Abstract
Mitochondria play a central role in maintaining cellular and metabolic homeostasis during vital development cycles of foetal growth. Optimal mitochondrial functions are important not only to sustain adequate energy production but also for regulated epigenetic programming. However, these organelles are subtle targets of environmental exposures, and any perturbance in the defined mitochondrial machinery during the developmental stage can lead to the re-programming of the foetal epigenetic landscape. As these modifications can be transferred to subsequent generations, we herein performed a cross-sectional study to have an in-depth understanding of this intricate phenomenon. The study was conducted with two arms: whereas the first group consisted of in utero pro-oxidant exposed individuals and the second group included controls. Our results showed higher levels of oxidative mtDNA damage and associated integrated stress response among the exposed individuals. These disturbances were found to be closely related to the observed discrepancies in mitochondrial biogenesis. The exposed group showed mtDNA hypermethylation and changes in allied mitochondrial functioning. Altered expression of mitomiRs and their respective target genes in the exposed group indicated the possibilities of a disturbed mitochondrial-nuclear cross talk. This was further confirmed by the modified activity of the mitochondrial stress regulators and pro-inflammatory mediators among the exposed group. Importantly, the disturbed DNMT functioning, hypermethylation of nuclear DNA, and higher degree of post-translational histone modifications established the existence of aberrant epigenetic modifications in the exposed individuals. Overall, our results demonstrate the first molecular insights of in utero pro-oxidant exposure associated changes in the mitochondrial-epigenetic axis. Although, our study might not cement an exposure-response relationship for any particular environmental pro-oxidant, but suffice to establish a dogma of mito-epigenetic reprogramming at intrauterine milieu with chronic illness, a hitherto unreported interaction.
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Albensi BC (2019) What is nuclear factor kappa B (NF-κB) doing in and to the mitochondrion? Front Cell Dev Biol 7:154. https://doi.org/10.3389/fcell.2019.00154
Ashar FN, Zhang Y, Longchamps RJ, Lane J, Moes A, Grove ML, Mychaleckyj JC, Taylor KD, Coresh J, Rotter JI, Boerwinkle E, Pankratz N, Guallar E, Arking DE (2017) Association of mitochondrial DNA copy number with cardiovascular disease. JAMA Cardiol 2(11):1247–1255. https://doi.org/10.1001/jamacardio.2017.3683
Ashraf UM, Hall DL, Rawls AZ, Alexander BT (2021) Epigenetic processes during preeclampsia and effects on foetal development and chronic health. Clin Sci (Lond) 135(19):2307–2327. https://doi.org/10.1042/CS20190070
Barker DJ (2003) The developmental origins of adult disease. Eur J Epidemiol 18(8):733–736. https://doi.org/10.1023/A:1025388901248
Bartho LA, O'Callaghan JL, Fisher JJ, Cuffe JSM, Kaitu'u-Lino TJ, Hannan NJ, Clifton VL, Perkins AV (2021) Analysis of mitochondrial regulatory transcripts in publicly available datasets with validation in placentae from pre-term, post-term and foetal growth restriction pregnancies. Placenta 112:162–171. https://doi.org/10.1016/j.placenta.2021.07.303
