Skip to main content
SpringerLink
Log in

Evaluation of combined developmental neurological toxicity of di (n-butyl) phthalates and lead using immature mice

  • Research Article
  • Published:
Environmental Science and Pollution Research Aims and scope Submit manuscript

Abstract

In this study, the immature mice were taken to assess the potential neurological toxicity of lead (Pb) and di (n-butyl) phthalates (DBP) combination exposure. Mouse administration with DBP combination with Pb exhibited longer escape latency and lower average number of crossing of the platform. Pb content in the tissues was increased, especially in the brain, after Pb exposure as compared to those without Pb exposure. The alterations of oxidative damages in tissues (MDA and SOD) and biochemical indicators in the brain (AChE, TNOS, and iNOS) were observed, as well as the synergistic effect of joint exposure. Expressions of apoptosis-related protein (bax/bcl-2 ratio and caspase-3) were significantly increased in the hippocampus, while the bcl-2 was remarkably decreased and no significant differences were observed on the bax. The results suggested that the possible mechanisms for the learning and memory ability impairments were as follows: Firstly, the combination exposure induced the occurrence of lipid peroxidation in the brain, leading to damage to the brain cells. Secondly, it destroyed the normal metabolic balance of ACh, causing nerve damage in mice. Thirdly, it induced apoptosis in mouse hippocampal cells. The overall findings revealed that Pb and DBP co-exposure greatly influenced the developmental nervous system and accompanied with synergistic toxic effect.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Alharbi OML, Basheer AA, Khattab RA, Ali I (2018) Health and environmental effects of persistent organic pollutants. J Mol Liq 263:442–453

    CAS  Google Scholar 

  • Arslan C, Altan H, Beşirli K, Aydemir B, Kiziler AR, Denli Ş (2010) The role of oxidative stress and antioxidant defenses in Buerger disease and atherosclerotic peripheral arterial occlusive disease. Ann Vasc Surg 24(4):455–460

    Google Scholar 

  • Alam MS, Ohsako S, Matsuwaki T, Zhu XB, Tsunekawa N, Kanai Y, Sone H, Tohyama C, Kurohmaru M (2010) Induction of spermatogenic cell apoptosis in prepubertal rat testes irrespective of testicular steroidogenesis: a possible estrogenic effect of di(n-butyl) phthalate. Reproduction 139(2):427–437

    CAS  Google Scholar 

  • Braun JM, Kahn RS, Froehlich T, Auinger P, Lanphear BP (2006) Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. Children. Environ. Health Perspectives 114:1904–1909

    Google Scholar 

  • Bokara KK, Brown E, Mccormick R, Yallapragada PR, Rajanna S, Bettaiya R (2008) Lead-induced increase in antioxidant enzymes and lipid peroxidation products in developing rat brain. Biometals 21:9–16

    CAS  Google Scholar 

  • Chen XP, Xu SS, Tan TF, Lee ST, Cheng SH, Lee FWF, Xu SJL, Ho KC (2014) Toxicity and estrogenic endocrine disrupting activity of phthalates and their mixtures. Int J Env Res Pub Heal 11(3):3156–3168

    Google Scholar 

  • Canfield RL, Henderson CR, Cory-Slechta DA, Cox C, Jusko TA, Lanphear BP (2003) Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter. N Engl J Med 348:1517–1526

    CAS  Google Scholar 

  • Chiang HM, Chang H, Yao PW, Chen YS, Jeng KC, Wang JS, Hou CW (2014) Sesamin reduces acute hepatic injury induced by lead coupled with lipopolysaccharide. J Chin Med Assoc 77(5):227–233

    Google Scholar 

  • Du L, Li GD, Liu MM, Li YQ, Yin SZ, Zhao J, Zhang XY (2015) Evaluation of DNA damage and antioxidant system induced by di-n-butyl phthalates exposure in earthworms (eisenia fetida). Ecotox Environ Safe 115:75–82

    CAS  Google Scholar 

  • Gao DW, Wen ZD (2016) Phthalate esters in the environment: a critical review of their occurrence, biodegradation, and removal during wastewater treatment processes. Sci Total Environ 541:986–1001

