Abstract
Di (2-ethyl-hexyl) phthalate (DEHP) mainly enters the human body through the digestive tract, respiratory tract, and skin. At the same time, it has reproductive and developmental toxicity, neurotoxicity, and so on, which can cause the decrease of sperm motility. Asthenospermia is also known as low sperm motility, and the semen quality of men in some areas of China is declining year by year. Interestingly, previous studies have shown that sleep disorders can also lead to asthenospermia. However, the relationship between sleep, DEHP, and asthenospermia is still unclear. Analysis of the National Health and Nutrition Examination Survey (NHANES) population database showed that DEHP was associated with sleep disorders, and subsequent experiments in mice and Drosophila indicated that DEHP exposure had certain effects on sleep and asthenospermia. Furthermore, we analyzed the Comparative Toxicogenomics Database (CTD) to find out the common signaling pathway among the three: hypoxia-inducible factor 1(HIF-1). Then Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) was used to screen out the proteins that DEHP affected the HIF-1 pathway: glyceraldehyde-3-phosphate dehydrogenase (GAPDH), serine/threonine-protein kinase (AKT1), epidermal growth factor receptor (EGFR), and finally Western blot analysis was used to detect the expression levels of the three proteins. Compared with the control group, DEHP decreased the protein expression levels of GAPDH and AKT1 in the HIF-1 pathway, and caused sleep disorders and decreased sperm motility. This study provides preliminary evidence for exploring the mechanism among DEHP, sleep disorders, and asthenospermia.
Graphical Abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
The data are available from the corresponding author on reasonable request.
References
Agin A, Blanc F, Bousiges O, Villette C, Philippi N, Demuynck C, Martin-Hunyadi C, Cretin B, Lang S, Zumsteg J, Namer IJ, Heintz D (2020) Environmental exposure to phthalates and dementia with Lewy bodies: contribution of metabolomics. J Neurol Neurosurg Psychiatry 91(9):968–974. https://doi.org/10.1136/jnnp-2020-322815
Albadari N, Deng S, Li W (2019) The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy. Expert Opin Drug Discovery 14(7):667–682. https://doi.org/10.1080/17460441.2019.1613370
Barakat R, Seymore T, Lin PP, Park CJ, Ko CJ (2019) Prenatal exposure to an environmentally relevant phthalate mixture disrupts testicular steroidogenesis in adult male mice. Environ Res 172:194–201. https://doi.org/10.1016/j.envres.2019.02.017
Chang WH, Herianto S, Lee CC, Hung H, Chen HL (2021) The effects of phthalate ester exposure on human health: a review. Sci Total Environ 786:147371. https://doi.org/10.1016/j.scitotenv.2021.147371
Colvonen PJ, Straus LD, Stepnowsky C, McCarthy MJ, Goldstein LA, Norman SB (2018) Recent advancements in treating sleep disorders in co-occurring PTSD. Curr Psychiatry Rep 20(7):48. https://doi.org/10.1007/s11920-018-0916-9
Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, Haugen TB, Kruger T, Wang C, Mbizvo MT, Vogelsong KM (2010) World Health Organization reference values for human semen characteristics. Hum Reprod Update 16(3):231–245. https://doi.org/10.1093/humupd/dmp048
Cornett K, Puderbaugh A, Back O, Craven R (2022) GAPDH in neuroblastoma: functions in metabolism and survival. Front Oncol 12:979683. https://doi.org/10.3389/fonc.2022.979683
Den Braver-Sewradj SP, Piersma A, Hessel EVS (2020) An update on the hazard of and exposure to diethyl hexyl phthalate (DEHP) alternatives used in medical devices. Crit Rev Toxicol 50(8):650–672. https://doi.org/10.1080/10408444.2020.1816896
Dzierzewski JM, Sabet SM, Ghose SM, Perez E, Soto P, Ravyts SG, Dautovich ND (2021) Lifestyle factors and sleep health across the lifespan. Int J Environ Res Public Health 18(12):6626. https://doi.org/10.3390/ijerph18126626
