Review Article Open Access

The Impact of Di-2-Ethylhexyl Phthalate (DEHP) in Focus on the Reproductive System and Toxicity in Rat or Mammalian Model

Venkataramanaiah Poli1 and Srinivasulu Reddy Motireddy1
  • 1 Department of Zoology, Faculty of Natural Sciences, Sri Venkateswara University, Tirupati, A.P.,, India

Abstract

Endocrine disruptor pollution and its effects on the human reproductive system have garnered significant interest. Di-2-Ethylhexyl Phthalate (DEHP) is a reproductive toxin and environmental endocrine disruptor. Due to their widespread use in consumer goods and flexible plastics, phthalate diesters are now common environmental pollutants. One of the many industrial and consumer products that contain environmental endocrine disruptors is DEHP. Examples of these products include toys, medical supplies, cleaning products, cosmetics, interior design, and décor materials. Since DEHP reaches the human body in large concentrations and can have an enhanced effect through biological concentration, it has gained widespread attention. In addition to changing the molecular, endocrinological, cytological, and biochemical elements of female reproduction, it also affects the structural and functional features, leading to irregularities in the ovarian cycle and infertility. The literature search was done through Scopus, ISI Web of Science, Google Scholar, PubMed, and Medline. Up until now, studies on the reproductive toxicity of DEHP exposure in adult females have been conducted. It can result in illnesses including uterine hemorrhage, sexual precocity, and infertility, which worries academics and the general public. Moreover, research on animals indicates that exposure to phthalates may alter the levels of circulating hormones, which could have a negative impact on reproductive physiology and the growth of target tissues that are susceptible to estrogen. As a result, we carried out a thorough analysis of the experimental animal and epidemiological literature to determine the connection between phthalate exposure and unfavorable results for the reproductive health of women. The epidemiological literature does not provide evidence for a conclusion that exposure to phthalates has a negative impact because it is lacking for the majority of outcomes examined, has small sample sizes, and has methodological flaws. We have come to the conclusion that there is enough data to imply that phthalates are reproductive toxicants, notwithstanding the dearth of experimental animal investigations for numerous phthalates. We do point out that the quantities required to cause harmful health consequences are higher than those seen in recent human biomonitoring studies. We suggest that additional research is necessary because of the patchwork of existing studies, the possibility of additive effects, and the indication of negative consequences of phthalate exposure in later generations at lower concentrations than in the parent generation.

References

Absalan, F., Saremy, S., Mansouri, E., Moghadam, M. T., Moghadam, A. R. E., & Razie, G. (2016). Effects of Mono-(2-Ethylhexyl) Phthalate and Di-(2-Ethylhexyl) Phthalate Administrations on Oocyte Meiotic Maturation, Apoptosis and Gene Quantification in Mouse Model. Cell Journal, 18(4), 503–513. https://doi.org/10.22074/cellj.2016.4717
Acevedo‐Rodriguez, A., Kauffman, A. S., Cherrington, B. D., Borges, C. S., Roepke, T. A., & Laconi, M. (2018). Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling. Journal of Neuroendocrinology, 30(10), e12590. https://doi.org/10.1111/jne.12590
Adibi, J. J., Hauser, R., Williams, P. L., Whyatt, R. M., Calafat, A. M., Nelson, H., Herrick, R., & Swan, S. H. (2009). Maternal Urinary Metabolites of Di-(2-Ethylhexyl) Phthalate in Relation to the Timing of Labor in a US Multicenter Pregnancy Cohort Study. American Journal of Epidemiology, 169(8), 1015–1024. https://doi.org/10.1093/aje/kwp001
Agarwal, A., Gupta, S., & Sharma, R. K. (2005). Role of oxidative stress in female reproduction. Reproductive Biology and Endocrinology, 3(1), 28. https://doi.org/10.1186/1477-7827-3-28
Akingbemi, B. T., Youker, R. T., Sottas, C. M., Ge, R., Katz, E., Klinefelter, G. R., Zirkin, B. R., & Hardy, M. P. (2001). Modulation of Rat Leydig Cell Steroidogenic Function by Di(2-Ethylhexyl)Phthalate1. Biology of Reproduction, 65(4), 1252–1259. https://doi.org/10.1095/biolreprod65.4.1252
Aksamitiene, E., Kiyatkin, A., & Kholodenko, B. N. (2012). Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance. Biochemical Society Transactions, 40(1), 139–146. https://doi.org/10.1042/bst20110609
Albert, O., & Jégou, B. (2014). A critical assessment of the endocrine susceptibility of the human testis to phthalates from fetal life to adulthood. Human Reproduction Update, 20(2), 231–249. https://doi.org/10.1093/humupd/dmt050
Aldyreva, M. V., Klimove, T. S., Iziumova, S. A., & Timofeevskaia, L. A. (1975). The effect of phthalate plasticizers on the generative function. Gigiena Truda i Professional’nye Zabolevaniia, 19(12), 25–29.
Ambe, K., Sakakibara, Y., Sakabe, A., Makino, H., Ochibe, T., & Tohkin, M. (2019). Comparison of the developmental/reproductive toxicity and hepatotoxicity of phthalate esters in rats using an open toxicity data source. The Journal of Toxicological Sciences, 44(4), 245–255. https://doi.org/10.2131/jts.44.245
Arbuckle, T. E., Davis, K., Marro, L., Fisher, M., Legrand, M., LeBlanc, A., Gaudreau, E., Foster, W. G., Choeurng, V., & Fraser, W. D. (2014). Phthalate and bisphenol A exposure among pregnant women in Canada — Results from the MIREC study. Environment International, 68, 55–65. https://doi.org/10.1016/j.envint.2014.02.010
Arcadi, F. A., Costa, C., Imperatore, C., Marchese, A., Rapisarda, A., Salemi, M., Trimarchi, G. R., & Costa, G. (1998). Oral Toxicity of Bis(2-Ethylhexyl) Phthalate During Pregnancy and Suckling in the Long–Evans Rat. Food and Chemical Toxicology, 36(11), 963–970. https://doi.org/10.1016/s0278-6915(98)00065-9
Arrigo, F., Impellitteri, F., Piccione, G., & Faggio, C. (2023). Phthalates and their effects on human health: Focus on erythrocytes and the reproductive system. Comparative Biochemistry and Physiology Part C: Toxicology and Pharmacology, 270, 109645. https://doi.org/10.1016/j.cbpc.2023.109645
ATSDR. (2022). Toxicological Profle, Di2-ethylhexyl. Agency for Toxic Substances and Disease Registry.
