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Choline, not folate, can attenuate the teratogenic effects ofdibutyl phthalate (DBP) during early chick embryo development

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Abstract

Dibutyl phthalate (DBP), a persistent environmental pollutant, can induce neural tube abnormal development in animals. The possible effects of DBP exposure on human neural tube defects (NTDs) remain elusive. In this study, the distribution of DBP in the body fluid of human NTDs was detected by GC-MS. Then, chick embryos were used to investigate the effects of DBP on early embryonic development. Oxidative stress indicators in chick embryos and the body fluid of human NTDs were detected by ELISA. The cell apoptosis and total reactive oxygen species (ROS) level in chick embryos were detected by whole-mount TUNEL and oxidized DCFDA, respectively. The study found that the detection ratio of positive DBP and its metabolites in maternal urine was higher in the NTD population than that in normal controls. 8-hydroxy-2 deoxyguanosine (8-OHDG) and malondialdehyde (MDA) were evidently upregulated and superoxide dismutase (SOD) was observably downregulated in amniotic fluid and urine. Animal experiments indicated that DBP treatment induced developmental toxicity in chick embryos by enhancing the levels of oxidative stress and cell apoptosis. MDA was increased and SOD was decreased in DBP-treated embryos. Interestingly, the supplement of high-dose choline (100 μg/μL), not folic acid, could partially restore the teratogenic effects of DBP. Our data collectively suggest that the incidence of NTDs is closely associated with DBP exposure. This study may provide new insight for NTD prevention.

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References

  • Adiguzel ACTIAE (2004) Shell-less culture of the chick embryo as a model system in the study of developmental neurobiology. Neuroanatomy 3:8–11

    Google Scholar 

  • Afshari A, Gunnarsen L, Clausen PA, Hansen V (2004) Emission of phthalates from PVC and other materials. Indoor Air 14:120–128

    Article  CAS  Google Scholar 

  • Ait Bamai Y, Araki A, Kawai T, Tsuboi T, Saito I, Yoshioka E, Cong S, Kishi R (2016) Exposure to phthalates in house dust and associated allergies in children aged 6-12 years. Environ Int 96:16–23

    Article  CAS  Google Scholar 

  • Aly HA, Hassan MH, El-Beshbishy HA et al (2016) Dibutyl phthalate induces oxidative stress and impairs spermatogenesis in adult rat. Toxicol Ind Health 32:1467–1477

    Article  CAS  Google Scholar 

  • Brill A, Torchinsky A, Carp H, Toder V (1999) The role of apoptosis in normal and abnormal embryonic development. J Assist Reprod Genet 16:512–519

    Article  CAS  Google Scholar 

  • Buttke TM, Sandstrom PA (1994) Oxidative stress as a mediator of apoptosis. Immunol Today 15:7–10

    Article  CAS  Google Scholar 

  • Cetinkal A, Colak A, Topuz K, Demircan MN, Simsek H, Berber U, Umur AS, Selcuki M, Vatansever HS (2010) The effects of meloxicam on neural tube development in the early stage of chick embryos. Turk Neurosurg 20:111–116

    Google Scholar 

  • Chang TI, Horal M, Jain SK, Wang F, Patel R, Loeken MR (2003) Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects. Diabetologia 46:538–545

    Article  CAS  Google Scholar 

  • Chu DP, Tian S, Sun DG, Hao CJ, Xia HF, Ma X (2013) Exposure to mono-n-butyl phthalate disrupts the development of preimplantation embryos. Reprod Fertil Dev 25:1174–1184

    Article  CAS  Google Scholar 

  • Cohen JJ (1993) Apoptosis. Immunol Today 14:126–130

    Article  CAS  Google Scholar 

  • Czeizel AE (2000) Primary prevention of neural-tube defects and some other major congenital abnormalities: recommendations for the appropriate use of folic acid during pregnancy. Paediatr Drugs 2:437–449

    Article  CAS  Google Scholar 

  • Du ZH, Xia J, Sun XC et al (2017) A novel nuclear xenobiotic receptors (AhR/PXR/CAR)-mediated mechanism of DEHP-induced cerebellar toxicity in quails (Coturnix japonica) via disrupting CYP enzyme system homeostasis. Environ Pollut 226:435–443

    Article  CAS  Google Scholar 

  • Ema M, Miyawaki E (2001) Adverse effects on development of the reproductive system in male offspring of rats given monobutyl phthalate, a metabolite of dibutyl phthalate, during late pregnancy. Reprod Toxicol 15:189–194