Berlin M, Flor-Hirsch H, Kohn E, Brik A, Keidar R, Livne A, Marom R, Ovental A, Mandel D, Lubetzky R, Factor-Litvak P, Tovbin J, Betser M, Moskovich M, Hazan A, Britzi M, Gueta I, Berkovitch M, Matok I, Hamiel U (2022) Maternal exposure to polychlorinated biphenyls and asthma, allergic rhinitis and atopic dermatitis in the offspring: the Environmental Health Fund Birth Cohort. Front Pharmacol 13:802974. https://doi.org/10.3389/fphar.2022.802974
Bhargava A, Tamrakar S, Aglawe A, Lad H, Srivastava RK, Mishra DK, Tiwari R, Chaudhury K, Goryacheva IY, Mishra PK (2018) Ultrafine particulate matter impairs mitochondrial redox homeostasis and activates phosphatidylinositol 3-kinase mediated DNA damage responses in lymphocytes. Environ Pollut 234:406–419. https://doi.org/10.1016/j.envpol.2017.11.093
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(Pt A):39–50. https://doi.org/10.1016/j.envpol.2019.05.065
Bhargava A, Kumari R, Khare S, Shandilya R, Gupta PK, Tiwari R, Rahman A, Chaudhury K, Goryacheva IY, Mishra PK (2020) Mapping the mitochondrial regulation of epigenetic modifications in association with carcinogenic and noncarcinogenic polycyclic aromatic hydrocarbon exposure. Int J Toxicol 39(5):465–476. https://doi.org/10.1177/1091581820932875
Borengasser SJ, Faske J, Kang P, Blackburn ML, Badger TM, Shankar K (2014) In utero exposure to prepregnancy maternal obesity and postweaning high-fat diet impair regulators of mitochondrial dynamics in rat placenta and offspring. Physiol Genomics 46(23):841–850. https://doi.org/10.1152/physiolgenomics.00059.2014
Bozack AK, Rifas-Shiman SL, Coull BA, Baccarelli AA, Wright RO, Amarasiriwardena C, Gold DR, Oken E, Hivert MF, Cardenas A (2021) Prenatal metal exposure, cord blood DNA methylation and persistence in childhood: an epigenome-wide association study of 12 metals. Clin Epigenetics 13:208. https://doi.org/10.1186/s13148-021-01198-z
Breton CV, Landon R, Kahn LG, Enlow MB, Peterson AK, Bastain T, Braun J, Comstock SS, Duarte CS, Hipwell A, Ji H, LaSalle JM, Miller RL, Musci R, Posner J, Schmidt R, Suglia SF, Tung I, Weisenberger D et al (2021) Exploring the evidence for epigenetic regulation of environmental influences on child health across generations. Commun Biol 4:769. https://doi.org/10.1038/s42003-021-02316-6
Brunst KJ, Sanchez-Guerra M, Chiu YM, Wilson A, Coull BA, Kloog I, Schwartz J, Brennan KJ, Bosquet Enlow M, Wright RO, Baccarelli AA, Wright RJ (2018) Prenatal particulate matter exposure and mitochondrial dysfunction at the maternal-fetal interface: Effect modification by maternal lifetime trauma and child sex. Environ Int 112:49–58. https://doi.org/10.1016/j.envint.2017.12.020
Bunkar N, Bhargava A, Khare NK, Mishra PK (2016) Mitochondrial anomalies: driver to age associated degenerative human ailments. Front Biosci (Landmark Ed) 21:769–793. https://doi.org/10.2741/4420
Bunkar N, Sharma J, Chouksey A, Kumari R, Gupta PK, Tiwari R, Lodhi L, Srivastava RK, Bhargava A, Mishra PK (2020) Clostridium perfringens phospholipase C impairs innate immune response by inducing integrated stress response and mitochondrial-induced epigenetic modifications. Cell Signal 75:109776. https://doi.org/10.1016/j.cellsig.2020.109776
Cediel Ulloa A, Gliga A, Love TM, Pineda D, Mruzek DW, Watson GE, Davidson PW, Shamlaye CF, Strain JJ, Myers GJ, van Wijngaarden E, Ruegg J, Broberg K (2021) Prenatal methylmercury exposure and DNA methylation in seven-year-old children in the Seychelles Child Development Study. Environ Int 147:106321. https://doi.org/10.1016/j.envint.2020.106321