Ayesha, J. V., & Goswami, D. (2016). Premature Ovarian Failure: An Association with Autoimmune Diseases. Journal of Clinical and Diagnostic Research, 10(10), QC10–QC12. https://doi.org/10.7860/JCDR/2016/22027.8671
Bay, K., Main, K. M., Toppari, J., & Skakkebæk, N. E. (2011). Testicular descent: INSL3, testosterone, genes and the intrauterine milieu. Nature Reviews Urology, 8(4), 187–196. https://doi.org/10.1038/nrurol.2011.23
Botelho, G. G. K., Bufalo, A. C., Boareto, A. C., Muller, J. C., Morais, R. N., Martino-Andrade, A. J., Lemos, K. R., & Dalsenter, P. R. (2009). Vitamin C and Resveratrol Supplementation to Rat Dams Treated with Di(2-ethylhexyl)phthalate: Impact on Reproductive and Oxidative Stress End Points in Male Offspring. Archives of Environmental Contamination and Toxicology, 57(4), 785–793. https://doi.org/10.1007/s00244-009-9385-9
Bramble, M. S., Vashist, N., & Vilain, E. (2019). Sex steroid hormone modulation of neural stem cells: a critical review. Biology of Sex Differences, 10(1), 28. https://doi.org/10.1186/s13293-019-0242-x
Caldwell, J. C. (2012). DEHP: Genotoxicity and potential carcinogenic mechanisms-A review. Mutation Research/Reviews in Mutation Research, 751(2), 82–157. https://doi.org/10.1016/j.mrrev.2012.03.001
Carnevali, O., Tosti, L., Speciale, C., Peng, C., Zhu, Y., & Maradonna, F. (2010). DEHP Impairs Zebrafish Reproduction by Affecting Critical Factors in Oogenesis. PLOS ONE, 5(4), e10201. https://doi.org/10.1371/journal.pone.0010201
Casarini, L., & Crépieux, P. (2019). Molecular Mechanisms of Action of FSH. Frontiers in Endocrinology, 10, 305. https://doi.org/10.3389/fendo.2019.00305
Cheon, Y.-P. (2020). Di-(2-ethylhexyl) Phthalate (DEHP) and Uterine Histological Characteristics. Development and Reproduction, 24(1), 1–17. https://doi.org/10.12717/dr.2020.24.1.1
Chou, Y., & Tzeng, C. (2021). The impact of phthalate on reproductive function in women with endometriosis. Reproductive Medicine and Biology, 20(2), 159–168. https://doi.org/10.1002/rmb2.12364
Cirillo, T., Fasano, E., Esposito, F., Montuori, P., & Amodio Cocchieri, R. (2013). Di(2-ethylhexyl)phthalate (DEHP) and di-n-butylphthalate (DBP) exposure through diet in hospital patients. Food and Chemical Toxicology, 51, 434–438. https://doi.org/10.1016/j.fct.2012.10.015
Çoban, J., Öztezcan, S., Doğru-Abbasoğlu, S., Bingül, I., Yeşil-Mizrak, K., & Uysal, M. (2014). Olive leaf extract decreases age-induced oxidative stress in major organs of aged rats. Geriatrics & Gerontology International, 14(4), 996–1002. https://doi.org/10.1111/ggi.12192
Cobellis, L. (2003). High plasma concentrations of di-(2-ethylhexyl)-phthalate in women with endometriosis. Human Reproduction, 18(7), 1512–1515. https://doi.org/10.1093/humrep/deg254
Colon, I., Caro, D., Bourdony, C. J., & Rosario, O. (2000). Identification of Phthalate Esters in the Serum of Young Puerto Rican Girls with Premature Breast Development. Environmental Health Perspectives, 108(9), 895–900. https://doi.org/10.2307/3434999
CSTEE. (2004). Opinion on the results of a second risk assessment of bis(2-ethylhexyl) phthalate [DEHP] human health part. Adopted by the CSTEE during the 41st plenary meeting of 8 January. European Commission.
Dalsenter, P. R., Santana, G. M., Grande, S. W., Andrade, A. J., & Araújo, S. L. (2006). Phthalate affect the reproductive function and sexual behavior of male Wistar rats. Human & Experimental Toxicology, 25(6), 297–303. https://doi.org/10.1191/0960327105ht624oa
Daniel, J. W., & Bratt, H. (1974). The absorption, metabolism and tissue distribution of di(2-ethylhexyl) phthalate in rats. Toxicology, 2(1), 51–65. https://doi.org/10.1016/0300-483x(74)90042-0
David, R. M. (2000). Chronic Toxicity of Di(2-ethylhexyl)phthalate in Rats. Toxicological Sciences, 55(2), 433–443. https://doi.org/10.1093/toxsci/55.2.433
Davis, B. J., Maronpot, R. R., & Heindel, J. J. (1994). Di-(2-ethylhexyl) Phthalate Suppresses Estradiol and Ovulation in Cycling Rats. Toxicology and Applied Pharmacology, 128(2), 216–223. https://doi.org/10.1006/taap.1994.1200
Erkekoglu, P., Rachidi, W., Yuzugullu, O. G., Giray, B., Favier, A., Ozturk, M., & Hincal, F. (2010). 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. Toxicology and Applied Pharmacology, 248(1), 52–62. https://doi.org/10.1016/j.taap.2010.07.016
Fayrouz, K. (2021). Di-(2-ethylhexyl) phthalate-induced reproductive toxicity and oxidative stress in male rabbits. Journal of Research in Environmental Science and Toxicology, 10(2), 1–2.
FDA. (2003). Safety Assessment of Di(2-ethylhexyl)phthalate (DEHP) Released from PVC Medical Devices. U.S. Food and Drug Administration.