    Article  CAS  Google Scholar 

  • Ema M, Amano H, Itami T et al (1993) Teratogenic evaluation of di-n-butyl phthalate in rats. Toxicol Lett 69:197–203

    Article  CAS  Google Scholar 

  • Ema M, Harazono A, Miyawaki E, Ogawa Y (1997) Developmental effects of di-n-butyl phthalate after a single administration in rats. J Appl Toxicol 17:223–229

    Article  CAS  Google Scholar 

  • Ertekin T, Bilir A, Aslan E, Koca B, Turamanlar O, Ertekin A, Albay S (2019) The effect of diclofenac sodium on neural tube development in the early stage of chick embryos. Send to. Folia Morphol (Warsz) 78:307–313

    Article  CAS  Google Scholar 

  • Gray TJ, Rowland IR, Foster PM et al (1982) Species differences in the testicular toxicity of phthalate esters. Toxicol Lett 11:141–147

    Article  CAS  Google Scholar 

  • Hamburger V, Hamilton HL (1992) A series of normal stages in the development of the chick embryo. 1951. Dev Dyn 195:231–272

    Article  CAS  Google Scholar 

  • Jiang X, Yan J, West AA, Perry CA, Malysheva OV, Devapatla S, Pressman E, Vermeylen F, Caudill MA (2012) Maternal choline intake alters the epigenetic state of fetal cortisol-regulating genes in humans. FASEB J 26:3563–3574

    Article  CAS  Google Scholar 

  • Kao T-T, Chu C-Y, Lee G-H, Hsiao T-H, Cheng N-W, Chang N-S, Chen B-H, Fu T-F (2014) Folate deficiency-induced oxidative stress contributes to neuropathy in young and aged zebrafish — implication in neural tube defects and Alzheimer’s diseases. Neurobiol Dis 71:234–244

    Article  CAS  Google Scholar 

  • Kovacheva VP, Mellott TJ, Davison JM, Wagner N, Lopez-Coviella I, Schnitzler AC, Blusztajn JK (2007) Gestational choline deficiency causes global and igf2 gene DNA hypermethylation by up-regulation ofdnmt1 expression. J Biol Chem 282:31777–31788

    Article  CAS  Google Scholar 

  • Lee W, Cho JH, Lee Y, Lee S, Kim DH, Ha S, Kondo Y, Ishigami A, Chung HY, Lee J (2019) Dibutyl phthalate impairs neural progenitor cell proliferation and hippocampal neurogenesis. Food Chem Toxicol 129:239–248

    Article  CAS  Google Scholar 

  • Li PC, Li XN, Du ZH et al (2018) Di (2-ethyl hexyl) phthalate (DEHP)-induced kidney injury in quail (Coturnix japonica) via inhibiting HSF1/HSF3-dependent heat shock response. Chemosphere 209:981–988

    Article  CAS  Google Scholar 

  • Li Y, Lu J, Yin X, Liu Z, Tong Y, Zhou L (2019) Indoor phthalate concentrations in residences in Shihezi, China: implications for preschool children's exposure and risk assessment. Environ Sci Pollut Res Int 26:19785–19794. https://doi.org/10.1007/s11356-019-05335-3

    Article  CAS  Google Scholar 

  • Liao Y, Zhang Y, He L, Wang J, Liu X, Zhang N, Xu B (2016) Temporal and spatial analysis of neural tube defects and detection of geographical factors in Shanxi Province, China. PLoS One 11:e0150332

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • Ma WL, Subedi B, Kannan K (2014) The occurrence of bisphenol A, phthalates, parabens and other environmental phenolic compounds in house dust: a review. Curr Org Chem 18:2182–2199

    Article  CAS  Google Scholar 

  • Maltzman W, Czyzyk L (1984) UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Mol Cell Biol 4:1689–1694

    Article  CAS  Google Scholar 

  • Mazumdar M, Ibne Hasan MO, Hamid R et al (2015) Arsenic is associated with reduced effect of folic acid in myelomeningocele prevention: a case control study in Bangladesh. Environ Health 14:34

    Article  CAS  Google Scholar 

  • Mehta AK, Arora N, Gaur SN, Singh BP (2009) Choline supplementation reduces oxidative stress in mouse model of allergic airway disease. Eur J Clin Investig 39:934–941

    Article  CAS  Google Scholar 

  • Memon S, Pratten MK (2009) Developmental toxicity of ethanol in chick heart in ovo and in micromass culture can be prevented by addition of vitamin C and folic acid. Reprod Toxicol 28:262–269

