Abstract
Prenatal air pollution, protein C (PROC) gene abnormal methylation, and genetic mutation can cause a series of neonatal diseases, but the complex relationship between them remains unclear. Here, we recruited 552 mothers and their own babies during January 2010–January 2012 in Zhengzhou to explore such association. The air pollutant data was obtained from the Environmental Monitoring Stations. The rs1799809 genotype and the methylation levels at the promoter region of PROC in genomic DNA samples were detected respectively by TaqMan probe and quantitative methylation specific PCR using real-time PCR system. The results show that the levels of neonatal PROC methylation were negatively associated with concentrations of NO2 during the entire pregnancy, particularly during the third trimester. Of particular significance, only in newborns carrying rs1799809 AA genotype, negatively significant associations between PROC methylation levels and exposure concentrations of air pollutants were observed. Further, we observed a significant interactive effect between neonatal rs1799809 genotype and SO2 exposure during the entire pregnancy on neonatal PROC methylation levels. Prenatal exposure to ambient air pollutants specifically was associated with the neonatal PROC promoter methylation level of newborns carrying the rs1799809 AA genotype. Taken together, these findings suggest that neonatal PROC methylation levels are associated with prenatal exposure to ambient air pollutants, and this association can be modified by rs1799809 genotype.
Similar content being viewed by others
References
Abraham E, Rousseaux S, Agier L, Giorgis-Allemand L, Tost J, Galineau J, Hulin A, Siroux V, Vaiman D, Charles MA, Heude B, Forhan A, Schwartz J, Chuffart F, Bourova-Flin E, Khochbin S, Slama R, Lepeule J (2018) Pregnancy exposure to atmospheric pollution and meteorological conditions and placental DNA methylation. Environ Int 118:334–347. https://doi.org/10.1016/j.envint.2018.05.007
Al Harbi MS, El-Hattab AW (2017) Protein C deficiency caused by a novel mutation in the PROC gene in an infant with delayed onset Purpura Fulminans. Case Reports in Dermatological Medicine 2017:8915608–8915603. https://doi.org/10.1155/2017/8915608
Bao BY, Pao JB, Huang CN, Pu YS, Chang TY, Lan YH, Lu TL, Lee HZ, Juang SH, Chen LM, Hsieh CJ, Huang SP (2011) Polymorphisms inside microRNAs and microRNA target sites predict clinical outcomes in prostate cancer patients receiving androgen-deprivation therapy. Clinical Cancer Research: an Official Journal of the American Association for Cancer Research 17:928–936. https://doi.org/10.1158/1078-0432.CCR-10-2648
Barciszewska AM, Giel-Pietraszuk M, Perrigue PM, Naskręt-Barciszewska M (2019) Total DNA methylation changes reflect random oxidative DNA damage in gliomas. Cells 8. https://doi.org/10.3390/cells8091065
Bhargava A, Shukla A, Bunkar N, Shandilya R, Lodhi L, Kumari R, Gupta PK, Rahman A, Chaudhury K, Tiwari R, Goryacheva IY, Mishra PK (2019) Exposure to ultrafine particulate matter induces NF-κβ mediated epigenetic modifications. Environ Pollut 252:39–50. https://doi.org/10.1016/j.envpol.2019.05.065
Breton CV, Yao J, Millstein J, Gao L, Siegmund KD, Mack W, Whitfield-Maxwell L, Lurmann F, Hodis H, Avol E, Gilliland FD (2016) Prenatal air pollution exposures, DNA methyl transferase genotypes, and associations with newborn LINE1 and alu methylation and childhood blood pressure and carotid intima-media thickness in the children's health study. Environ Health Perspect 124:1905–1912. https://doi.org/10.1289/EHP181
Breton CV, Song AY, Xiao J, Kim SJ, Mehta HH, Wan J, Yen K, Sioutas C, Lurmann F, Xue S, Morgan TE, Zhang J, Cohen P (2019) Effects of air pollution on mitochondrial function, mitochondrial DNA methylation, and mitochondrial peptide expression. Mitochondrion 46:22–29. https://doi.org/10.1016/j.mito.2019.04.001
Bulato C, Campello E, Gavasso S, Maggiolo S, Tormene D, Simioni P (2018) Peculiar laboratory phenotype/genotype relationship due to compound inherited protein C defects in a child with severe venous thromboembolism. Hamostaseologie 38:33–38. https://doi.org/10.5482/HAMO-17-03-0013
Cai L, Wang S, Gao P, Shen X, Jalaludin B, Bloom MS, Wang Q, Bao J, Zeng X, Gui Z, Chen Y, Huang C (2019) Effects of ambient particulate matter on fasting blood glucose among primary school children in Guangzhou, China. Environ Res 176:18. https://doi.org/10.1016/j.envres.2019.108541
Chen S, He Y, Yan M, Zhou Y, He Q, Tan J, Yang B (2021a) The interaction effects of FEN1 rs174538 polymorphism and polycyclic aromatic hydrocarbon exposure on damage in exon 19 and 21 of EGFR gene in coke oven workers. Environ Sci Pollut Res 23:021–15013. https://doi.org/10.1007/s11356-021-15013-y