Ferguson, K. K., McElrath, T. F., & Meeker, J. D. (2014). Environmental Phthalate Exposure and Preterm Birth. JAMA Pediatrics, 168(1), 61–67. https://doi.org/10.1001/jamapediatrics.2013.3699
Foster, P. M. D., Mylchreest, E., Gaido, K. W., & Sar, M. (2001). Effects of phthalate esters on the developing reproductive tract of male rats. APMIS, 109(S103), S272–S277. https://doi.org/10.1111/j.1600-0463.2001.tb05776.x
Gallicchio, L., Miller, S., Greene, T., Zacur, H., & Flaws, JA. (2009). Premature ovarian failure among hairdressers. Human Reproduction, 24(10), 2636–2641. https://doi.org/10.1093/humrep/dep252
Ge, R.-S., Dong, Q., Sottas, C. M., Latif, S. A., Morris, D. J., & Hardy, M. P. (2005). Stimulation of testosterone production in rat Leydig cells by aldosterone is mineralocorticoid receptor mediated. Molecular and Cellular Endocrinology, 243(1–2), 35–42. https://doi.org/10.1016/j.mce.2005.08.004
Ghosh, A., Tripathy, A., & Ghosh, D. (2022). Impact of Endocrine Disrupting Chemicals (EDCs) on Reproductive Health of Human. Proceedings of the Zoological Society, 75(1), 16–30. https://doi.org/10.1007/s12595-021-00412-3
Giguère, V. (2002). To ERR in the estrogen pathway. Trends in Endocrinology and Metabolism, 13(5), 220–225. https://doi.org/10.1016/S1043-2760(02)00592-1
Golestanzadeh, M., Riahi, R., & Kelishadi, R. (2020). Association of phthalate exposure with precocious and delayed pubertal timing in girls and boys: a systematic review and meta-analysis. Environmental Science: Processes & Impacts, 22(4), 873–894. https://doi.org/10.1039/c9em00512a
Grande, S. W., Andrade, A. J. M., Talsness, C. E., Grote, K., & Chahoud, I. (2006). A Dose-Response Study Following In Utero and Lactational Exposure to Di(2-ethylhexyl)phthalate: Effects on Female Rat Reproductive Development. Toxicological Sciences, 91(1), 247–254. https://doi.org/10.1093/toxsci/kfj128
Grande, S. W., Andrade, A. J. M., Talsness, C. E., Grote, K., Golombiewski, A., Sterner-Kock, A., & Chahoud, I. (2007). A dose–response study following in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP): Reproductive effects on adult female offspring rats. Toxicology, 229(1–2), 114–122. https://doi.org/10.1016/j.tox.2006.10.005
Gray, L. E. (2000). Perinatal Exposure to the Phthalates DEHP, BBP, and DINP, but Not DEP, DMP, or DOTP, Alters Sexual Differentiation of the Male Rat. Toxicological Sciences, 58(2), 350–365. https://doi.org/10.1093/toxsci/58.2.350
Gray, L. E., Barlow, N. J., Howdeshell, K. L., Ostby, J. S., Furr, J. R., & Gray, C. L. (2009). Transgenerational Effects of Di (2-Ethylhexyl) Phthalate in the Male CRL:CD(SD) Rat: Added Value of Assessing Multiple Offspring per Litter. Toxicological Sciences, 110(2), 411–425. https://doi.org/10.1093/toxsci/kfp109
Gray, L. E., Wolf, C., Lambright, C., Mann, P., Price, M., Cooper, R. L., & Ostby, J. (1999). 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. Toxicology and Industrial Health, 15(1–2), 94–118. https://doi.org/10.1177/074823379901500109
Grynnerup, A. G., Lindhard, A., & Sørensen, S. (2012). The role of anti‐Müllerian hormone in female fertility and infertility – an overview. Acta Obstetricia et Gynecologica Scandinavica, 91(11), 1252–1260. https://doi.org/10.1111/j.1600-0412.2012.01471.x
Gupta, R. K., Singh, J. M., Leslie, T. C., Meachum, S., Flaws, J. A., & Yao, H. H.-C. (2010). Di-(2-ethylhexyl) phthalate and mono-(2-ethylhexyl) phthalate inhibit growth and reduce estradiol levels of antral follicles in vitro. Toxicology and Applied Pharmacology, 242(2), 224–230. https://doi.org/10.1016/j.taap.2009.10.011
Hammond, G. L. (2016). Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action. Journal of Endocrinology, 230(1), R13–R25. https://doi.org/10.1530/joe-16-0070
Hannon, P. R., Brannick, K. E., Wang, W., & Flaws, J. A. (2015). Mono(2-Ethylhexyl) Phthalate Accelerates Early Folliculogenesis and Inhibits Steroidogenesis in Cultured Mouse Whole Ovaries and Antral Follicles1. Biology of Reproduction, 92(5), 1–11. https://doi.org/10.1095/biolreprod.115.129148
Hannon, P. R., Brannick, K. E., Wang, W., Gupta, R. K., & Flaws, J. A. (2015). Di(2-ethylhexyl) phthalate inhibits antral follicle growth, induces atresia, and inhibits steroid hormone production in cultured mouse antral follicles. Toxicology and Applied Pharmacology, 284(1), 42–53. https://doi.org/10.1016/j.taap.2015.02.010
Hannon, P. R., & Flaws, J. A. (2015). The effects of phthalates on the ovary. Frontiers in Endocrinology, 6(8). https://doi.org/10.3389/fendo.2015.00008
Hannon, P. R., Peretz, J., & Flaws, J. A. (2014). Daily Exposure to Di(2-ethylhexyl) Phthalate Alters Estrous Cyclicity and Accelerates Primordial Follicle Recruitment Potentially Via Dysregulation of the Phosphatidylinositol 3-Kinase Signaling Pathway in Adult Mice1. Biology of Reproduction, 90(6), 1–11. https://doi.org/10.1095/biolreprod.114.119032
Harter, C. J. L., Kavanagh, G. S., & Smith, J. T. (2018). The role of kisspeptin neurons in reproduction and metabolism. Journal of Endocrinology, 238(3), R173–R183. https://doi.org/10.1530/joe-18-0108
Heindel, R. J., & Chapin, R. E. (1989). Inhibition of FSH-stimulated cAMP accumulation by mono(2-ethylhexyl) phthalate in primary rat sertoli cell cultures. Toxicology and Applied Pharmacology, 97(2), 377–385. https://doi.org/10.1016/0041-008x(89)90342-6
Heinlein, C. A., & Chang, C. (2002). The Roles of Androgen Receptors and Androgen-Binding Proteins in Nongenomic Androgen Actions. Molecular Endocrinology, 16(10), 2181–2187. https://doi.org/10.1210/me.2002-0070
Herreros, M. A., Gonzalez-Bulnes, A., Iñigo-Nuñez, S., Letelier, C., Contreras-Solis, I., Ros-Rodriguez, J. M., & Encinas, T. (2010). Pregnancy-associated changes in plasma concentration of the endocrine disruptor di(2-ethylhexyl) phthalate in a sheep model. Theriogenology, 73(2), 141–146. https://doi.org/10.1016/j.theriogenology.2009.07.029
Hirosawa, N., Yano, K., Suzuki, Y., & Sakamoto, Y. (2006). Endocrine disrupting effect of di-(2-ethylhexyl)phthalate on female rats and proteome analyses of their pituitaries. Proteomics, 6(3), 958–971. https://doi.org/10.1002/pmic.200401344
Hoyer, P. B. (2001). Reproductive toxicology: current and future directions. Biochemical Pharmacology, 62(12), 1557–1564. https://doi.org/10.1016/S0006-2952(01)00814-0
IARC. (2018). Monographs on the Evaluation of Carcinogenic Risks to Humans. Some Industrial Chemicals, 77, 41–148.
