuzugullu OG, Giray B, Favier A, Ozturk M, 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(1):52–62. https://doi.org/10.1016/j.taap.2010.07.016.CrossRefPubMedGoogle Scholar
- 25.•• Albert O, Jegou B. A critical assessment of the endocrine susceptibility of the human testis to phthalates from fetal life to adulthood. Hum Reprod Update. 2014;20(2):231–49. https://doi.org/10.1093/humupd/dmt050. A comprehensive overview of animal and human studies reporting on the association between phthalate exposure and reproductive health throughout life.CrossRefPubMedGoogle Scholar
- 32.National Research Council Committee on the Health Risks of P. Phthalates and cumulative risk assessment: the tasks ahead. Washington (DC): National Academies Press (US). Copyright 2008 by the National Academy of Sciences. All rights reserved.; 2008.Google Scholar
- 42.Zhang YH, Chen BH, Zheng LX, Wu XY. Study on the level of phthalates in human biological samples. Zhonghua yu fang yi xue za zhi. Chin J Prevent Med. 2003;37(6):429–34.Google Scholar
- 43.Chen X, Ma J, Yu H, Leng L, Zhou Q, Sun Z, et al. Study on the association between maternal urinary phthalate metabolites and testicular steroid hormones in the cord blood in a Chinese population. Zhonghua yu fang yi xue za zhi. Chin J Prevent Med. 2014;48(3):167–71.Google Scholar
- 45.Duty SM, Silva MJ, Barr DB, Brock JW, Ryan L, Chen Z, et al. Phthalate exposure and human semen parameters. Epidemiology (Cambridge, Mass). 2003;14(3):269–77. https://doi.org/10.1097/01.EDE.0000059950.11836.16.Google Scholar
- 46.Duty SM, Calafat AM, Silva MJ, Ryan L, Hauser R. Phthalate exposure and reproductive hormones in adult men. Hum Reprod 2005;20(3):604–610. doi: https://doi.org/10.1093/humrep/deh656.
- 47.Mendiola J, Meeker JD, Jorgensen N, Andersson AM, Liu F, Calafat AM, et al. Urinary concentrations of di(2-ethylhexyl) phthalate metabolites and serum reproductive hormones: pooled analysis of fertile and infertile men. J Androl. 2012;33(3):488–98. https://doi.org/10.2164/jandrol.111.013557.CrossRefPubMedGoogle Scholar
- 48.Pan G, Hanaoka T, Yu L, Na J, Yamano Y, Hara K, et al. Associations between hazard indices of di-n-butylphthalate and di-2-ethylhexylphthalate exposure and serum reproductive hormone levels among occupationally exposed and unexposed Chinese men. Int J Androl. 2011;34(5 Pt 2):e397–406. https://doi.org/10.1111/j.1365-2605.2011.01201.x.CrossRefPubMedGoogle Scholar
- 49.Huang LP, Lee CC, Fan JP, Kuo PH, Shih TS, Hsu PC. Urinary metabolites of di(2-ethylhexyl) phthalate relation to sperm motility, reactive oxygen species generation, and apoptosis in polyvinyl chloride workers. Int Arch Occup Environ Health. 2014;87(6):635–46. https://doi.org/10.1007/s00420-013-0905-6.CrossRefPubMedGoogle Scholar
- 50.Lenters V, Portengen L, Smit LA, Jonsson BA, Giwercman A, Rylander L, et al. Phthalates, perfluoroalkyl acids, metals and organochlorines and reproductive function: a multipollutant assessment in Greenlandic, Polish and Ukrainian men. Occup Environ Med. 2015;72(6):385–93. https://doi.org/10.1136/oemed-2014-102264.CrossRefPubMedGoogle Scholar
- 51.Hauser R, Meeker JD, Duty S, Silva MJ, Calafat AM. Altered semen quality in relation to urinary concentrations of phthalate monoester and oxidative metabolites. Epidemiology (Cambridge, Mass). 2006;17(6):682–91. https://doi.org/10.1097/01.ede.0000235996.89953.d7. CrossRefGoogle Scholar
- 55.Jurewicz J, Radwan M, Sobala W, Ligocka D, Radwan P, Bochenek M, et al. Human urinary phthalate metabolites level and main semen parameters, sperm chromatin structure, sperm aneuploidy and reproductive hormones. Reprod Toxicol. 2013;42:232–41. https://doi.org/10.1016/j.reprotox.2013.10.001.CrossRefPubMedGoogle Scholar