Chen X, Zhou Y, Hu C, Xia W, Xu S, Cai Z, Li Y (2020) Prenatal exposure to benzotriazoles and benzothiazoles and cord blood mitochondrial DNA copy number: a prospective investigation. Environ Int 143:105920. https://doi.org/10.1016/j.envint.2020.105920
Chen T, Wang X, Jia J, Wang D, Gao Y, Yang X, Zhang S, Niu P, Shi Z (2022) Reduced mitochondrial DNA copy number in occupational workers from brominated flame retardants manufacturing plants. Sci Total Environ 809:151086. https://doi.org/10.1016/j.scitotenv.2021.151086
Deodati A, Inzaghi E, Cianfarani S (2020) Epigenetics and in utero acquired predisposition to metabolic disease. Front Genet 10:1270. https://doi.org/10.3389/fgene.2019.01270
Dhar SK, Scott T, Wang C, Fan TWM, St Clair DK (2022) Mitochondrial superoxide targets energy metabolism to modulate epigenetic regulation of NRF2-mediated transcription. Free Radic Biol Med 179:181–189. https://doi.org/10.1016/j.freeradbiomed.2021.12.309
Dostal V, Churchill MEA (2019) Cytosine methylation of mitochondrial DNA at CpG sequences impacts transcription factor A DNA binding and transcription. Biochim Biophys Acta Gene Regul Mech 1862(5):598–607. https://doi.org/10.1016/j.bbagrm.2019.01.006
Fessler E, Eckl EM, Schmitt S, Mancilla IA, Meyer-Bender MF, Hanf M, Philippou-Massier J, Krebs S, Zischka H, Jae LT (2020) A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol. Nature 579(7799):433–437. https://doi.org/10.1038/s41586-020-2076-4
Fujii R, Sato S, Tsuboi Y, Cardenas A, Suzuki K (2021) DNA methylation as a mediator of associations between the environment and chronic diseases: a scoping review on application of mediation analysis. Epigenetics 1-27. https://doi.org/10.1080/15592294.2021.1959736
Gureev AP, Shaforostova EA, Popov VN (2019) Regulation of mitochondrial biogenesis as a way for active longevity: interaction between the Nrf2 and PGC-1α signaling pathways. Front Genet 10:435. https://doi.org/10.3389/fgene.2019.00435
Gyllenhammer LE, Entringer S, Buss C, Wadhwa PD (2020) Developmental programming of mitochondrial biology: a conceptual framework and review. Proc R Soc B 287:20192713. https://doi.org/10.1098/rspb.2019.2713
Hanson MA, Gluckman PD (2015) Developmental origins of health and disease--global public health implications. Best Pract Res Clin Obstet Gynaecol 29(1):24–31. https://doi.org/10.1016/j.bpobgyn.2014.06.007
Hillen HS, Temiakov D, Cramer P (2018) Structural basis of mitochondrial transcription. Nat Struct Mol Biol 25(9):754–765. https://doi.org/10.1038/s41594-018-0122-9
Janssen BG, Byun HM, Gyselaers W, Lefebvre W, Baccarelli AA, Nawrot TS (2015) Placental mitochondrial methylation and exposure to airborne particulate matter in the early life environment: an ENVIRONAGE birth cohort study. Epigenetics 10(6):536–544. https://doi.org/10.1080/15592294.2015.1048412
Jiang S, Teague AM, Tryggestad JB, Lyons TJ, Chernausek SD (2020) Foetal circulating human resistin increases in diabetes during pregnancy and impairs placental mitochondrial biogenesis. Mol Med 26(1):76. https://doi.org/10.1186/s10020-020-00205-y
Johnson RF, Witzel II, Perkins ND (2011) p53-dependent regulation of mitochondrial energy production by the RelA subunit of NF-kappaB. Cancer Res 71:5588–5597. https://doi.org/10.1158/0008-5472.CAN-10-4252