Erythropel HC, Maric M, Nicell JA, Leask RL, Yargeau V (2014) Leaching of the plasticizer di(2-ethylhexyl) phthalate (DEHP) from plastic containers and the question of human exposure. Appl Microbiol Biotechnol 98(24):9967–9981. https://doi.org/10.1007/s00253-014-6183-8
Fantus RJ, Packiam VT, Wang CH, Erickson BA, Helfand BT (2018) The relationship between sleep disorders and lower urinary tract symptoms: results from the NHANES. J Urol 200(1):161–166. https://doi.org/10.1016/j.juro.2018.01.083
Fu H, Zhu X, Di Q, Sun J, Jiang Q, Xu Q (2023) m6A contributes to a pro-survival state in GC-2 cells by facilitating DNA damage repair: novel perspectives on the mechanism underlying DEHP genotoxicity in male germ cells. Sci Total Environ 859(Pt 2):160432. https://doi.org/10.1016/j.scitotenv.2022.160432
Gabryelska A, Sochal M, Turkiewicz S, Białasiewicz P (2020) Relationship between HIF-1 and circadian clock proteins in obstructive sleep apnea patients-preliminary study. J Clin Med 9(5):1599. https://doi.org/10.3390/jcm9051599
Ginsberg G, Ginsberg J, Foos B (2016) Approaches to children’s exposure assessment: case study with diethylhexylphthalate (DEHP). Int J Environ Res Public Health 13(7):670. https://doi.org/10.3390/ijerph13070670
Hsu PC, Kuo YT, Leon Guo Y, Chen JR, Tsai SS, Chao HR, Teng YN, Pan MH (2016) The adverse effects of low-dose exposure to y(2-ethylhexyl) phthalate during adolescence on sperm function in adult rats. Environ Toxicol 31(6):706–712. https://doi.org/10.1002/tox.22083
Kamrin MA (2009) Phthalate risks, phthalate regulation, and public health: a review. J Toxicol Environ Health - B: Crit Rev 12(2):157–174. https://doi.org/10.1080/10937400902729226
Khan WAA, Conduit R, Kennedy GA, Jackson ML (2020) The relationship between shift-work, sleep, and mental health among paramedics in Australia. Sleep Health 6(3):330–337. https://doi.org/10.1016/j.sleh.2019.12.002
Khasin LG, Della Rosa J, Petersen N, Moeller J, Kriegsfeld LJ, Lishko PV (2020) The impact of di-2-ethylhexyl phthalate on sperm fertility. Front Cell Dev Biol 8:426. https://doi.org/10.3389/fcell.2020.00426
Korbecki J, Simińska D, Gąssowska-Dobrowolska M, Listos J, Gutowska I, Chlubek D, Baranowska-Bosiacka I (2021) Chronic and cycling hypoxia: drivers of cancer chronic inflammation through HIF-1 and NF-κB activation: a review of the molecular mechanisms. Int J Mol Sci 22(19):10701. https://doi.org/10.3390/ijms221910701
Lateef OM, Akintubosun MO (2020) Sleep and reproductive health. J Circadian Rhythms 18:1. https://doi.org/10.5334/jcr.190
Li X, Wang X, Wu Q, Guo R, Leng X, Du Q, Pan B, Zhao Y (2022) Short total sleep duration and poor sleep quality might be associated with asthenozoospermia risk: a case-control study. Front Physiol 13:959009. https://doi.org/10.3389/fphys.2022.959009
Lin J, Cheng S, Zhang J, Yuan S, Zhang L, Wu J, Chen J, Tang M, Zhao L, Yin Y (2022) The relationship between daily dietary intake of fiber and short sleep duration in the presence of di(2-ethylhexyl) phthalate: a population-based study. Front Nutr 9:910892. https://doi.org/10.3389/fnut.2022.910892
Liu G, Gong P, Bernstein LR, Bi Y, Gong S, Cai L (2007) Apoptotic cell death induced by low-dose radiation in male germ cells: hormesis and adaptation. Crit Rev Toxicol 37(7):587–605. https://doi.org/10.1080/10408440701493061
Liu J, Dai Y, Li Y, Yuan E, Wang Q, Wang X, Guan Y (2020) A longitudinal study of semen quality among Chinese sperm donor candidates during the past 11 years. Sci Rep 10(1):10771. https://doi.org/10.1038/s41598-020-67707-x
Lu WC, Omari R, Ray H, Wang J, Williams I, Jacobs C, Hockaden N, Bochman ML, Carpenter RL (2022) AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation. FEBS J 289(13):3876–3893. https://doi.org/10.1111/febs.16375
Luo Y, Li XN, Zhao Y, Du ZH, Li JL (2019) DEHP triggers cerebral mitochondrial dysfunction and oxidative stress in quail (Coturnix japonica) via modulating mitochondrial dynamics and biogenesis and activating Nrf2-mediated defense response. Chemosphere 224:626–633. https://doi.org/10.1016/j.chemosphere.2019.02.142