- 60.Toshima H, Suzuki Y, Imai K, Yoshinaga J, Shiraishi H, Mizumoto Y, et al. Endocrine disrupting chemicals in urine of Japanese male partners of subfertile couples: a pilot study on exposure and semen quality. Int J Hyg Environ Health. 2012;215(5):502–6. https://doi.org/10.1016/j.ijheh.2011.09.005.CrossRefPubMedGoogle Scholar
- 69.Mendiola J, Jorgensen N, Andersson AM, Calafat AM, Silva MJ, Redmon JB, et al. Associations between urinary metabolites of di(2-ethylhexyl) phthalate and reproductive hormones in fertile men. Int J Androl. 2011;34(4):369–78. https://doi.org/10.1111/j.1365-2605.2010.01095.x.CrossRefPubMedGoogle Scholar
- 71.• Buck Louis GM, Sundaram R, Sweeney AM, Schisterman EF, Maisog J, Kannan K. Urinary bisphenol A, phthalates, and couple fecundity: the Longitudinal Investigation of Fertility and the Environment (LIFE) Study. Fertil Steril. 2014;101(5):1359–66. https://doi.org/10.1016/j.fertnstert.2014.01.022. The first prospective study reporting on the association between DEHP exposure and time to pregnancy.CrossRefPubMedGoogle Scholar
- 74.Joensen UN, Frederiksen H, Blomberg Jensen M, Lauritsen MP, Olesen IA, Lassen TH, et al. Phthalate excretion pattern and testicular function: a study of 881 healthy Danish men. Environ Health Perspect. 2012;120(10):1397–403. https://doi.org/10.1289/ehp.1205113.CrossRefPubMedCentralPubMedGoogle Scholar
- 76.• Axelsson J, Rylander L, Rignell-Hydbom A, Jonsson BA, Lindh CH, Giwercman A. Phthalate exposure and reproductive parameters in young men from the general Swedish population. Environ Int. 2015;85:54–60. https://doi.org/10.1016/j.envint.2015.07.005. A well performed study of the association between DEHP exposure, semen quality markers, and reproductive hormones.CrossRefPubMedGoogle Scholar
- 81.Pan G, Hanaoka T, Yoshimura M, Zhang S, Wang P, Tsukino H, et al. Decreased serum free testosterone in workers exposed to high levels of di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP): a cross-sectional study in China. Environ Health Perspect. 2006;114(11):1643–8.PubMedCentralPubMedGoogle Scholar
- 84.Fong JP, Lee FJ, Lu IS, Uang SN, Lee CC. Relationship between urinary concentrations of di(2-ethylhexyl) phthalate (DEHP) metabolites and reproductive hormones in polyvinyl chloride production workers. Occup Environ Med. 2015;72(5):346–53. https://doi.org/10.1136/oemed-2014-102532.CrossRefPubMedGoogle Scholar
- 86.Wolf C Jr, Lambright C, Mann P, Price M, Cooper RL, Ostby J, et al. Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat. Toxicol Ind Health. 1999;15(1–2):94–118. https://doi.org/10.1177/074823379901500109.CrossRefPubMedGoogle Scholar
- 87.Hallmark N, Walker M, McKinnell C, Mahood IK, Scott H, Bayne R, et al. Effects of monobutyl and di(n-butyl) phthalate in vitro on steroidogenesis and Leydig cell aggregation in fetal testis explants from the rat: comparison with effects in vivo in the fetal rat and neonatal marmoset and in vitro in the human. Environ Health Perspect. 2007;115(3):390–6. https://doi.org/10.1289/ehp.9490. CrossRefPubMedGoogle Scholar
- 88.Lambrot R, Muczynski V, Lecureuil C, Angenard G, Coffigny H, Pairault C, et al. Phthalates impair germ cell development in the human fetal testis in vitro without change in testosterone production. Environ Health Perspect. 2009;117(1):32–7. https://doi.org/10.1289/ehp.11146.CrossRefPubMedGoogle Scholar
- 91.Frederiksen H, Jorgensen N, Andersson AM. Correlations between phthalate metabolites in urine, serum, and seminal plasma from young Danish men determined by isotope dilution liquid chromatography tandem mass spectrometry. J Anal Toxicol. 2010;34(7):400–10. https://doi.org/10.1093/jat/34.7.400.CrossRefPubMedGoogle Scholar
- 102.Wogatzky J, Wirleitner B, Stecher A, Vanderzwalmen P, Neyer A, Spitzer D, et al. The combination matters—distinct impact of lifestyle factors on sperm quality: a study on semen analysis of 1683 patients according to MSOME criteria. Reprod Biol Endocrinol. 2012;10(1):115. https://doi.org/10.1186/1477-7827-10-115.CrossRefPubMedCentralPubMedGoogle Scholar