    Article  CAS  Google Scholar 

  • Niculescu MD, Craciunescu CN, Zeisel SH (2006) Dietary choline deficiency alters global and gene- specific DNA methylation in the developing hippocampus of mouse fetal brains. FASEB J 20:43–49

    Article  CAS  Google Scholar 

  • Rasmussen LM, Sen N, Vera JC, Liu X, Craig ZR (2017) Effects of in vitro exposure to dibutyl phthalate, mono-butyl phthalate, and acetyl tributyl citrate on ovarian antral follicle growth and viability. Biol Reprod 96:1105–1117

    Article  Google Scholar 

  • Rosenquist TH, Ratashak SA, Selhub J (1996) Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc Natl Acad Sci U S A 93:15227–15232

    Article  CAS  Google Scholar 

  • Russell JW, Golovoy D, Vincent AM et al (2002) High glucose-induced oxidative stress and mitochondrial dysfunction in neurons. FASEB J 16:1738–1748

    Article  CAS  Google Scholar 

  • Saillenfait AM, Langonné I, Leheup B (2001) Effects of mono-n-butyl phthalate on the development of rat embryos: in vivo and in vitro observations. Pharmacol Toxicol 89:104–112

    Article  CAS  Google Scholar 

  • Schecter A, Lorber M, Guo Y, Wu Q, Yun SH, Kannan K, Hommel M, Imran N, Hynan LS, Cheng D, Colacino JA, Birnbaum LS (2013) Phthalate concentrations and dietary exposure from food purchased in New York State. Environ Health Perspect 121:473–494

    Article  Google Scholar 

  • Schwartzman RA, Cidlowski JA (1993) Endocr Rev 14:133–151

    CAS  Google Scholar 

  • Shaw GM, Finnell RH, Blom HJ, Carmichael SL, Vollset SE, Yang W, Ueland PM (2009) Choline and risk of neural tube defects in a folate-fortified population. Epidemiology 20:714–719

    Article  Google Scholar 

  • Shiota K, Nishimura H (1982) Teratogenicity of di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) in mice. Environ Health Perspect 45:65–70

    Article  CAS  Google Scholar 

  • Siman CM, Eriksson UJ (1997) Vitamin C supplementation of the maternal diet reduces the rate of malformation in the offspring of diabetic rats. Diabetologia 40:1416–1424

    Article  CAS  Google Scholar 

  • Song G, Cui Y, Han ZJ, Xia HF, Ma X (2012) Effects of choline on sodium arsenite-induced neural tube defects in chick embryos. Food Chem Toxicol 50:4364–4474

    Article  CAS  Google Scholar 

  • Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, Mao CS, Redmon JB, Ternand CL, Sullivan S, Teague JL, the Study for Future Families Research Team (2005) Study for future families research team. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect 113:1056–1061

    Article  CAS  Google Scholar 

  • Swartz MD, Cai Y, Chan W, Symanski E, Mitchell LE, Danysh HE, Langlois PH, Lupo PJ (2015) Air toxics and birth defects: a Bayesian hierarchical approach to evaluate multiple pollutants and spina bifida. Environ Health 14:16

    Article  CAS  Google Scholar 

  • Takeda K, Matsuzawa A, Nishitoh H, Ichijo H (2003) Roles of MAPKKK ASK1 in stress-induced cell death. Cell Struct Funct 28:23–29

    Article  CAS  Google Scholar 

  • Temiz C, Temiz P, Demirel A, Sayın M, Umur AS, Özer FD (2009) Effect of sodium phenytoin concentration on neural tube development in the early stages of chicken embryo development. J Clin Neurosci 16:307–311

    Article  CAS  Google Scholar 

  • Uranga RM, Giusto NM, Salvador GA (2009) Iron-induced oxidative injury differentially regulates PI3K/Akt/GSK3beta pathway in synaptic endings from adult and aged rats. Toxicol Sci 111:331–344

    Article  CAS  Google Scholar 

  • Vincent AM, Brownlee M, Russell JW (2002) Oxidative stress and programmed cell death in diabetic neuropathy. Ann N Y Acad Sci 959:368–383

    Article  CAS  Google Scholar 

  • Vural M, Camuzcuoglu H, Toy H, Aksoy N (2010) Amniotic fluid prolidase activity and oxidative status in neural tube defects. Fetal Diagn Ther 28:34–39

    Article  Google Scholar 

  • Wang L, Li Z, Jin L, Li K, Yuan Y, Fu Y, Zhang Y, Ye R, Ren A (2014) Indoor air pollution and neural tube defects: effect modification by maternal genes. Epidemiology 25:658–665

