孕鼠DEHP暴露对子代神经行为的影响及其机制

doi:10.13481/j.1671-587X.20210210

Abstract

Abstract:

Objective：To investigate the effect of bis（2-ethylhexyl） phthalate （DEHP） exposure during the perinatal period on the neurobehaviors of the mice， and to clarify the possible mechanism of DEHP’s influence in the neurobehaviors.

Methods

A total of 32 pregnant ICR mice were selected and randomly divided into different doses of DEHP groups and corn oil control group. From the 3rd day of pregnancy to the 17th day of pregnancy， the mice were given by gavage with low dose （10 mg?kg^－1） of DEHP， medium dose （50 mg?kg^－1） of DEHP， high dose （250 mg?kg^－1） of DEHP and corn oil， respectively. The neurodevelopmental indicators were observed after birth， and neurobehavioral tests were performed after 7 weeks of age； the expression levels of cofilin and Pak1 proteins in the prefrontal cortex tissue of the offsprings were detected by Western blotting method. The in vitro cultured Neuro-2A cells were divided into different doses of DEHP groups and DMSO control group；the Neuro-2A cells were incubated respectively with 1 nmol?L^－1， 10 nmol?L^－1， 1 μmol?L^－1 DEHP and DMSO. After 0， 6， 12， 24， and 48 h of incubation， cell scratch test was used to observe the migration abilities of cells， and the neurite outgrowth of cells were observed under phase-contrast microscope.

Results

Compared with corn oil control group， the neurodevelopmental indicators of the newborn mice in different doses of DEHP groups had no significant differences（P>0.05），and the ability to freely explore new environments of the female offsprings in medium dose of DEHP exposure group was significantly decreased （P<0.01）. The Western blotting results showed that compared with corn oil control group， the expression level of cofilin protein in prefrontal cortex tissue of the offsprings in medium dose of DEHP group was significantly decreased （P<0.05）， but the expression level of Pak1 had no significant difference （P>0.05）. The results of cell scratch test showed that compared with DMSO control group， the cell migration rates in different doses of DEHP groups were reduced after 12 h of incubation （P<0.05）， the mean neurite lengths were also shortened after 6 h of incubation in 1 μmol?L^-1 DEHP group （P<0.05）， and the percentage of neurite-bearing cells was decreased after 48 h of incubation in 1 μmol?L^－1 DEHP group （P<0.05）.

Conclusion

Exposure of the ICR mice to DEHP at a dose of 50 mg?kg^－1 or more during pregnancy can lead to the abnormal neurobehaviors of the offsprings； to incubate the Neuro-2A cells with 1 μmol?L^－1DEHP for 12 h can significantly inhibit the cell migration and neurite growth； its mechanism may be related to inhibiting the expression of cytoskeleton regulatory protein cofilin.

Key words: phthalate esters, neurobehavioral disorder, neuronal migration, cytoskeleton

CLC Number:

R114

Zhangqi LOU,Qifan YU,Xuezhi SHEN,Hongqing CHEN,Yufeng LUO,Qianye CHEN,Guofen ZHENG,Yuemin DING,Xiong ZHANG. Effect of DEHP exposure in pregnant mice on neurobehavior of offsprings and its mechanism[J].Journal of Jilin University(Medicine Edition), 2021, 47(2): 323-329.