    CAS  Google Scholar 

  • Guo YY, Yang YJ, Gao Y, Wang XF, Zhou BS (2015) The impact of long term exposure to phthalic acid esters on reproduction in Chinese rare minnow (Gobiocypris rarus). Environ Pollut 203:130–136

    CAS  Google Scholar 

  • Gogal RM, Smith BJ, Kalnitsky J, Holladay SD (2000) Analysis of apoptosis of lymphoid cells in fish exposed to immunotoxic compounds. Cytometry 39(4):310–318

    CAS  Google Scholar 

  • Huang FN, Schneider JS (2005) Effects of lead exposure on proliferation and differentiation of neural stem cells derived from different regions of embryonic rat brain. Neurotoxicol 25(6):1001–1012

    Google Scholar 

  • Hossain MA, Awal MA, Mostofa M, Akanda MR (2014) Determination of environmental deposition of lead (Pb) in certain selected samples in the industrial areas of Gazipur District of Bangladesh. Int J Scientific Res Agricultural Sci 1(8):148–155

    Google Scholar 

  • International Program on Chemical Safety (IPCS) (1997) Environmental Health Criteria 189. Di-n-butyl phthalate, World Health Organization, Geneva

    Google Scholar 

  • Jacob JM, Karthik C, Saratale RG, Kumar SS, Prabakar D, Kadirvelu K, Pugazhendhi A (2018) Biological approaches to tackle heavy metal pollution: a survey of literature. J Environ Manage 217:56–70

    CAS  Google Scholar 

  • Koch HM, Preuss R, Drexler H, Angerer J (2005) Exposure of nursery school children and their parents and teachers to di-n-butylphthalate and butylbenzylphthalate. Int Arch Occup Environ Health 78:223–229

    CAS  Google Scholar 

  • Kang HG, Jeong SH, Cho MR, Cho JH, Bischoff K (2009) Time-dependent changes in lead and delta-aminolevulinic acid after subchronic lead exposure in rats. Hum Exp Toxicol 28(10):647–654

    CAS  Google Scholar 

  • Khodamoradi N, Komaki A, Salehi I, Shahidi S, Sarihi A (2015) Effect of vitamin E on lead exposure-induced learning and memory impairment in rats. Physiol Behav 144:90–94

    CAS  Google Scholar 

  • Lamb JC, Chapin RE, Teague J, Lawton AD, Reel JR (1987) Reproductive effects of four phthalic acid esters in the mouse. Toxicol Appl Pharm 88:255–269

    CAS  Google Scholar 

  • Liu XW, Shi JH, Bo T, Zhang H, Wu W, Chen QC, Zhan XM (2014) Occurrence of phthalic acid esters in source waters: a nationwide survey in China during the period of 2009–2012. Environ Pollut 184:262–270

    CAS  Google Scholar 

  • Li MM, Cao J, Xu J, Cai SZ, Shen XM, Yan CH (2014) The national trend of blood lead levels among Chinese children aged 0–18 years old, 1990–2012. Environ Int 71:109–117

    CAS  Google Scholar 

  • López FJS, Garcia MDG, Morito NPS, Vidal JLM (2003) Determination of heavy metals in crayfish by ICP-MS with a microwave-assisted digestion treatment. Ecotox Environ Safety 54(2):223–228

    Google Scholar 

  • Liu X, Zhang DY, Li YS, Xiong J, He DW, Lin T, Li XL, Wei GH (2009) Di-(2-ethylhexyl) phthalate upregulates ATF3 expression and suppresses apoptosis in mouse genital tubercle. J occup health 51(1):57–63

    CAS  Google Scholar 

  • Matsumoto M, Hirata-Koizumi M, Ema M (2008) Potential adverse effects of phthalic acid esters on human health: a review of recent studies on reproduction. Regul Toxicol Phar 50:37–49

    CAS  Google Scholar 

  • Mao GH, Zhou ZX, Chen Y, Wang W, Wu XS, Feng WW, Samuel JC, Huang J, Zhang Z, Xu H, Yang LQ, Wu XY (2015) Neurological toxicity of individual and mixtures of low dose arsenic, mono and di (n-butyl) phthalates on sub-chronic exposure to mice. Biol Trace Elem Res 170:183–193