Ikeda, G. J., Sapienza, P. P., Couvillion, J. L., & Farber, T. M. (1980). Comparative distribution, excretion and metabolism of di-(2-ethylhexyl) phthalate in rats, dogs and miniature pigs. Food and Cosmetics Toxicology, 18(6), 637–642. https://doi.org/10.1016/s0015-6264(80)80012-5
Ito, Y., & Nakajima, T. (2008). PPARα- and DEHP-Induced Cancers. PPAR Research, 2008, 759716. https://doi.org/10.1155/2008/759716
Jankowska, K. (2017). Premature ovarian failure. Przeglad Menopauzalny, 16(2), 51–56. https://doi.org/10.5114/pm.2017.68592
Jones, R. E., & Lopez, K. H. (2006). Endocrinology, Brain and Pituitary Gland. In Human Reproductive Biology (3rd ed., pp. 3–29). Academic Press. https://doi.org/10.1016/B978-0-08-050836-8.50005-6
Kalo, D., Hadas, R., Furman, O., Ben-Ari, J., Maor, Y., Patterson, D. G., Tomey, C., & Roth, Z. (2015). Carryover Effects of Acute DEHP Exposure on Ovarian Function and Oocyte Developmental Competence in Lactating Cows. PLOS ONE, 10(7), e0130896. https://doi.org/10.1371/journal.pone.0130896
Kamińska, A., Pardyak, L., Marek, S., Wróbel, K., Kotula‐Balak, M., Bilińska, B., & Hejmej, A. (2020). Notch signaling regulates nuclear androgen receptor AR and membrane androgen receptor ZIP9 in mouse Sertoli cells. Andrology, 8(2), 457–472. https://doi.org/10.1111/andr.12691
Kariyazono, Y., Taura, J., Hattori, Y., Ishii, Y., Narimatsu, S., Fujimura, M., Takeda, T., & Yamada, H. (2015). Effect of in utero exposure to endocrine disruptors on fetal steroidogenesis governed by the pituitary-gonad axis: a study in rats using different ways of administration. The Journal of Toxicological Sciences, 40(6), 909–916. https://doi.org/10.2131/jts.40.909
Kasahara, E., Sato, E. F., Miyoshi, M., Konaka, R., Hiramoto, K., Sasaki, J., Tokuda, M., Nakano, Y., & Inoue, M. (2002). Role of oxidative stress in germ cell apoptosis induced by di(2-ethylhexyl)phthalate. Biochemical Journal, 365(3), 849–856. https://doi.org/10.1042/bj20020254
Kaul, A. F., Souney, P. F., & Osathanondh, R. (1982). A Review of Possible Toxicity of DI-2-Ethylhexylphthalate (DEHP) in Plastic Intravenous Containers: Effects on Reproduction. Drug Intelligence & Clinical Pharmacy, 16(9), 689–692. https://doi.org/10.1177/106002808201600908
Kavlock, R., Barr, D., Boekelheide, K., Breslin, W., Breysse, P., Chapin, R., Gaido, K., Hodgson, E., Marcus, M., Shea, Katherine, & Williams, P. (2006). NTP-CERHR Expert Panel Update on the Reproductive and Developmental Toxicity of Di(2-ethylhexyl) phthalate. Reproductive Toxicology, 22(3), 291–399. https://doi.org/10.1016/j.reprotox.2006.04.007
Kavlock, R., Boekelheide, K., Chapin, R., Cunningham, M., Faustman, E., Foster, P., Golub, M., Henderson, R., Hinberg, I., Little, R., Seed, J., Shea, K., Tabacova, S., Tyl, R., Williams, P., & Zacharewski, T. (2002). NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di(2-ethylhexyl) phthalate. Reproductive Toxicology, 16(5), 529–653. https://doi.org/10.1016/s0890-6238(02)00032-1
Kimber, I., & Dearman, R. J. (2010). An assessment of the ability of phthalates to influence immune and allergic responses. Toxicology, 271(3), 73–82. https://doi.org/10.1016/j.tox.2010.03.020
Klimisch, H.-J., Gamer, A. O., Hellwig, J., Kaufmann, W., & Jäckh, R. (1992). Di-(2-ethylhexyl) phthalate: A short-term repeated inhalation toxicity study including fertility assessment. Food and Chemical Toxicology, 30(11), 915–919. https://doi.org/10.1016/0278-6915(92)90175-k
Knapczyk-Stwora, K., Grzesiak, M., Ciereszko, R. E., Czaja, E., Koziorowski, M., & Slomczynska, M. (2018). The impact of sex steroid agonists and antagonists on folliculogenesis in the neonatal porcine ovary via cell proliferation and apoptosis. Theriogenology, 113, 19–26. https://doi.org/10.1016/j.theriogenology.2018.02.008
Koch, H. M., Preuss, R., & Angerer, J. (2006). Di(2-ethylhexyl)phthalate (DEHP): human metabolism and internal exposure – an update and latest results1. International Journal of Andrology, 29(1), 155–165. https://doi.org/10.1111/j.1365-2605.2005.00607.x
Kotula-Balak, M., Pawlicki, P., Milon, A., Tworzydlo, W., Sekula, M., Pacwa, A., Gorowska-Wojtowicz, E., Bilinska, B., Pawlicka, B., Wiater, J., Zarzycka, M., & Galas, J. (2018). The role of G-protein-coupled membrane estrogen receptor in mouse Leydig cell function—in vivo and in vitro evaluation. Cell and Tissue Research, 374(2), 389–412. https://doi.org/10.1007/s00441-018-2861-7
Kurahashi, N., Kondo, T., Omura, M., Umemura, T., Ma, M., & Kishi, R. (2005). The Effects of Subacute Inhalation of Di (2‐ethylhexyl) Phthalate (DEHP) on the Testes of Prepubertal Wistar Rats. Journal of Occupational Health, 47(5), 437–444. https://doi.org/10.1539/joh.47.437
Kurata, M., Leon, R. T., & DesRoches, R. (2012). Rapid Seismic Rehabilitation Strategy: Concept and Testing of Cable Bracing with Couples Resisting Damper. Journal of Structural Engineering, 138(3), 354–362. https://doi.org/10.1061/(asce)st.1943-541x.0000401
Laskey, J. W., & Berman, E. (1993). Steroidogenic assessment using ovary culture in cycling rats: Effects of bis (2-diethylhexyl) phthalate on ovarian steroid production. Reproductive Toxicology, 7(1), 25–33. https://doi.org/10.1016/0890-6238(93)90006-s
Latini, G., De Felice, C., Presta, G., Del Vecchio, A., Paris, I., Ruggieri, F., & Mazzeo, P. (2003). In utero exposure to di-(2-ethylhexyl)phthalate and duration of human pregnancy. Environmental Health Perspectives, 111(14), 1783–1785. https://doi.org/10.1289/ehp.6202
Latini, G., Verrotti, A., & De Felice, C. (2004). DI-2-Ethylhexyl Phthalate and Endocrine Disruption: A Review. Current Drug Targets - Immune, Endocrine & Metabolic Disorders, 4(1), 37–40. https://doi.org/10.2174/1568008043340017