Chen X, Huang L, Zhong C, Li Q, Chen R, Sun G, Jin Z, Yang X, Hao L, Yang H, Yang N (2021b) Association between environmental tobacco smoke before and during pregnancy and the risk of adverse birth outcomes: a birth cohort study in Wuhan, China. Environ Sci Pollut Res 28:27230–27237. https://doi.org/10.1007/s11356-021-12626-1
Dreyfus M, Magny JF, Bridey F, Schwarz HP, Planche C, Dehan M, Tchernia G (1991) Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate. N Engl J Med 325:1565–1568. https://doi.org/10.1056/NEJM199111283252207
Emmerechts J, De Vooght V, Haenen S, Loyen S, Van Kerckhoven S, Hemmeryckx B, Vanoirbeek JA, Hoet PH, Nemery B, Hoylaerts MF (2012) Thrombogenic changes in young and old mice upon subchronic exposure to air pollution in an urban roadside tunnel. Thromb Haemost 108:756–768. https://doi.org/10.1160/TH12-03-0161
English JA, Lopez LM, O'Gorman A, Focking M, Hryniewiecka M, Scaife C, Sabherwal S, Wynne K, Dicker P, Rutten BPF, Lewis G, Zammit S, Cannon M, Cagney G, Cotter DR (2018)Blood-based protein changes in childhood are associated with increased risk for later psychotic disorder: evidence from a nested case-control study of the ALSPAC longitudinal birth cohort. Schizophr Bull 44:297–306. https://doi.org/10.1093/schbul/sbx075
Esmon CT (1989) The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 264:4743–4746
Greiff G, Pleym H, Stenseth R, Wahba A, Videm V (2015) Genetic variation influences the risk of bleeding after cardiac surgery: novel associations and validation of previous findings. Acta Anaesthesiol Scand 59:796–806. https://doi.org/10.1111/aas.12504
Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C (1981) Deficiency of protein C in congenital thrombotic disease. J Clin Invest 68:1370–1373. https://doi.org/10.1172/jci110385
Gruzieva O, Xu CJ, Yousefi P, Relton C, Merid SK, Breton CV, Gao L, Volk HE, Feinberg JI, Ladd-Acosta C, Bakulski K, Auffray C, Lemonnier N, Plusquin M, Ghantous A, Herceg Z, Nawrot TS, Pizzi C, Richiardi L et al (2019) Prenatal particulate air pollution and DNA methylation in newborns: an epigenome-wide meta-analysis. Environ Health Perspect 127:57012. https://doi.org/10.1289/EHP4522
Kass SU, Landsberger N, Wolffe AP (1997) DNA methylation directs a time-dependent repression of transcription initiation. Current Biology : CB 7:157–165. https://doi.org/10.1016/s0960-9822(97)70086-1
Liu X, Ye Y, Chen Y, Li X, Feng B, Cao G, Xiao J, Zeng W, Sun J, Ning D, Yang Y, Yao Z, Guo Y, Wang Q, Zhang Y, Ma W, Du Q, Zhang B, Liu T (2019) Effects of prenatal exposure to air particulate matter on the risk of preterm birth and roles of maternal and cord blood LINE-1 methylation: a birth cohort study in Guangzhou, China. Environ Int 133:105177. https://doi.org/10.1016/j.envint.2019.105177
Lynch AM, Wagner BD, Deterding RR, Giclas PC, Gibbs RS, Janoff EN, Holers VM, Santoro NF (2016) The relationship of circulating proteins in early pregnancy with preterm birth. Am J Obstet Gynecol 214, 214:517 e1, 517.e1–517 e8, 517.e8. https://doi.org/10.1016/j.ajog.2015.11.001
MacIntyre EA et al (2014) GSTP1 and TNF Gene variants and associations between air pollution and incident childhood asthma: the traffic, asthma and genetics (TAG) study. Environ Health Perspect 122:418–424. https://doi.org/10.1289/ehp.1307459
Madrigano J, Baccarelli A, Mittleman MA, Wright RO, Sparrow D, Vokonas PS, Tarantini L, Schwartz J (2011) Prolonged exposure to particulate pollution, genes associated with glutathione pathways, and DNA methylation in a cohort of older men. Environ Health Perspect 119:977–982. https://doi.org/10.1289/ehp.1002773
Mei M, Song H, Chen L, Hu B, Bai R, Xu D, Liu Y, Zhao Y, Chen C (2018) Early-life exposure to three size-fractionated ultrafine and fine atmospheric particulates in Beijing exacerbates asthma development in mature mice. Particle and Fibre Toxicology 15:13. https://doi.org/10.1186/s12989-018-0249-1
Ocak G, Drechsler C, Vossen CY, Vos HL, Rosendaal FR, Reitsma PH, Hoffmann MM, Marz W, Ouwehand WH, Krediet RT, Boeschoten EW, Dekker FW, Wanner C, Verduijn M (2014) Single nucleotide variants in the protein C pathway and mortality in dialysis patients. PLoS ONE 9:e97251. https://doi.org/10.1371/journal.pone.0097251
Pun VC, Dowling R, Mehta S (2021) Ambient and household air pollution on early-life determinants of stunting-a systematic review and meta-analysis. Environ Sci Pollut Res 28:26404–26412. https://doi.org/10.1007/s11356-021-13719-7
Shukla A, Bunkar N, Kumar R, Bhargava A, Tiwari R, Chaudhury K, Goryacheva IY, Mishra PK (2019) Air pollution associated epigenetic modifications: transgenerational inheritance and underlying molecular mechanisms. Sci Total Environ 656:760–777. https://doi.org/10.1016/j.scitotenv.2018.11.381