McGettrick AF, O'Neill LAJ (2020) The role of HIF in immunity and inflammation. Cell Metab 32(4):524–536. https://doi.org/10.1016/j.cmet.2020.08.002
Moniruzzaman M, Ghosal I, Das D, Chakraborty SB (2018) Melatonin ameliorates HO-induced oxidative stress through modulation of Erk/Akt/NFkB pathway. Biol Res 51(1):17. https://doi.org/10.1186/s40659-018-0168-522
Nakajima H, Itakura M, Kubo T, Kaneshige A, Harada N, Izawa T, Azuma YT, Kuwamura M, Yamaji R, Takeuchi T (2017) Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) aggregation causes mitochondrial dysfunction during oxidative stress-induced cell death. J Biol Chem 292(11):4727–4742. https://doi.org/10.1074/jbc.M116.759084
O'Byrne NA, Yuen F, Niaz W, Liu PY (2021) Sleep and the testis. Curr Opin Endocr Metab Res 18:83–93. https://doi.org/10.1016/j.coemr.2021.03.002
Okosun IS, Annor FB, Seale JP, Eriksen MP (2014) Abdominal adiposity and family income-to-poverty ratio in American women. Obes Res Clin Pract 8(3):e201–e298. https://doi.org/10.1016/j.orcp.2012.12.002
Pavlova KM, Latreille V (2019) Sleep disorders. Am J Med 132(3):292–299. https://doi.org/10.1016/j.amjmed.2018.09.021
Prados J, Stenz L, Somm E, Stouder C, Dayer A, Paoloni-Giacobino A (2015) Prenatal exposure to DEHP affects spermatogenesis and sperm DNA methylation in a strain-dependent manner. PLoS One 10(7):e0132136. https://doi.org/10.1371/journal.pone.0132136
Rahman HH, Niemann D, Yusuf KK (2022) Association of urinary arsenic and sleep disorder in the US population: NHANES 2015-2016. Environ Sci Pollut Res Int 29(4):5496–5504. https://doi.org/10.1007/s11356-021-16085-6
Rowdhwal SSS, Chen J (2018) Toxic effects of di-2-ethylhexyl phthalate: an overview. Biomed Res Int 2018:1750368. https://doi.org/10.1155/2018/1750368
Sabbah DA, Hajjo R, Sweidan K (2020) Review on epidermal growth factor receptor (EGFR) structure, signaling pathways, interactions, and recent updates of EGFR inhibitors. Curr Top Med Chem 20(10):815–834. https://doi.org/10.2174/1568026620666200303123102
Sampson J, de Korte D (2011) DEHP-plasticised PVC: relevance to blood services. Transfus Med (Oxford, England) 21(2):73–83. https://doi.org/10.1111/j.1365-3148.2010.01056.x
Scinicariello F, Buser MC, Feroe AG, Attanasio R (2017) Antimony and sleep-related disorders: NHANES 2005-2008. Environ Res 156:247–252. https://doi.org/10.1016/j.envres.2017.03.036
Shahrokhi SZ, Salehi P, Alyasin A, Taghiyar S, Deemeh MR (2020) Asthenozoospermia: cellular and molecular contributing factors and treatment strategies. Andrologia 52(2):e13463. https://doi.org/10.1111/and.13463
Sun SY, Chen GH (2022) Treatment of circadian rhythm sleep-wake disorders. Curr Neuropharmacol 20(6):1022–1034. https://doi.org/10.2174/1570159X19666210907122933
Wang X, Chen Q, Zou P, Liu T, Mo M, Yang H, Zhou N, Sun L, Chen H, Ling X, Peng K, Ao L, Yang H, Cao J, Cui Z (2018) Sleep duration is associated with sperm chromatin integrity among young men in Chongqing, China. J Sleep Res 27(4):e12615. https://doi.org/10.1111/jsr.12615
Wang Y, Chen Q, Liu K, Wang X, Yang H, Zhou N, Ao L, Liu J, Cao J (2021) Sleep behavior is associated with over two-fold decrease of sperm count in a chronotype-specific pattern: path analysis of 667 young men in the MARHCS study. Chronobiol Int 38(6):871–882. https://doi.org/10.1080/07420528.2021.1896534
Win-Shwe TT, Yanagisawa R, Koike E, Nitta H, Takano H (2013) Expression levels of neuroimmune biomarkers in hypothalamus of allergic mice after phthalate exposure. J Appl Toxicol 33(10):1070–1078. https://doi.org/10.1002/jat.2835
Wu M, Xu L, Teng C, Xiao X, Hu W, Chen J, Tu W (2019) Involvement of oxidative stress in di-2-ethylhexyl phthalate (DEHP)-induced apoptosis of mouse NE-4C neural stem cells. Neurotoxicology 70:41–47. https://doi.org/10.1016/j.neuro.2018.10.013
Wu X, Liu S, Wen L, Tan Y, Zeng H, Liang H, Weng X, Wu Y, Yao H, Fu Y, Yang Z, Li Y, Chen Q, Zeng Z, Fei Q, Wang R, Jing C (2023) Association between phthalates and sleep problems in the U.S. adult females from NHANES 2011-2014. Int J Environ Health Res:1–16. Advance online publication. https://doi.org/10.1080/09603123.2023.2196056