Lee, E. J., Bajracharya, P., Jang, E. J., Chang, J. S., Lee, H. J., Hong, S. K., & Choi, I. (2010). Effect of Sex Steroid Hormones on Bovine Myogenic Satellite Cell Proliferation, Differentiation and Lipid Accumulation in Myotube. Asian-Australasian Journal of Animal Sciences, 23(5), 649–658. https://doi.org/10.5713/ajas.2010.90227
Li, L., Liu, J.-C., Lai, F.-N., Liu, H.-Q., Zhang, X.-F., Dyce, P. W., Shen, W., & Chen, H. (2016). Di (2-ethylhexyl) Phthalate Exposure Impairs Growth of Antral Follicle in Mice. PLOS ONE, 11(2), e0148350. https://doi.org/10.1371/journal.pone.0148350
Li, L., Liu, J.-C., Zhao, Y., Lai, F.-N., Yang, F., Ge, W., Dou, C.-L., Shen, W., Zhang, X.-F., & Chen, H. (2015). Impact of diethylhexyl phthalate on gene expression and development of mammary glands of pregnant mouse. Histochemistry and Cell Biology, 144(4), 389–402. https://doi.org/10.1007/s00418-015-1348-9
Li, N., Zhou, L., Zhu, J., Liu, T., & Ye, L. (2020). Role of the 17β-hydroxysteroid dehydrogenase signalling pathway in di-(2-ethylhexyl) phthalate-induced ovarian dysfunction: An in vivo study. Science of The Total Environment, 712, 134406. https://doi.org/10.1016/j.scitotenv.2019.134406
Li, S.-W., How, C. M., & Liao, V. H.-C. (2018). Prolonged exposure of di(2-ethylhexyl) phthalate induces multigenerational toxic effects in Caenorhabditis elegans. Science of The Total Environment, 634, 260–266. https://doi.org/10.1016/j.scitotenv.2018.03.355
Liang, C.-C., Lee, T.-H., & Chang, S.-D. (2013). Effects of sex hormones on cell proliferation and apoptosis in the urinary bladder muscle of ovariectomized rat. Taiwanese Journal of Obstetrics and Gynecology, 52(3), 335–340. https://doi.org/10.1016/j.tjog.2012.11.003
Liao, K.-W., Kuo, P.-L., Huang, H.-B., Chang, J.-W., Chiang, H.-C., & Huang, P.-C. (2018). Increased risk of phthalates exposure for recurrent pregnancy loss in reproductive-aged women. Environmental Pollution, 241, 969–977. https://doi.org/10.1016/j.envpol.2018.06.022
Liu, J.-C., Lai, F.-N., Li, L., Sun, X.-F., Cheng, S.-F., Ge, W., Wang, Y.-F., Li, L., Zhang, X.-F., De Felici, M., Dyce, P. W., & Shen, W. (2017). Di (2-ethylhexyl) phthalate exposure impairs meiotic progression and DNA damage repair in fetal mouse oocytes in vitro. Cell Death and Disease, 8(8), e2966. https://doi.org/10.1038/cddis.2017.350
Liu, J.-C., Xing, C.-H., Xu, Y., Pan, Z.-N., Zhang, H.-L., Zhang, Y., & Sun, S.-C. (2021). DEHP exposure to lactating mice affects ovarian hormone production and antral follicle development of offspring. Journal of Hazardous Materials, 416, 125862. https://doi.org/10.1016/j.jhazmat.2021.125862
Liu, K., Zou, C., & Qin, B. (2017). The association between nuclear receptors and ocular diseases. Oncotarget, 8(16), 27603–27615. https://doi.org/10.18632/oncotarget.15178
Liu, T., Jia, Y., Zhou, L., Wang, Q., Sun, D., Xu, J., Wu, J., Chen, H., Xu, F., & Ye, L. (2016). Effects of Di-(2-ethylhexyl) Phthalate on the Hypothalamus–Uterus in Pubertal Female Rats. International Journal of Environmental Research and Public Health, 13(11), 1130. https://doi.org/10.3390/ijerph13111130
Liu, T., Li, N., Zhu, J., Yu, G., Guo, K., Zhou, L., Zheng, D., Qu, X., Huang, J., Chen, X., Wang, S., & Ye, L. (2014). Effects of di-(2-ethylhexyl) phthalate on the hypothalamus-pituitary-ovarian axis in adult female rats. Reproductive Toxicology, 46, 141–147. https://doi.org/10.1016/j.reprotox.2014.03.006
Lovekamp, T. N., & Davis, B. J. (2001). Mono-(2-ethylhexyl) Phthalate Suppresses Aromatase Transcript Levels and Estradiol Production in Cultured Rat Granulosa Cells. Toxicology and Applied Pharmacology, 172(3), 217–224. https://doi.org/10.1006/taap.2001.9156
Lovekamp-Swan, T., & Davis, B. J. (2003). Mechanisms of phthalate ester toxicity in the female reproductive system. Environmental Health Perspectives, 111(2), 139–145. https://doi.org/10.1289/ehp.5658
Lu, Z., Zhang, C., Han, C., An, Q., Cheng, Y., Chen, Y., Meng, R., Zhang, Y., & Su, J. (2019). Plasticizer Bis(2-ethylhexyl) Phthalate Causes Meiosis Defects and Decreases Fertilization Ability of Mouse Oocytes in Vivo. Journal of Agricultural and Food Chemistry, 67(12), 3459–3468. https://doi.org/10.1021/acs.jafc.9b00121
Luo, J., & Liu, D. (2020). Does GPER Really Function as a G Protein-Coupled Estrogen Receptor in vivo? Frontiers in Endocrinology, 11, 148. https://doi.org/10.3389/fendo.2020.00148
Ma, M., Kondo, T., Ban, S., Umemura, T., Kurahashi, N., Takeda, M., & Kishi, R. (2006). Exposure of Prepubertal Female Rats to Inhaled Di(2-ethylhexyl)phthalate Affects the Onset of Puberty and Postpubertal Reproductive Functions. Toxicological Sciences, 93(1), 164–171. https://doi.org/10.1093/toxsci/kfl036
Martinez-Arguelles, D. B., Culty, M., Zirkin, B. R., & Papadopoulos, V. (2009). In Utero Exposure to Di-(2-Ethylhexyl) Phthalate Decreases Mineralocorticoid Receptor Expression in the Adult Testis. Endocrinology, 150(12), 5575–5585. https://doi.org/10.1210/en.2009-0847
Martinez-Arguelles, D. B., Guichard, T., Culty, M., Zirkin, B. R., & Papadopoulos, V. (2011). In Utero Exposure to the Antiandrogen Di-(2-Ethylhexyl) Phthalate Decreases Adrenal Aldosterone Production in the Adult Rat1. Biology of Reproduction, 85(1), 51–61. https://doi.org/10.1095/biolreprod.110.089920
Martinez–Arguelles, D. B., McIntosh, M., Rohlicek, C. V., Culty, M., Zirkin, B. R., & Papadopoulos, V. (2013). Maternal in utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate affects the blood pressure of adult male offspring. Toxicology and Applied Pharmacology, 266(1), 95–100. https://doi.org/10.1016/j.taap.2012.10.027