Kasai S, Yamazaki H, Tanji K, Engler MJ, Matsumiya T, Itoh K (2019) Role of the ISR-ATF4 pathway and its cross talk with Nrf2 in mitochondrial quality control. J Clin Biochem Nutr 64(1):1–12. https://doi.org/10.3164/jcbn.18-37
Khan S, Raghuram GV, Bhargava A, Pathak N, Chandra DH, Jain SK, Mishra PK (2011) Role and clinical significance of lymphocyte mitochondrial dysfunction in type 2 diabetes mellitus. Transl Res 158(6):344–359. https://doi.org/10.1016/j.trsl.2011.08.007
Kundakovic M, Jaric I (2017) The epigenetic link between prenatal adverse environments and neurodevelopmental disorders. Genes (Basel) 8(3):104. https://doi.org/10.3390/genes8030104
Ladd-Acosta C, Feinberg JI, Brown SC, Lurmann FW, Croen LA, Hertz-Picciotto I, Newschaffer CJ, Feinberg AP, Fallin MD, Volk HE (2019) Epigenetic marks of prenatal air pollution exposure found in multiple tissues relevant for child health. Environ Int 126:363–376. https://doi.org/10.1016/j.envint.2019.02.028
Laforge M, Rodrigues V, Silvestre R, Gautier C, Weil R, Corti O, Estaquier J (2016) NF-kappaB pathway controls mitochondrial dynamics. Cell Death Differ 23:89–98. https://doi.org/10.1038/cdd.2015.42
Li Y, Takeda K, Yamamoto M, Kawada T (2021) Potential of NRF2 pathway in preventing developmental and reproductive toxicity of fine particles. Front Toxicol 3:710225. https://doi.org/10.3389/ftox.2021.710225
Lopes AFC (2020) Mitochondrial metabolism and DNA methylation: a review of the interaction between two genomes. Clin Epigenetics 12:182. https://doi.org/10.1186/s13148-020-00976-5
McCabe CF, Padmanabhan V, Dolinoy DC, Domino SE, Jones TR, Bakulski KM, Goodrich JM (2020) Maternal environmental exposure to bisphenols and epigenome-wide DNA methylation in infant cord blood. Environ Epigenet 6(1):dvaa021. https://doi.org/10.1093/eep/dvaa021
Mishra PK, Raghuram GV, Panwar H, Jain D, Pandey H, Maudar KK (2009) Mitochondrial oxidative stress elicits chromosomal instability after exposure to isocyanates in human kidney epithelial cells. Free Radic Res 43(8):718–728. https://doi.org/10.1080/10715760903037699
Mishra PK, Khan S, Bhargava A, Panwar H, Banerjee S, Jain SK, Maudar KK (2010) Regulation of isocyanate-induced apoptosis, oxidative stress, and inflammation in cultured human neutrophils: isocyanate-induced neutrophils apoptosis. Cell Biol Toxicol 26(3):279–291. https://doi.org/10.1007/s10565-009-9127-9
Mishra PK, Raghuram GV, Jain D, Jain SK, Khare NK, Pathak N (2014) Mitochondrial oxidative stress-induced epigenetic modifications in pancreatic epithelial cells. Int J Toxicol 33(2):116–129. https://doi.org/10.1177/1091581814524064
Mishra PK, Bunkar N, Raghuram GV, Khare NK, Pathak N, Bhargava A (2015) Epigenetic dimension of oxygen radical injury in spermatogonial epithelial cells. Reprod Toxicol 52:40–56. https://doi.org/10.1016/j.reprotox.2015.02.006
Mishra PK, Bunkar N, Singh RD, Kumar R, Gupta PK, Tiwari R, Lodhi L, Bhargava A, Chaudhury K (2021) Comparative profiling of epigenetic modifications among individuals living in different high and low air pollution zones: a pilot study from India. Environ Adv 4:100052. https://doi.org/10.1016/j.envadv.2021.100052
Mishra PK, Bhargava A, Kumari R, Bunkar N, Chauhan P, Mukherjee S, Shandilya R, Singh RD, Tiwari R, Chaudhury K (2022) Integrated mitoepigenetic signalling mechanisms associated with airborne particulate matter exposure: a cross-sectional pilot study. Atm Pollut Res 13(5):101399. https://doi.org/10.1016/j.apr.2022.101399
