Science Selection January 2018 | Volume 126 | Issue 1
Love Song Blues: DEHP Alters Courtship Vocalizations in Mice
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Published: 17 January 2018
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Related EHP Article
Neural Mechanisms Underlying the Disruption of Male Courtship Behavior by Adult Exposure to Di(2-ethylhexyl) Phthalate in Mice
Due to its prevalence and known endocrine-disrupting properties,1,2 DEHP [di(2-ethylhexyl) phthalate] has been subject to extensive research into potential human health effects, especially related to the reproductive system.3,4 An article in Environmental Health Perspectives reports evidence that even small doses of DEHP may alter the courtship behavior of otherwise healthy adult male mice by reducing the number of androgen receptors in the brain.5 These receptors perform vital functions related to reproduction and sexuality.6
Phthalates, including DEHP, are widespread in modern life.7 About a dozen variants are commonly used worldwide to make the plastics in consumer products, packaging, and medical devices more flexible or durable.8 DEHP, by far the most common of these, represents more than a third of the global plasticizer market9 and has been detected in more than 75% of analyzed individuals in industrial countries.10,11,12
Over the years, experimental and epidemiological studies have implicated DEHP in a range of health effects,13 leading some countries, including the United States, to ban or limit its use in certain applications.14,15,16 Less is known about the chemical’s potential effects on the brain, but recent research has suggested associations between developmental exposure to DEHP and impaired neurodevelopment,17,18 behavioral problems,19 anxiety and depression,20 and altered stress responses.21
In this new experimental study, researchers from France’s National Center for Scientific Research fed healthy adult mice 0.5, 5, or 50 μg/kg/day DEHP. The highest dose corresponds to the tolerable daily intake for humans established by the European Food Safety Authority,22 while the lower two are in the range of global exposure levels documented in previous studies.23,24,25,26
After a period of 4 weeks, the researchers performed a series of tests to assess reproductive behavior in the DEHP-dosed mice and nonexposed controls. They found all three doses to be associated with altered courtship vocalizations—key to the reproductive behavior of not only mice, but also many fish, amphibian, bird, and mammal species. The two higher doses of 50 and 5 μg/kg/day also were associated with delayed initiation of mating by the male mice.
The researchers then sacrificed the mice for further study and chemical analyses. This led to the study’s second major finding, particularly in terms of potential implications for humans: Behavioral changes were associated with DEHP-induced changes in the neurons that control mating behavior. They also found that DEHP caused changes in the activity of androgen receptors in the region of the hypothalamus that controls male sexual behavior.
In a previous study, led by senior author Sakina Mhaouty-Kodja, a research director at the National Center of Scientific Research, the research team also saw mating delays after exposure to low doses of another nearly ubiquitous plastic additive, bisphenol A.27 In that case, the change was not associated with a reduction in androgen receptor expression.
Carlos Dombret, who served as lead author of the new paper while a postdoc at France’s Pierre and Marie Curie University under adviser Mhaouty-Kodja, cautions that the findings are both limited in scope and not directly translatable to humans. However, the study does contribute to an ongoing discussion on how researchers and governments view common endocrine-disrupting chemicals such as bisphenols and phthalates, Dombret says. “What was most surprising to me was seeing effects with very, very low doses,” he says—levels below regulatory reference doses and on par with global exposure estimates.
Rutgers University associate professor Emily Barrett, lead author of a 2014 epidemiological paper showing an association between environmental exposure to DEHP and lower self-reported interest in sexual activity among pregnant women,28 says the new animal experiments add an important dimension to the study of reproductive effects of DEHP and other endocrine-disrupting phthalates.
“The vast majority of interest has been in early-life exposures, and this paper is one of the relative few to look at adult exposures,” says Barrett, who was not involved in the new study. “Sometimes we have the idea that it’s only pregnant women who matter [in terms of phthalate exposures], and this paper makes the point that no, other adult exposures matter, too.”
Jay Ko, an associate professor at the University of Illinois at Urbana-Champaign who has studied the effects of DEHP on fertility in male mice,29 says he believes the researchers should have tested exposure periods of varying lengths as opposed to a single one-month window. As a result, he says, the findings should be interpreted with caution—especially when extrapolating to humans. Ko also was not involved in the study.