Figures/Tables 5

References 22

1	DONG R， WU Y， CHEN J， et al. Lactational exposure to phthalates impaired the neurodevelopmental function of infants at 9 months in a pilot prospective study［J］. Chemosphere， 2019， 226： 351-359.
2	TESTA C， NUTI F， HAYEK J， et al. Di-（2-ethylhexyl） phthalate and autism spectrum disorders［J］. ASN Neuro， 2012， 4 （4）： 223-229.
3	DOHERTY B T， ENGEL S M， BUCKLEY J P， et al. Prenatal phthalate biomarker concentrations and performance on the Bayley Scales of Infant Development-Ⅱ in a population of young urban children［J］. Environ Res， 2017， 152： 51-58.
4	KOBROSLY R W， EVANS S， MIODOVNIK A， et al. Prenatal phthalate exposures and neurobehavioral development scores in boys and girls at 6‒10 years of age［J］. Environ Health Perspect， 2014， 122 （5）： 521-528.
5	LIEN Y J， KU H Y， SU P H， et al. Prenatal exposure to phthalate esters and behavioral syndromes in children at 8 years of age： Taiwan Maternal and Infant Cohort Study［J］. Environ Heal Perspect， 2015， 123（1）： 95-100.
6	YOLTON K， XU Y， STRAUSS D， et al. Prenatal exposure to bisphenol A and phthalates and infant neurobehavior［J］. Neurotoxicol Teratol， 2011， 33 （5）： 558-566.
7	QIAN X， LI J， XU S， et al. Prenatal exposure to phthalates and neurocognitive development in children at two years of age［J］. Environ Int， 2019， 131： 105023.
8	徐晓虹，竹庆杰，杨艳玲，等.出生前后DEHP暴露对小鼠神经行为的影响［J］. 浙江师范大学学报（自然科学版）， 2015， 38（1）： 15-22.
9	姬艳丽，佘素贞，豆正东，等. 昆明种小鼠正常行为发育指标探讨［J］. 安徽医科大学学报，2002，37（6）： 429-432.
10	TYPLT M， MIRKOWSKI M， AZZOPARDI E， et al. Mice with deficient BK channel function show impaired prepulse inhibition and spatial learning， but normal working and spatial reference memory［J］. PLoS One， 2013， 8 （11）： e81270.
11	陆阳. DEHP对大鼠离体海马神经元树突和突触形态发育的影响［D］.金华：浙江师范大学， 2015.
12	JEDDI M Z， JANANI L， MEMARI A H， et al. The role of phthalate esters in autism development： A systematic review［J］. Environ Res， 2016， 151： 493-504.
13	ABBOTT N J. Blood-brain barrier structure and function and the challenges for CNS drug delivery［J］. J Inherit Metab Dis， 2013， 36 （3）： 437-449.
14	ZHANG S， SUN C， ZHAO S， et al. Exposure to DEHP or its metabolite MEHP promotes progesterone secretion and inhibits proliferation in mouse placenta or JEG-3 cells［J］. Environ Pollut， 2020，257： 113593.
15	ZHANG Q， CHEN X Z， HUANG X， et al. The association between prenatal exposure to phthalates and cognition and neurobehavior of children-evidence from birth cohorts［J］. Neurotoxicology， 2019， 73： 199-212.
16	LORD C， BRUGHA T S， CHARMAN T， et al. Autism spectrum disorder［J］. Nat Rev Dis Primers， 2020， 6 （1）： 5.
17	REX C S， CHEN L Y， SHARMA A， et al. Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation［J］. J Cell Biol， 2009， 186 （1）： 85-97.
18	HEASMAN S J， RIDLEY A J. Mammalian Rho GTPases： new insights into their functions from in vivo studies［J］. Nat Rev Mol Cell Biol， 2008， 9（9）： 690-701.
19	RATHINAM R， BERRIER A， ALAHARI S K. Role of Rho GTPases and their regulators in cancer progression［J］. Front Biosci （Landmark Ed）， 2011， 16： 2561-2571.
20	DING Y M， LU L C， XUAN C K， et al. Di-n-butyl phthalate exposure negatively influences structural and functional neuroplasticity via Rho-GTPase signaling pathways［J］. Food Chem Toxicol， 2017， 105： 34-43.
21	OSTROWSKA Z， MORACZEWSKA J. Cofilin-a protein controlling dynamics of actin filaments［J］. Postepy Hig Med Dosw （Online），2017， 71：339-351.
22	KANELLOS G， FRAME M C. Cellular functions of the ADF/cofilin family at a glance［J］. J Cell Sci， 2016， 129 （17）： 3211-3218.

[1]	LIU Qingju, GAO Xin, QIU Bing, WANG Yan, SHI Lingna, GAO Xia. Protective effect of extractum trametes robiniophila murr on puromycinaminonucleoside-induced podocyte injury in vitro of mice and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2019, 45(05): 1020-1024.
[2]	XU Jin, CHEN Huaiji, XU Feng, WANG Qi, ZHANG Yuezhu, LIU Hongbo, ZHANG Tianrong, YE Lin. Association between phthalate ester exposure and population obesity:A Meta-analysis [J]. Journal of Jilin University Medicine Edition, 2017, 43(02): 306-310.

Effect of DEHP exposure in pregnant mice on neurobehavior of offsprings and its mechanism

RichHTML

PDF (PC)

Like

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 5

References 22

Related Articles 2

Metrics

Comments

Recommended 10