Wu Y, Wang J, Zhao T, Chen J, Kang L, Wei Y, Han L, Shen L, Long C, Wu S, Wei G (2022) Di-(2-ethylhexyl) phthalate exposure leads to ferroptosis via the HIF-1α/HO-1 signaling pathway in mouse testes. J Hazard Mater 426:127807. https://doi.org/10.1016/j.jhazmat.2021.127807
XueXia L, YaNan L, Zi T, YuSheng Z, ZeLin W, Peng Z, MeiNa X, FuJun L (2023) Di-2-ethylhexyl phthalate (DEHP) exposure induces sperm quality and functional defects in mice. Chemosphere 312(Pt 1):137216. https://doi.org/10.1016/j.chemosphere.2022.137216
Zamora AN, Peterson KE, Téllez-Rojo MM, Song PXK, Meeker JD, Cantoral A, Goodrich JM, Dolinoy DC, Jansen EC (2023) Urinary phthalates, phenols, and parabens in relation to sleep health markers among a cohort of Mexican adolescents. Sci Total Environ 861:160651. https://doi.org/10.1016/j.scitotenv.2022.160651
Zhang C, Wang Z, Chen R, Wang S, Zhang H, Ma S, Hua Z (2022) Transcriptomic and proteomic characteristics of the di(2-ethylhexyl) phthalate-induced sperm dna damage mouse model. Hum Exp Toxicol 41:9603271221139444. https://doi.org/10.1177/09603271221139444
Zhao M, Tuo H, Wang S, Zhao L (2020) The effects of dietary nutrition on sleep and sleep disorders. Mediat Inflamm 2020:3142874. https://doi.org/10.1155/2020/3142874
Zhao Y, Li XN, Zhang H, Cui JG, Wang JX, Chen MS, Li JL (2022) Phthalate-induced testosterone/androgen receptor pathway disorder on spermatogenesis and antagonism of lycopene. J Hazard Mater 439:129689. https://doi.org/10.1016/j.jhazmat.2022.129689
Acknowledgements
We extend our sincere gratitude to Wenwen Wang from the Cancer Center of Zhejiang University for her guidance in bioinformatics, along with other study participants.
Funding
This work was supported by the National Natural Science Foundation of China [82073593], the Scientific Research Projects in Colleges and Universities of Anhui Education Department [KJ2019A0281 and KJ2020A0666], Domestic Visiting and Training Project for Excellent Young Key Teachers of Colleges and Universities [gxgnfx2020115], Research level improvement program of Anhui Medical University[2021xkjT010], National College Students Innovation and Entrepreneurship Project [202210366028], and National College Students Innovation and Entrepreneurship Project [S202310366113].
Author information
Authors and Affiliations
Contributions
Xiao-lu Li: project administration, investigation, formal analysis, writing—original draft, and writing—editing. Xiao-yue Cai: project administration, investigation, formal analysis, and writing—review. Xia Ning: methodology, visualization, and writing—review. Yue-yue Liang: methodology. Yun Hong: methodology. Qi-meng Li: methodology. Die Hu: methodology. Yuan-zhuo Zheng: methodology. Yang Cai: methodology. Wenwen Wang: methodology. Tao Xu: conceptualization, project administration, supervision, and funding acquisition. Ling-li Zhao: conceptualization, project administration, writing—review and editing, supervision, and funding acquisition.
Corresponding author
Ethics declarations
Ethical approval
This work has received approval for research ethics from Anhui Medical University and a certificate of approval is available upon request (20170394, LLSC20200694).
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Responsible Editor: Lotfi Aleya
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplemental information
Supplementary file 1
Eight-week-old ICR male mice were treated with DEHP (0 and 500 mg/kg/ day) by oral gavage for 35 days, and sperm motility in the cauda epididymidis was measured using a sperm motility analyzer. The video is a sperm motility video of the tail of the mouse epididymis.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Li, Xl., Cai, Xy., Ning, X. et al. Role of sleep in asthenospermia induced by di (2-ethyl-hexyl) phthalate. Environ Sci Pollut Res 31, 13965–13980 (2024). https://doi.org/10.1007/s11356-024-32030-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-024-32030-9