The study does, however, raise interesting questions about DEHP’s potential effects on the brain, an area that demands greater attention, Ko says. “I think this will be the way research is heading,” he says. “Initially [interest in DEHP] was all cancer or toxicity, but now it is heading toward the neurons. This type of a study … will be something that will really stimulate future research directions.”
Nate Seltenrich covers science and the environment from Petaluma, California. His work has appeared in High Country News, Sierra, Yale Environment 360, Earth Island Journal, and other regional and national publications.
1.National Institute of Environmental Health Sciences. 2017. Endocrine Disruptors. Durham, NC:National Institute of Environmental Health Sciences. https://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm [accessed 29 September 2017].
2.van Wezel AP, van Vlaardingen P, Posthumus R, Crommentuijn GH, Sijm DT. 2000. Environmental risk limits for two phthalates, with special emphasis on endocrine disruptive properties. Ecotoxicol Environ Saf 46(3):305–321, PMID: 10903828, 10.1006/eesa.2000.1930.
4.Singh AR, Lawrence WH, Autian J. 1974. Mutagenic and antifertility sensitivities of mice to di-2-ethylhexyl phthalate (DEHP) and dimethoxyethyl phthalate (DMEP). Toxicol Appl Pharmacol 29(1):35–46, PMID: 4283679, 10.1016/0041-008X(74)90159-8.
5.Dombret C, Capela D, Poissenot K, Parmentier C, Bergsten E, Pionneau C, et al. 2017. Neural mechanisms underlying the disruption of male courtship behavior by adult exposure to di-(2-ethylexyl)phthalate in mice. Environ Health Perspect 125(9):097001, PMID: 28934723, 10.1289/EHP1443.
6.National Institutes of Health. 2015. AR gene. Genetics Home Reference. Bethesda, MD:U.S. National Library of Medicine, National Institutes of Health. https://ghr.nlm.nih.gov/gene/AR [accessed 13 December 2017].
7.Centers for Disease Control and Prevention. 2016. Factsheet—Phthalates. Atlanta, GA:Centers for Disease Control and Prevention. https://www.cdc.gov/biomonitoring/phthalates_factsheet.html [accessed 29 September 2017].
8.American Chemistry Council. 2017. Phthalates. Washington, DC:American Chemistry Council. https://phthalates.americanchemistry.com [accessed 29 September 2017].
9.European Chemical Industry Council. 2017. Plasticisers. Brussels, Belgium:European Chemical Industry Council’s European Plasticisers Group. http://www.plasticisers.org/wp-content/uploads/2017/07/EP_Factsheet_2017_EN_FINAL.pdf [accessed 29 September 2017].
10.Woodruff TJ, Zota AR, Schwartz JM. 2011. Environmental chemicals in pregnant women in the United States: NHANES 2003–2004. Environ Health Perspect 119(6):878–885, PMID: 21233055, 10.1289/ehp.1002727.
12.Silva MJ, Barr DB, Reidy JA, Malek NA, Hodge CC, Caudill SP, et al. 2004. 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 112(3):331–338, PMID: 14998749, 10.1289/ehp.6723.
13.Zarean M, Keikha M, Poursafa P, Khalighinejad P, Amin M, Kelishadi R, et al. 2016. A systematic review on the adverse health effects of di-2-ethylhexyl phthalate. Environ Sci Pollut Res Int 23(24):24642–24693, PMID: 27714658, 10.1007/s11356-016-7648-3.
14.Wilkinson E. 2014. Warning over plastics used in treating premature babies. BBC News, 13 November 2014. http://www.bbc.com/news/health-30034760 [accessed 29 September 2017].
15.U.S. Consumer Product Safety Commission. 2015. Phthalates. Bethesda, MD:U.S. Consumer Product Safety Commission. https://www.cpsc.gov/business–manufacturing/business-education/business-guidance/phthalates-information/ [accessed 29 September 2017].
16.Health Care Without Harm. 2017. Regulation of DEHP. Reston, VA:Health Care Without Harm US. https://noharm-uscanada.org/content/europe/regulation-dehp [accessed 29 September 2017].
17.Komada M, Gendai Y, Kagawa N, Nagao T. 2016. Prenatal exposure to di(2-ethylhexyl) phthalate impairs development of the mouse neocortex. Toxicol Lett 259:69–79, PMID: 27472966, 10.1016/j.toxlet.2016.07.019.