Mohammed SA, Ambrosini S, Lüscher T, Paneni F, Costantino S (2020) Epigenetic control of mitochondrial function in the vasculature. Front Cardiovasc Med 7:28. https://doi.org/10.3389/fcvm.2020.00028
Nan J, Hu H, Sun Y, Zhu L, Wang Y, Zhong Z, Zhao J, Zhang N, Wang Y, Wang Y, Ye J, Zhang L, Hu X, Zhu W, Wang J (2017) TNFR2 stimulation promotes mitochondrial fusion via Stat3- and NF-kB-dependent activation of OPA1 expression. Circ Res 121:392–410. https://doi.org/10.1161/CIRCRESAHA.117.311143
Navasumrit P, Chaisatra K, Promvijit J, Parnlob V, Waraprasit S, Chompoobut C, Binh TT, Hai DN, Bao ND, Hai NK, Kim KW, Samson LD, Graziano JH, Mahidol C, Ruchirawat M (2019) Exposure to arsenic in utero is associated with various types of DNA damage and micronuclei in newborns: a birth cohort study. Environ Health 18(1):51. https://doi.org/10.1186/s12940-019-0481-7
Nozadi SS, Li L, Luo L, MacKenzie D, Erdei E, Du R, Roman CW, Hoover J, O'Donald E, Burnette C, Lewis J (2021) Prenatal metal exposures and infants’ developmental outcomes in a Navajo population. Int J Environ Res Public Health 19(1):425. https://doi.org/10.3390/ijerph19010425
Panwar H, Jain D, Khan S, Pathak N, Raghuram GV, Bhargava A, Banerjee S, Mishra PK (2013) Imbalance of mitochondrial-nuclear cross talk in isocyanate mediated pulmonary endothelial cell dysfunction. Redox Biol 1(1):163–171. https://doi.org/10.1016/j.redox.2013.01.009
Raghuram GV, Pathak N, Jain D, Panwar H, Pandey H, Jain SK, Mishra PK (2010a) Molecular mechanisms of isocyanate induced oncogenic transformation in ovarian epithelial cells. Reprod Toxicol 30(3):377–386. https://doi.org/10.1016/j.reprotox.2010.05.087
Raghuram GV, Pathak N, Jain D, Pandey H, Panwar H, Jain SK, Banerjee S, Mishra PK (2010b) Molecular characterization of isocyanate-induced male germ-line genomic instability. J Environ Pathol Toxicol Oncol 29(3):213–234. https://doi.org/10.1615/jenvironpatholtoxicoloncol.v29.i3.50
Rippo MR, Olivieri F, Monsurro V, Prattichizzo F, Albertini MC, Procopio AD (2014) MitomiRs in human inflamm-aging: a hypothesis involving miR-181a, miR-34a and miR-146a. Exp Gerontol 56:154–163. https://doi.org/10.1016/j.exger.2014.03.002
Sharma J, Parsai K, Raghuwanshi P, Ali SA, Tiwari V, Bhargava A, Mishra PK (2021a) Emerging role of mitochondria in airborne particulate matter-induced immunotoxicity. Environ Pollut 270:116242. https://doi.org/10.1016/j.envpol.2020.116242
Sharma J, Kumari R, Bhargava A, Tiwari R, Mishra PK (2021b) Mitochondrial-induced epigenetic modifications: from biology to clinical translation. Curr Pharm Des 27(2):159–176. https://doi.org/10.2174/1381612826666200826165735
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
Singh R, Mills IG (2021) The interplay between prostate cancer genomics, metabolism, and the epigenome: perspectives and future prospects. Front Oncol 11:704353. https://doi.org/10.3389/fonc.2021.704353
Sly P, Blake T, Islam Z (2021) Impact of prenatal and early life environmental exposures on normal human development. Paediatr Respir Rev 40:10–14. https://doi.org/10.1016/j.prrv.2021.05.007
Stewart KR, Veselovska L, Kelsey G (2016) Establishment and functions of DNA methylation in the germline. Epigenomics 8(10):1399–1413. https://doi.org/10.2217/epi-2016-0056