Mastorakos, G., Karoutsou, E. I., Mizamtsidi, M., & Creatsas, G. (2007). The menace of endocrine disruptors on thyroid hormone physiology and their impact on intrauterine development. Endocrine, 31(3), 219–237. https://doi.org/10.1007/s12020-007-0030-y
Meltzer, D., Martinez–Arguelles, D. B., Campioli, E., Lee, S., & Papadopoulos, V. (2015). In utero exposure to the endocrine disruptor di(2-ethylhexyl) phthalate targets ovarian theca cells and steroidogenesis in the adult female rat. Reproductive Toxicology, 51, 47–56. https://doi.org/10.1016/j.reprotox.2014.12.005
Mes, J., Coffin, D. E., & Campbell, D. S. (1974). Di-n-butyl-and Di-2-ethylhexyl phthalate in human adipose tissue. Bulletin of Environmental Contamination and Toxicology, 12(6), 721–725. https://doi.org/10.1007/bf01685921
Messerlian, C., Souter, I., Gaskins, A. J., Williams, P. L., Ford, J. B., Chiu, Y.-H., Calafat, A. M., & Hauser, R. (2016). Urinary phthalate metabolites and ovarian reserve among women seeking infertility care. Human Reproduction, 31(1), 75–83. https://doi.org/10.1093/humrep/dev292
Messerlian, C., Wylie, B. J., Mínguez-Alarcón, L., Williams, P. L., Ford, J. B., Souter, I. C., Calafat, A. M., & Hauser, R. (2016). Urinary Concentrations of Phthalate Metabolites and Pregnancy Loss Among Women Conceiving with Medically Assisted Reproduction. Epidemiology, 27(6), 879–888. https://doi.org/10.1097/ede.0000000000000525
Miller, W. L., & Auchus, R. J. (2011). The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders. Endocrine Reviews, 32(1), 81–151. https://doi.org/10.1210/er.2010-0013
Mirihagalle, S., You, T., Suh, L., Patel, C., Gao, L., Rattan, S., & Qiao, H. (2019). Prenatal exposure to di-(2-ethylhexyl) phthalate and high-fat diet synergistically disrupts mouse fetal oogenesis and affects folliculogenesis†. Biology of Reproduction, 100(6), 1561–1570. https://doi.org/10.1093/biolre/ioz051
Momeni, H. R. (2011). Role of calpain in apoptosis. Cell Journal, 13(2), 65–72.
Moore, R. W., Rudy, T. A., Lin, T. M., Ko, K., & Peterson, R. E. (2001). Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate. Environmental Health Perspectives, 109(3), 229–237. https://doi.org/10.1289/ehp.01109229
Moyer, B., & Hixon, M. L. (2012). Reproductive effects in F1 adult females exposed in utero to moderate to high doses of mono-2-ethylhexylphthalate (MEHP). Reproductive Toxicology, 34(1), 43–50. https://doi.org/10.1016/j.reprotox.2012.02.006
Navarrete, F. A., García-Vázquez, F. A., Alvau, A., Escoffier, J., Krapf, D., Sánchez-Cárdenas, C., Salicioni, A. M., Darszon, A., & Visconti, P. E. (2015). Biphasic Role of Calcium in Mouse Sperm Capacitation Signaling Pathways. Journal of Cellular Physiology, 230(8), 1758–1769. https://doi.org/10.1002/jcp.24873
Nohynek, G. J., Borgert, C. J., Dietrich, D., & Rozman, K. K. (2013). Endocrine disruption: Fact or urban legend? Toxicology Letters, 223(3), 295–305. https://doi.org/10.1016/j.toxlet.2013.10.022
North, M. L., Takaro, T. K., Diamond, M. L., & Ellis, A. K. (2014). Effects of phthalates on the development and expression of allergic disease and asthma. Annals of Allergy, Asthma and Immunology, 112(6), 496–502. https://doi.org/10.1016/j.anai.2014.03.013
Park, J. D., Habeebu, S. S. M., & Klaassen, C. D. (2002). Testicular toxicity of di-(2-ethylhexyl)phthalate in young Sprague–Dawley rats. Toxicology, 171(2–3), 105–115. https://doi.org/10.1016/s0300-483x(01)00567-4
Patiño-García, D., Cruz-Fernandes, L., Buñay, J., Palomino, J., & Moreno, R. D. (2018). Reproductive Alterations in Chronically Exposed Female Mice to Environmentally Relevant Doses of a Mixture of Phthalates and Alkylphenols. Endocrinology, 159(2), 1050–1061. https://doi.org/10.1210/en.2017-00614
Peters, J. M., Taubeneck, M. W., Keen, C. L., & Gonzalez, F. J. (1997). Di(2‐Ethylhexyl) phthalate induces a functional zinc deficiency during pregnancy and teratogenesis that is independent of peroxisome proliferator‐activated receptor‐α. Teratology, 56(5), 311–316. https://doi.org/10.1002/(SICI)1096-9926(199711)56:5<311::AID-TERA4>3.0.CO;2-%23
Piferrer, F. (2013). Epigenetics of sex determination and gonadogenesis. Developmental Dynamics, 242(4), 360–370. https://doi.org/10.1002/dvdy.23924
Pinkas, A., Gonçalves, C. L., & Aschner, M. (2017). Neurotoxicity of fragrance compounds: A review. Environmental Research, 158, 342–349. https://doi.org/10.1016/j.envres.2017.06.035
Plotnikov, A., Zehorai, E., Procaccia, S., & Seger, R. (2011). The MAPK cascades: Signaling components, nuclear roles and mechanisms of nuclear translocation. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1813(9), 1619–1633. https://doi.org/10.1016/j.bbamcr.2010.12.012
Pocar, P., Fiandanese, N., Secchi, C., Berrini, A., Fischer, B., Schmidt, J. S., Schaedlich, K., & Borromeo, V. (2012). Exposure to Di(2-ethyl-hexyl) phthalate (DEHP) in Utero and during Lactation Causes Long-Term Pituitary-Gonadal Axis Disruption in Male and Female Mouse Offspring. Endocrinology, 153(2), 937–948. https://doi.org/10.1210/en.2011-1450
Podda, M. V., & Grassi, C. (2014). New perspectives in cyclic nucleotide-mediated functions in the CNS: the emerging role of cyclic nucleotide-gated (CNG) channels. Pflügers Archiv - European Journal of Physiology, 466(7), 1241–1257. https://doi.org/10.1007/s00424-013-1373-2
Puzianowska-Kuznicka, M., Pawlik-Pachucka, E., Owczarz, M., Budzińska, M., & Polosak, J. (2013). Small-Molecule Hormones: Molecular Mechanisms of Action. International Journal of Endocrinology, 2013, 1–21. https://doi.org/10.1155/2013/601246