    Google Scholar 

  • Mylchreest E, Wallace DG, Cattley RC, Foster PMD (2000) Dose-dependent alterations in androgen-regulated male reproductive development in rats exposed to di(n-butyl) phthalate during late gestation. Toxicol Sci 55:143–151

    CAS  Google Scholar 

  • Modak AT, Weintraub ST, Stavinoha WB (1975) Effect of chronic ingestion of lead on the central cholinergic system in rat brain regions. Toxicol Appl Pharm 34:340–347

    CAS  Google Scholar 

  • Moneim AE, Dkhil AM, Al-Quraishy S (2011) Effects of flaxseed oil on lead acetate-induced neurotoxicity in rats. Biol Trace Elem Res 144(144):904–913

    Google Scholar 

  • Metcalfe NB, Alonso-Alvarez C (2010) Oxidative stress as a life-history constraint: the role of reactive oxygen species in shaping phenotypes from conception to death. Funct Ecol 24(5):984–996

    Google Scholar 

  • Niu LL, Xu Y, Xu C, Yun LX, Liu WP (2014) Status of phthalate esters contamination in agricultural soils across china and associated health risks. Environ Pollut 195:16–23

    CAS  Google Scholar 

  • Phyu MP, Tangpong J (2014) Neuroprotective effects of xanthone derivative of Garcinia mangostana against lead-induced acetylcholinesterase dysfunction and cognitive impairment. Food Chem Toxicol 70(2):151–156

    CAS  Google Scholar 

  • Qi YB, Chen CZ, Tang Y, Jiang XJ, Qiu CY, Peng B, Tu BJ (2013) The synergistic effect of benzo[a] pyrene and lead on learning and memory of mice. Toxicol Ind Health 29:387–395

    Google Scholar 

  • Rai A, Maurya SK, Khare P, Bandyopadhyay S (2010) Arsenic, cadmium and lead-mixture synergistically induces astrocyte toxicity in developing rat brain. J Neurochem 115(7):20

    Google Scholar 

  • Reddy GR, Suresh A, Murthy KS, Chetty CS (2002) Lead neurotoxicity: heme oxygenase and nitric oxide synthase activities in developing rat brain. Neurotox Res 4(1):33–39

    CAS  Google Scholar 

  • Sawut R, Kasim N, Maihemuti B, Hu L, Abliz A, Abdujappar A, Kurban M (2018) Pollution characteristics and health risk assessment of heavy metals in the vegetable bases of northwest China. Sci Total Environ 642:864–878

    CAS  Google Scholar 

  • Srivastava S, Singh GB, Srivastava SP, Seth PK (1990) Testicular toxicity of di-n-butyl phthalate in adult rats: effect on marker enzymes of spermatogenesis. Indian J Exp Biol 28(1):67–70

    CAS  Google Scholar 

  • Struzyńska L, Sułkowski G, Lenkiewicz A, Rafałowska U (2002) Lead stimulates the glutathione system in selective regions of rat brain. Folia Neuropathol 40:203–209

    Google Scholar 

  • Senut MC, Sen A, Cingolani P, Shaik A, Land SJ, Ruden DM (2014) Lead exposure disrupts global DNA methylation in human embryonic stem cells and alters their neuronal differentiation. Toxicol Sci 139(1):142–161

    CAS  Google Scholar 

  • Staples CA, Peterson DR, Parkerton TF, Adams WJ (1997) The environmental fate of phthalate esters: a literature review. Chemosphere 35:667–749

    CAS  Google Scholar 

  • Surkan, P.J., Zhang, A., Trachtenberg, F., Daniel, D.B., McKinlay, S., Bellinger, D.C., 2007. Neuropsychological function in children with blood lead levels <10 microg/dL . Neurotoxicology 28, 1170–1177, Neuropsychological function in children with blood lead levels &lt;10 microg/dL

  • Sarin S, Gupta V, Gill KD (1997) Alterations in lipid composition and neuronal injury in primates following chronic aluminium exposure. Biol Trace Elem Res 59(1-3):133–143

    CAS  Google Scholar 

  • Sharma P, Chambial S, Shukla KK (2015) Lead and neurotoxicity. Indian J Clin Biochem 30(1):1–2