Stoccoro A, Coppedè F (2021) Mitochondrial DNA methylation and human diseases. Int J Mol Sci 22:4594. https://doi.org/10.3390/ijms22094594
Stoccoro A, Smith AR, Baldacci F, Del Gamba C, Lo Gerfo A, Ceravolo R, Lunnon K, Migliore L, Coppedè F (2021) Mitochondrial D-loop region methylation and copy number in peripheral blood DNA of Parkinson’s disease patients. Genes (Basel) 12(5):720. https://doi.org/10.3390/genes12050720
Suárez-Rivero JM, Villanueva-Paz M, de la Cruz-Ojeda P, de la Mata M, Cotán D, Oropesa-Ávila M, de Lavera I, Álvarez-Córdoba M, Luzón-Hidalgo R, Sánchez-Alcázar JA (2016) Mitochondrial dynamics in mitochondrial diseases. Diseases 5(1):1. https://doi.org/10.3390/diseases5010001
Sussan TE, Sudini K, Talbot CC Jr, Wang X, Wills-Karp M, Burd I, Biswal S (2017) Nrf2 regulates gene-environment interactions in an animal model of intrauterine inflammation: Implications for preterm birth and prematurity. Sci Rep 7:40194. https://doi.org/10.1038/srep40194
Vos S, Nawrot TS, Martens DS, Byun HM, Janssen BG (2021) Mitochondrial DNA methylation in placental tissue: a proof of concept study by means of prenatal environmental stressors. Epigenetics 16(2):121–131. https://doi.org/10.1080/15592294.2020.1790923
Wang Y, Perera F, Guo J, Riley KW, Durham T, Ross Z, Ananth CV, Baccarelli A, Wang S, Herbstman JB (2022) A methodological pipeline to generate an epigenetic marker of prenatal exposure to air pollution indicators. Epigenetics 17(1):32–40. https://doi.org/10.1080/15592294.2021.1872926
Xia Y, Brewer A, Bell JT (2021) DNA methylation signatures of incident coronary heart disease: findings from epigenome-wide association studies. Clin Epigenetics 13(1):186. https://doi.org/10.1186/s13148-021-01175-6
Acknowledgements
The technical assistance received from Ms. Anju Chouksey and Mr. Pushpendra Kumar Gupta for sample collection and processing is acknowledged.
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PKM received financial support from the Indian Council of Medical Research (ICMR), Department of Health Research (DHR), Ministry of Health and Family Welfare (MoHFW), Government of India, New Delhi(Project ID: 65/1/PM/NIREH/2016-NCD-II). RK also received Senior Research Fellowship from ICMR.
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Pradyumna Kumar Mishra: conceptualization, supervision, project administration, funding acquisition, resources, writing-original draft preparation. Roshani Kumari: investigation, visualization, formal analysis. Arpit Bhargava: Writing-original draft preparation, investigation, formal analysis. Neha Bunkar: investigation, visualization. Prachi Chauhan: visualization, investigation. Rajnarayan Tiwari: writing-reviewing and editing, formal analysis. Ruchita Shandilya: investigation, formal analysis. Rupesh Kumar Srivastava: writing-reviewing and editing, formal analysis. Radha Dutt Singh: writing-reviewing and editing, investigation. All authors read and approved the manuscript.
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Mishra, P.K., Kumari, R., Bhargava, A. et al. Prenatal exposure to environmental pro-oxidants induces mitochondria-mediated epigenetic changes: a cross-sectional pilot study. Environ Sci Pollut Res 29, 74133–74149 (2022). https://doi.org/10.1007/s11356-022-21059-3
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DOI: https://doi.org/10.1007/s11356-022-21059-3