18.Philippat C, Bennett DH, Krakowiak P, Rose M, Hwang H-M, Hertz-Picciotto I, et al. 2015. Phthalate concentrations in house dust in relation to autism spectrum disorder and developmental delay in the CHildhood Autism Risks from Genetics and the Environment (CHARGE) study. Environ Health 14:56, PMID: 26108271, 10.1186/s12940-015-0024-9.
19.Lien YJ Ku HY, Su PH, Chen SJ, Chen HY, Liao PC, et al. 2014. Prenatal exposure to phthalate esters and behavioral syndromes in children at 8 years of age: Taiwan Maternal and Infant Cohort Study. Environ Health Perspect 123(1):95–100, PMID: 25280125, 10.1289/ehp.1307154.
20.Xu X, Yang Y, Wang R, Wang Y, Ruan Q, Lu Y, et al. 2015. Perinatal exposure to di-(2-ethylhexyl) phthalate affects anxiety- and depression-like behaviors in mice. Chemosphere 124:22–31, PMID: 25441928, 10.1016/j.chemosphere.2014.10.056.
21.Quinnies KM, Doyle TJ, Kim KH, Rissman EF. 2015. Transgenerational effects of di-(2-ethylhexyl) phthalate (DEHP) on stress hormones and behavior. Endocrinology 156(9):3077–3083, PMID: 26168342, 10.1210/EN.2015-1326.
22.European Food Safety Authority, 2005. Opinion of the scientific panel on food additives, flavourings, processing aids and materials in contact with food (AFC) related to bis(2-ethylhexyl)phthalate (DEHP) for use in food contact materials. EFSA Journal 3(9):243, 10.2903/j.efsa.2005.243.
23.Martine B, Marie-Jeanne T, Cendrine D, Fabrice A, Marc C. 2013. Assessment of adult human exposure to phthalate esters in the urban centre of Paris (France). Bull Environ Contam Toxicol 90(1):91–96, PMID: 23090363, 10.1007/s00128-012-0859-5.
24.Dewalque L, Charlier C, Pirard C. 2014. Estimated daily intake and cumulative risk assessment of phthalate diesters in a Belgian general population. Toxicol Lett 231(2):161–168, PMID: 24968065, 10.1016/j.toxlet.2014.06.028.
25.Koch HM, Preuss R, Angerer J. 2006. Di(2-ethylhexyl)phthalate (DEHP): human metabolism and internal exposure—an update and latest results. Int J Androl 29(1):155–165, PMID: 16466535, 10.1111/j.1365-2605.2005.00607.x.
26.Lorber M, Angerer J, Koch HM. 2010. A simple pharmacokinetic model to characterize exposure of Americans to di-2-ethylhexyl phthalate. J Expo Sci Environ Epidemiol 20(1):38–53, PMID: 19127283, 10.1038/jes.2008.74.
27.Picot M, Naulé L, Marie-Luce C, Martini M, Raskin K, Grange-Messent V, et al. 2014. Vulnerability of the neural circuitry underlying sexual behavior to chronic adult exposure to oral bisphenol A in male mice. Endocrinology 155(2):502–512, PMID: 24265451, 10.1210/en.2013-1639.
28.Barrett ES, Parlett LE, Wang C, Drobnis EZ, Redmon JB, Swan SH, et al. 2014. Environmental exposure to di-2-ethylhexyl phthalate is associated with low interest in sexual activity in premenopausal women. Horm Behav 66(5):787–792, PMID: 25448532, 10.1016/j.yhbeh.2014.10.003.
29.Barakat R, Lin PP, Rattan S, Brehm E, Canisso IF, Abosalum ME, et al. 2017. Prenatal exposure to DEHP induces premature reproductive sensescence in male mice. Toxicol Sci 156(1):96–108, PMID: 28082598, 10.1093/toxsci/kfw248.
EHP is pleased to present the abstracts from the 29th Annual Scientific Conference of the International Society for Environmental Epidemiology (ISEE), held in Sydney, Australia, 24–28 September 2017. The conference was hosted by The University of Sydney and cosponsored by the Woolcock Institute of Medical Research, with the theme “Healthy Places, Healthy People—Where Are the Connections?”
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