    Article  CAS  Google Scholar 

  • Wang H, Li XN, Li PC, Liu W, du ZH, Li JL (2019) Modulation of heat-shock response is associated with Di (2-ethylhexyl) phthalate (DEHP)-induced cardiotoxicity in quail (Coturnix japonica). Chemosphere. 214:812–820

    Article  CAS  Google Scholar 

  • Wiedeman AM, Barr SI, Green TJ, Xu Z, Innis SM, Kitts DD (2018) Dietary choline intake: current state of knowledge across the life cycle. Nutrients 16;10(10)

  • Wine RN, Li LH, Barnes LH et al (1997) Reproductive toxicity of di-n-butylphthalate in a continuous breeding protocol in Sprague-Dawley rats. Environ Health Perspect 10:102–107

    Article  Google Scholar 

  • Xia HF, Chi Y, Qi X, Su M, Cao Y, Song P, Li X, Chen T, Zhao A, Zhang Y, Cao Y, Ma X, Jia W (2011) Metabolomicevaluation of di-n-butyl phthalate (DBP)-induced teratogenesis in mice. Metabolomics 7:559–571

    Article  CAS  Google Scholar 

  • Youn CK, Song PI, Kim MH, Kim JS, Hyun JW, Choi SJ, Yoon SP, Chung MH, Chang IY, You HJ (2007) Human 8-oxoguanine DNA glycosylase suppresses the oxidative stress induced apoptosis through a p53-mediated signaling pathway in human fibroblasts. Mol Cancer Res 5:1083–1098

    Article  CAS  Google Scholar 

  • Yuan Y, Zhang L, Jin L, Liu J, Li Z, Wang L, Ren A (2015) Markers of macromolecular oxidative damage in maternal serum and risk of neural tube defects in offspring. Free Radic Biol Med 80:27–32

    Article  CAS  Google Scholar 

  • Zhang Q, Zhao Y, Talukder M, Han Y, Zhang C, Li XN, Li JL (2019) Di(2-ethylhexyl) phthalate induced hepatotoxicity in quail (Coturnix japonica) via modulating the mitochondrial unfolded protein response and NRF2 mediated antioxidant defense. Sci Total Environ 651:885–894

    Article  CAS  Google Scholar 

  • Zhao Y, Du ZH, Talukder M et al (2018) Crosstalk between unfolded protein response and Nrf2-mediated antioxidant defense in Di-(2-ethylhexyl) phthalate-induced renal injury in quail (Coturnix japonica). Environ Pollut 242:1871–1879

    Article  CAS  Google Scholar 

  • Zhao Y, Fan JH, Luo Y, Talukder M, Li XN, Zuo YZ, Li JL (2019) Di-(2-ethylhexyl) phthalate (DEHP)-induced hepatotoxicity in quail (Coturnix japonica) via suppression of the heat shock response. Chemosphere 228:685–693

    Article  CAS  Google Scholar 

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Funding

This work was financially supported by grants from The National Key Research and Development Program of China (2016YFC1000307), CAMS Innovation Fund for Medical Sciences (CIFMS, 2018-I2M-1-004), and the Open Grant from Chongqing Key Laboratory of Birth Defects and Reproductive Health (No. 1111).

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  1. Rui Wang, Da-Guang Sun and Ge Song contributed equally to this work.

Authors and Affiliations

  1. Department of Blood Transfusion, First medical center, Chinese People’s Liberation Army General Hospital, Beijing, China

    Rui Wang

  2. Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, 100081, China

    Rui Wang, Da-Guang Sun, Ge Song, Chun Yi Guan, Yi Cui, Xu Ma & Hong-Fei Xia

  3. Chongqing Key Laboratory of Birth Defects and Reproductive Health, Chongqing, China

    Da-Guang Sun

  4. Graduate School, Peking Union Medical College, Beijing, China

    Da-Guang Sun, Ge Song, Chun Yi Guan, Yi Cui, Xu Ma & Hong-Fei Xia

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  1. Rui Wang
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  2. Da-Guang Sun
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  3. Ge Song
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Correspondence to Xu Ma or Hong-Fei Xia.

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Highlights

• The incidence of NTDs is closely associated with DBP exposure

• DBP exposure disturbs neural tube development by strengthening oxidative stress

• The supplementary of high dose choline could partially restore the teratogenic effects of DBP

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Wang, R., Sun, DG., Song, G. et al. Choline, not folate, can attenuate the teratogenic effects ofdibutyl phthalate (DBP) during early chick embryo development. Environ Sci Pollut Res 26, 29763–29779 (2019). https://doi.org/10.1007/s11356-019-06087-w

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