Rhodes, C., Orton, T. C., Pratt, I. S., Batten, P. L., Bratt, H., Jackson, S. J., & Elcombe, C. R. (1986). Comparative Pharmacokinetics and Subacute Toxicity of Di(2-Ethylhexyl) Phthalate (DEHP) in Rats and Marmosets: Extrapolation of Effects in Rodents to Man. Environmental Health Perspectives, 65, 299–207. https://doi.org/10.2307/3430197
Rusyn, I., & Corton, J. C. (2012). Mechanistic considerations for human relevance of cancer hazard of di(2-ethylhexyl) phthalate. Mutation Research/Reviews in Mutation Research, 750(2), 141–158. https://doi.org/10.1016/j.mrrev.2011.12.004
Sai Sandeep, S. R., & Jiaxiang, C. (2018). Toxic Effects of Di-2-ethylhexyl Phthalate: An Overview. BioMed Research International, 2018, 1750368. https://doi.org/10.1155/2018/1750368
Sands, P., & Galizzi, P. (2006). Communication from the Commission of 2 February 2000 on the precautionary principle (COM (2000) 12.02.2000 p. 1). In Documents in European Community Environmental Law (pp. 90–115). Cambridge University Press. https://doi.org/10.1017/cbo9780511610851.008
Schmidt, J.-S., Schaedlich, K., Fiandanese, N., Pocar, P., & Fischer, B. (2012). Effects of Di(2-ethylhexyl) Phthalate (DEHP) on Female Fertility and Adipogenesis in C3H/N Mice. Environmental Health Perspectives, 120(8), 1123–1129. https://doi.org/10.1289/ehp.1104016
Sever, R., & Glass, C. K. (2013). Signaling by Nuclear Receptors. Cold Spring Harbor Perspectives in Biology, 5(3), a016709. https://doi.org/10.1101/cshperspect.a016709
Sharpe, R. M. (2001). Hormones and testis development and the possible adverse effects of environmental chemicals. Toxicology Letters, 120(1–3), 221–232. https://doi.org/10.1016/s0378-4274(01)00298-3
Sheikh, I. A., Turki, R. F., Abuzenadah, A. M., Damanhouri, G. A., & Beg, M. A. (2016). Endocrine Disruption: Computational Perspectives on Human Sex Hormone-Binding Globulin and Phthalate Plasticizers. PLOS ONE, 11(3), e0151444. https://doi.org/10.1371/journal.pone.0151444
Shoaito, H., Petit, J., Chissey, A., Auzeil, N., Guibourdenche, J., Gil, S., Laprévote, O., Fournier, T., & Degrelle, S. A. (2019). The Role of Peroxisome Proliferator–Activated Receptor Gamma (PPARγ) in Mono(2-ethylhexyl) Phthalate (MEHP)-Mediated Cytotrophoblast Differentiation. Environmental Health Perspectives, 127(2), 027003. https://doi.org/10.1289/ehp3730
Soltysik, K., & Czekaj, P. (2013). Membrane estrogen receptors-Is it an alternative way of estrogen action? Journal of Physiology and Pharmacology, 64(2), 129–142.
Somasundaram, D. B., Selvanesan, B. C., Ramachandran, I., & Bhaskaran, R. S. (2016). Lactational Exposure to Di (2-ethylhexyl) Phthalate Impairs the Ovarian and Uterine Function of Adult Offspring Rat. Reproductive Sciences, 23(4), 549–559. https://doi.org/10.1177/1933719115607995
Somboonporn, W., & Davis, S. R. (2004). Testosterone Effects on the Breast: Implications for Testosterone Therapy for Women. Endocrine Reviews, 25(3), 374–388. https://doi.org/10.1210/er.2003-0016
Südhof, T. C. (2012). Calcium control of neurotransmitter release. Cold Spring Harbor Perspectives in Biology, 4(1), a011353. https://doi.org/10.1101/cshperspect.a011353
Svechnikova, I., Svechnikov, K., & Söder, O. (2007). The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats. Journal of Endocrinology, 194(3), 603–609. https://doi.org/10.1677/joe-07-0238
Thomas, J. A., Thomas, M. J., & Gangolli, S. D. (1984). Biological Effects of DI-(2-Ethylhexyl) Phthalate and Other Phthalic Acid Esters. CRC Critical Reviews in Toxicology, 13(4), 283–317. https://doi.org/10.3109/10408448409023761
Thompson, E. B. (1994). Apoptosis and steroid hormones. Molecular Endocrinology, 8(6), 665–673. https://doi.org/10.1210/mend.8.6.7935482
Tickner, J. A., Schettler, T., Guidotti, T., McCally, M., & Rossi, M. (2001). Health risks posed by use of Di‐2‐ethylhexyl phthalate (DEHP) in PVC medical devices: A critical review. American Journal of Industrial Medicine, 39(1), 100–111. https://doi.org/10.1002/1097-0274(200101)39:1<100::aid-ajim10>3.3.co;2-h
Toft, G., Jönsson, B. A. G., Lindh, C. H., Jensen, T. K., Hjollund, N. H., Vested, A., & Bonde, J. P. (2012). Association between Pregnancy Loss and Urinary Phthalate Levels around the Time of Conception. Environmental Health Perspectives, 120(3), 458–463. https://doi.org/10.1289/ehp.1103552
Vabre, P., Gatimel, N., Moreau, J., Gayrard, V., Picard-Hagen, N., Parinaud, J., & Leandri, R. D. (2017). Environmental pollutants, a possible etiology for premature ovarian insufficiency: a narrative review of animal and human data. Environmental Health, 16(1), 37. https://doi.org/10.1186/s12940-017-0242-4
Valadez-Cosmes, P., Vázquez-Martínez, E. R., Cerbón, M., & Camacho-Arroyo, I. (2016). Membrane progesterone receptors in reproduction and cancer. Molecular and Cellular Endocrinology, 434, 166–175. https://doi.org/10.1016/j.mce.2016.06.027
Ventrice, P., Ventrice, D., Russo, E., & De Sarro, G. (2013). Phthalates: European regulation, chemistry, pharmacokinetic and related toxicity. Environmental Toxicology and Pharmacology, 36(1), 88–96. https://doi.org/10.1016/j.etap.2013.03.014
Wakabayashi, T. (2015). Mechanism of the calcium-regulation of muscle contraction — In pursuit of its structural basis —. Proceedings of the Japan Academy, Series B, 91(7), 321–350. https://doi.org/10.2183/pjab.91.321
Wallin, R. F., Klamer, B., Nicora, R. W., & Thompson, C. R. (1974). Di (2-ethylhexyl) phthalate (DEHP) metabolism in animals and post-transfusion tissue levels in man. Bulletin of the Parenteral Drug Association, 28(6), 278–287.