Strand LB, Barnett AG, Tong S (2011) Methodological challenges when estimating the effects of season and seasonal exposures on birth outcomes. BMC Med Res Methodol 11:1471–2288. https://doi.org/10.1186/1471-2288-11-49
Yang W, Bai J, Song X, Zhang S, Chen N, You T, Yi K, Li Z, Xie D, Xie X (2021) CCN1 gene polymorphisms associated with congenital heart disease susceptibility in Northwest Chinese population from different high-altitude areas. Environ Sci Pollut Res 3:021–14428. https://doi.org/10.1007/s11356-021-14428-x
Yeung EH, Guan W, Mumford SL, Silver RM, Zhang C, Tsai MY, Schisterman EF (2019) Measured maternal prepregnancy anthropometry and newborn DNA methylation. Epigenomics 11:187–198. https://doi.org/10.2217/epi-2018-0099
Zhang Z, Wang J, Guo M, Xiong M, Zhou Q, Li D, Shu J, Lu W, Sun D (2016) Air quality improvement during 2010 Asian games on blood coagulability in COPD patients. Environ Sci Pollut Res 23:6631–6638. https://doi.org/10.1007/s11356-015-5871-y
Zhao C, Li Q, Cui Z, Wang J, Sun L, Yin Y (2021) Impact of ambient fine particulate matter on emergency department admissions for circulatory system disease in a city in Northeast China. Environ Sci Pollut Res 3:021–15222. https://doi.org/10.1007/s11356-021-15222-5
Zhou G, He T, Huang H, Feng F, Liu X, Li Z, Zhang Y, Ba Y (2019) Prenatal ambient air pollution exposure and SOD2 promoter methylation in maternal and cord blood. Ecotoxicol Environ Saf 181:428–434. https://doi.org/10.1016/j.ecoenv.2019.06.039
Zhuang J, Bai H, Sun J, Zhang T, Li J, Chen Y, Zhang H, Sun Q (2021) The association between fine particulate matter and acute lower respiratory infections in Yancheng City, China. Environ Sci Pollut Res 29:021–15102. https://doi.org/10.1007/s11356-021-15102-y
Acknowledgements
We would like to express our gratitude to the members of the Houzhai Health Hospital and all the subjected investigated for their consent, help, and support. This study was supported by the National Natural Science Foundation of China, and the Opening Foundation of National Health Commission Key Laboratory of Birth Defects Prevention and Henan Key Laboratory of Population Defects Prevention. The sponsors were not involved in study design, information collection, data analysis, report writing, and publication.
Availability of data and materials
The datasets generated during and/or analyzed during the current study are not publicly available due to the sensitivity of human data but are available from the corresponding author on reasonable request.
Funding
This study was supported by the National Natural Science Foundation of China (82003401 and 81972981 and 81673116), and the Opening Foundation of National Health Commission Key Laboratory of Birth Defects Prevention and Henan Key Laboratory of Population Defects Prevention (ZD202001).
Author information
Authors and Affiliations
Contributions
Zhiyuan Li: conceptualization, investigation, writing—original draft. Meng Yang: writing—original draft; visualization. Leizhen Duan: methodology, formal analysis, visualization. Yongxiang Gong: visualization, writing—review and editing. Hongxia Xia: validation, writing—review and editing. Francis-Kojo Afrim: validation, writing—review and editing. Hui Huang: investigation, writing—review and editing. Xiaoxue Liu: resources, writing—review and editing. Fangfang Yu: data curation, writing—review and editing. Yawei Zhang: writing—review and editing. Yue Ba: conceptualization; supervision; funding acquisition; writing—review and editing. Guoyu Zhou: methodology; conceptualization; project administration; funding acquisition; writing—review and editing.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
This study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study design was approved by the Ethics Committee of Zhengzhou University. And the private information was de-identified to protect the privacy of participants.
Consent for publication
Not applicable
Competing interests
The authors declare no competing interests.
Disclaimer
The sponsors were not involved in study design, information collection, data analysis, report writing, and publication.
Additional information
Responsible Editor: Lotfi Aleya
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
ESM 1
(DOCX 263 kb)
Rights and permissions
About this article
Cite this article
Li, Z., Yang, M., Duan, L. et al. The neonatal PROC gene rs1799809 polymorphism modifies the association between prenatal air pollutants exposure and PROC promoter methylation. Environ Sci Pollut Res 29, 14575–14583 (2022). https://doi.org/10.1007/s11356-021-16694-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-021-16694-1