    Google Scholar 

  • Sulejczak D, Czarkowska-Bauch J, Macias M, Skup M (2004) Bcl-2 and Bax proteins are increased in neocortical but not in thalamic apoptosis following devascularizing lesion of the cerebral cortex in the rat: an immunohistochemical study. Brain Res 1006(2):133–149

    CAS  Google Scholar 

  • Sambaziotis D, Kapranos N, Kontogeorgos G (2003) Correlation of Bcl-2 and Bax with apoptosis in human pituitary adenomas. Pituitary 6(3):127–133

    CAS  Google Scholar 

  • Triantafyllidou S, Edwards M (2012) Lead (Pb) in tap water and in blood: implications for lead exposure in the united states. Crit Rev Env Sci Tec 42:1297–1352

    CAS  Google Scholar 

  • Ueoka, R., Matsumoto, Y., 2004. Apoptosis inducers, caspase cascade activators and anticancer agent. US, US20040043918.

  • Valavanidis A, Vlahogianni T, Dassenakis M, Scoullos M (2006) Molecular biomarkers of oxidative stress in aquatic organisms in relation to toxic environmental pollutants. Ecotoxicol Environ Saf 64:178–189

    CAS  Google Scholar 

  • Vázquez A, Ortiz SPD (2004) Lead (Pb2+) impairs long-term memory and blocks learning-induced increases in hippocampal protein kinase C activity. Toxicol Appl Pharmacol 200:27–39

    Google Scholar 

  • Verina T, Rohde CA, Guilarte TR (2007) Environmental lead exposure during early life alters granule cell neurogenesis and morphology in the hippocampus of young adult rats. Neurosci 145(3):1037–1047

    CAS  Google Scholar 

  • Wittassek M, Angerer J, Kolossa-Gehring M, Schäfer SD, Klockenbusch W, Dobler L, Günsel AK, Müller A, Wiesmüller GA (2009) Fetal exposure to phthalates – a pilot study. Int J Hyg Environ Heal 212:492–498

    CAS  Google Scholar 

  • Xu XR, Li HB, Gu JD (2005) Biodegradation of an endocrine-disrupting chemical di- n-butyl phthalate ester by pseudomonas fluorescens b-1. Int Biodeter Biodegr 55(1):9–15

    CAS  Google Scholar 

  • Xu H, Shao XL, Zhang Z, Zou YM, Chen Y, Han SL, Wang SS, Wu XY, Yang LQ, Chen ZL (2013) Effects of di-n-butyl phthalate and diethyl phthalate on acetylcholinesterase activity and neurotoxicity related gene expression in embryonic zebrafish. Bull Environ Contam Toxicol 91:635–639

    CAS  Google Scholar 

  • Zhang J, Li H, Yu J, Jin S, Sun Z (2011) Synergistic effect on genotoxicity of cadmium chloride and dibutyl phthalate in male ICR mice. J Converg Inf Technol 6:353–359

    Google Scholar 

  • Zhou DX, Wang HX, Zhang J (2011) Di-n-butyl phthalate (DBP) exposure induces oxidative stress in epididymis of adult rats. Toxicol Ind Health 27(1):65–71

    CAS  Google Scholar 

Download references

Acknowledgments

This work was supported financially by the Natural Science Foundation of Jiangsu Province (BK20160497), the Priority Academic Program Development of Jiangsu Higher Education Institutions, and the Collaborative Innovation Center of Technology and Material of Water Treatment.

Author information

Authors and Affiliations

  1. School of the Environment and Safety Engineering, Jiangsu University, Zhenjiang, China

    Guanghua Mao, Hongyang Liu, Yangyang Ding, Hui Chen, Weiwei Feng & Xiangyang Wu

  2. School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China

    Weijie Zhang

  3. School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang, China

    Ting Zhao & Liuqing Yang

Authors
  1. Guanghua Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hongyang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yangyang Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weijie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hui Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ting Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Weiwei Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiangyang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Liuqing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xiangyang Wu or Liuqing Yang.

Additional information

Responsible editor: Philippe Garrigues

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mao, G., Liu, H., Ding, Y. et al. Evaluation of combined developmental neurological toxicity of di (n-butyl) phthalates and lead using immature mice. Environ Sci Pollut Res 27, 9318–9326 (2020). https://doi.org/10.1007/s11356-019-06692-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11356-019-06692-9

Keywords

Search

Navigation