Wang, W., Craig, Z. R., Basavarajappa, M. S., Gupta, R. K., & Flaws, J. A. (2012). Di (2-ethylhexyl) phthalate inhibits growth of mouse ovarian antral follicles through an oxidative stress pathway. Toxicology and Applied Pharmacology, 258(2), 288–295. https://doi.org/10.1016/j.taap.2011.11.008
Wang, W., Craig, Z. R., Basavarajappa, M. S., Hafner, K. S., & Flaws, J. A. (2012). Mono-(2-Ethylhexyl) Phthalate Induces Oxidative Stress and Inhibits Growth of Mouse Ovarian Antral Follicles1. Biology of Reproduction, 87(6), 1–10. https://doi.org/10.1095/biolreprod.112.102467
Wang, Y., & Qian, H. (2021). Phthalates and Their Impacts on Human Health. Healthcare, 9(5), 603. https://doi.org/10.3390/healthcare9050603
Wensing, M., Uhde, E., & Salthammer, T. (2005). Plastics additives in the indoor environment—flame retardants and plasticizers. Science of The Total Environment, 339(1–3), 19–40. https://doi.org/10.1016/j.scitotenv.2004.10.028
WHO. (1992). Diethylhexyl phthalate; EHC 131. World Health Organization.
Wierman, M. E. (2007). Sex steroid effects at target tissues: mechanisms of action. Advances in Physiology Education, 31(1), 26–33. https://doi.org/10.1152/advan.00086.2006
Williams, C. J. (2002). Signalling mechanisms of mammalian oocyte activation. Human Reproduction Update, 8(4), 313–321. https://doi.org/10.1093/humupd/8.4.313
Williams, R., Timmis, J., & Qwarnstrom, E. (2014). Computational Models of the NF-KB Signalling Pathway. Computation, 2(4), 131–158. https://doi.org/10.3390/computation2040131
Wójtowicz, A. K., Sitarz-Głownia, A. M., Szczęsna, M., & Szychowski, K. A. (2019). The Action of Di-(2-Ethylhexyl) Phthalate (DEHP) in Mouse Cerebral Cells Involves an Impairment in Aryl Hydrocarbon Receptor (AhR) Signaling. Neurotoxicity Research, 35(1), 183–195. https://doi.org/10.1007/s12640-018-9946-7
Wolfe, G., Layton, K., Nehrebecky, L., Wang, Y., Chapin, R., Rousselle, S., & Bishop, J. (2002). Reproductive effects of diethylhexylphthalate (DEHP) in Sprague-Dawley rats when assessed by the continuous breeding protocol. The Toxicologist, 66(1-S), 234.
Xu, R., Mao, B., Li, S., Liu, J., Li, X., Li, H., Su, Y., Hu, G., Lian, Q.-Q., & Ge, R.-S. (2016). Structure-activity relationships of phthalates in inhibition of human placental 3β-hydroxysteroid dehydrogenase 1 and aromatase. Reproductive Toxicology, 61, 151–161. https://doi.org/10.1016/j.reprotox.2016.04.004
Yi, H., Gu, H., Zhou, T., Chen, Y., Wang, G., Jin, Y., Yuan, W., Zhao, H., & Zhang, L. (2016). A pilot study on association between phthalate exposure and missed miscarriage. European Review for Medical and Pharmacological Sciences, 20(9), 1894–1902.
Yin, J., Liu, R., Jian, Z., Yang, D., Pu, Y., Yin, L., & Wang, D. (2018). Di (2-ethylhexyl) phthalate-induced reproductive toxicity involved in dna damage-dependent oocyte apoptosis and oxidative stress in Caenorhabditis elegans. Ecotoxicology and Environmental Safety, 163, 298–306. https://doi.org/10.1016/j.ecoenv.2018.07.066
Yu, Z., Han, Y., Shen, R., Huang, K., Xu, Y., Wang, Q., Zhou, S., Xu, D., & Tao, F. (2018). Gestational di-(2-ethylhexyl) phthalate exposure causes fetal intrauterine growth restriction through disturbing placental thyroid hormone receptor signaling. Toxicology Letters, 294, 1–10. https://doi.org/10.1016/j.toxlet.2018.05.013
Zhang, L., Liu, J., Liu, H., Wan, G., & Zhang, S. (2015). The occurrence and ecological risk assessment of phthalate esters (PAEs) in urban aquatic environments of China. Ecotoxicology, 24(5), 967–984. https://doi.org/10.1007/s10646-015-1446-4
Zhang, T., Li, L., Qin, X., Zhou, Y., Zhang, X., Wang, L., De Felici, M., Chen, H., Qin, G., & Shen, W. (2014). Di‐(2‐ethylhexyl) phthalate and bisphenol A exposure impairs mouse primordial follicle assembly in vitro. Environmental and Molecular Mutagenesis, 55(4), 343–353. https://doi.org/10.1002/em.21847
Zhang, T., Shen, W., De Felici, M., & Zhang, X. (2016). Di(2‐ethylhexyl)phthalate: Adverse effects on folliculogenesis that cannot be neglected. Environmental and Molecular Mutagenesis, 57(8), 579–588. https://doi.org/10.1002/em.22037
Zhang, X., Zhang, L., Li, L., Feng, Y., Chen, B., Ma, J., Huynh, E., Shi, Q., De Felici, M., & Shen, W. (2013). Diethylhexyl phthalate exposure impairs follicular development and affects oocyte maturation in the mouse. Environmental and Molecular Mutagenesis, 54(5), 354–361. https://doi.org/10.1002/em.21776
Zhang, X.-F., Zhang, T., Wang, L., Zhang, H.-Y., Chen, Y.-D., Qin, X.-S., Feng, Y.-M., Feng, Y.-N., Shen, W., & Li, L. (2013). Effects of diethylhexyl phthalate (DEHP) given neonatally on spermatogenesis of mice. Molecular Biology Reports, 40(11), 6509–6517. https://doi.org/10.1007/s11033-013-2769-y
Zhou, C., Gao, L., & Flaws, J. A. (2017). Prenatal exposure to an environmentally relevant phthalate mixture disrupts reproduction in F1 female mice. Toxicology and Applied Pharmacology, 318, 49–57. https://doi.org/10.1016/j.taap.2017.01.010
Zong, T., Lai, L., Hu, J., Guo, M., Li, M., Zhang, L., Zhong, C., Yang, B., Wu, L., Zhang, D., Tang, M., & Kuang, H. (2015). Maternal exposure to di-(2-ethylhexyl) phthalate disrupts placental growth and development in pregnant mice. Journal of Hazardous Materials, 297, 25–33. https://doi.org/10.1016/j.jhazmat.2015.04.065

American Journal of Pharmacology and Toxicology
Volume 19 No. 1, 2024, 1-26

DOI: https://doi.org/10.3844/ajptsp.2024.1.26

Submitted On: 2 March 2024 Published On: 6 June 2024

How to Cite: Poli, V. & Motireddy, S. R. (2024). The Impact of Di-2-Ethylhexyl Phthalate (DEHP) in Focus on the Reproductive System and Toxicity in Rat or Mammalian Model. American Journal of Pharmacology and Toxicology, 19(1), 1-26. https://doi.org/10.3844/ajptsp.2024.1.26

  • 1,683 Views
  • 778 Downloads
  • 0 Citations

Download

Keywords

  • Plasticisers
  • Di-2-Ethylhexyl Phthalate (DEHP)
  • Endocrine Disruptor
  • Fertility
  • Reproductive System
  • Toxicity