Abstract
Adverse experiences in childhood are associated with altered hypothalamic–pituitary–adrenal (HPA) axis function and negative health outcomes throughout life. It is now commonly accepted that abuse and neglect can alter epigenetic regulation of HPA genes. Accumulated evidence suggests harsh parenting practices such as spanking are also strong predictors of negative health outcomes. We predicted harsh parenting at 2.5 years old would predict HPA gene DNA methylation similarly to abuse and neglect, and cortisol output at 8.5 years old. Saliva samples were collected three times a day across 3 days to estimate cortisol diurnal slopes. Methylation was quantified using the Illumina Infinium MethylationEPIC array BeadChip (850 K) with DNA collected from buccal cells. We used principal components analysis to compute a summary statistic for CpG sites across candidate genes. The first and second components were used as outcome variables in mixed linear regression analyses with harsh parenting as a predictor variable. We found harsh parenting significantly predicted methylation of several HPA axis genes, including novel gene associations with AVPRB1, CRHR1, CRHR2, and MC2R (FDR corrected p < 0.05). Further, we found NR3C1 methylation predicted a steeper diurnal cortisol slope. Our results extend the current literature by demonstrating harsh parenting may influence DNA methylation similarly to more extreme early life experiences such as abuse and neglect. Further, we show NR3C1 methylation is associated with diurnal HPA function. Elucidating the molecular consequences of harsh parenting on health can inform best parenting practices and provide potential treatment targets for common complex disorders.
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References
Adam EK, Kumari M (2009) Assessing salivary cortisol in large-scale, epidemiological research. Psychoneuroendocrinology. https://doi.org/10.1016/j.psyneuen.2009.06.011
Afifi TO, Ford D, Gershoff ET et al (2017) Spanking and adult mental health impairment: the case for the designation of spanking as an adverse childhood experience. Child Abuse Negl. https://doi.org/10.1016/j.chiabu.2017.01.014
American Psychological Association (2019) Resolution on physical discipline of children by parents
Anacker C, O’Donnell KJ, Meaney MJ (2014) Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function. Dialogues Clin Neurosci 16:321
Aryee MJ, Jaffe AE, Corrada-Bravo H et al (2014) Minfi: a flexible and comprehensive bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. https://doi.org/10.1093/bioinformatics/btu049
Bell JT, Pai AA, Pickrell JK et al (2011) DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol. https://doi.org/10.1186/gb-2011-12-1-r10
Berlin LJ, Ispa JM, Fine MA et al (2009) Correlates and consequences of spanking and verbal punishment for low-income white, African American, and Mexican American toddlers. Child Dev. https://doi.org/10.1111/j.1467-8624.2009.01341.x
Caldwell B, Bradley R (1984) Home observation for measurement of the environment (HOME)-revised edition. Univ Arkansas Little Rock. https://doi.org/10.1097/00006199
Chase-Lansdale PL, Pittman LD (2002) Welfare reform and parenting: reasonable expectations. Fut Child 12:166
Child Trends (2015) Attitudes toward spanking: indicators on children and youth. https://www.childtrends.org/indicators/attitudes-toward-spanking
Ciciolla L, Luthar SS (2019) Invisible household labor and ramifications for adjustment: mothers as captains of households. Sex Roles. https://doi.org/10.1007/s11199-018-1001-x
Conradt E, Fei M, LaGasse L et al (2015) Prenatal predictors of infant self-regulation: the contributions of placental DNA methylation of NR3C1 and neuroendocrine activity. Front Behav Neurosci. https://doi.org/10.3389/fnbeh.2015.00130
Dadds MR, Moul C, Hawes DJ et al (2015) Individual differences in childhood behavior disorders associated with epigenetic modulation of the cortisol receptor gene. Child Dev. https://doi.org/10.1111/cdev.12391
Daskalakis NP, Yehuda R (2014) Site-specific methylation changes in the glucocorticoid receptor exon 1F promoter in relation to life adversity: systematic review of contributing factors. Front Neurosci 8:1–8. https://doi.org/10.3389/fnins.2014.00369
Davies MN, Volta M, Pidsley R et al (2012) Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood. Genome Biol. https://doi.org/10.1186/gb-2012-13-6-r43
De Bellis MD, Zisk A (2014) The biological effects of childhood trauma. Child Adolesc Psychiatr Clin N Am. https://doi.org/10.1016/j.chc.2014.01.002
Dressendörfer RA, Kirschbaum C, Rohde W et al (1992) Synthesis of a cortisol-biotin conjugate and evaluation as a tracer in an immunoassay for salivary cortisol measurement. J Steroid Biochem Mol Biol. https://doi.org/10.1016/0960-0760(92)90294-S
Du P, Zhang X, Huang CC et al (2010) Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis. BMC Bioinform. https://doi.org/10.1186/1471-2105-11-587
Dube SR, Fairweather D, Pearson WS et al (2009) Cumulative childhood stress and autoimmune diseases in adults. Psychosom Med. https://doi.org/10.1097/PSY.0b013e3181907888
Dunn EC, Soare TW, Zhu Y, Simpkin AJ, Suderman MJ, Klengel T, Smith ADAC, Ressler K (2019) Sensitive periods for the effect of childhood adversity on DNA methylation: results from a prospective, longitudinal study. Biol Psychiatry 85:838
Elliott E, Ezra-Nevo G, Regev L et al (2010) Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice. Nat Neurosci 13:1351–1353. https://doi.org/10.1038/nn.2642
Farrell C, Doolin K, O’Leary N et al (2018) DNA methylation differences at the glucocorticoid receptor gene in depression are related to functional alterations in hypothalamic–pituitary–adrenal axis activity and to early life emotional abuse. Psychiatry Res 265:341–348. https://doi.org/10.1016/j.psychres.2018.04.064
Felitti VJ (2009) Adverse childhood experiences and adult health. Acad Pediatr. https://doi.org/10.1016/j.acap.2009.03.001
Franklin TB, Russig H, Weiss IC et al (2010) Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry 68:408–415. https://doi.org/10.1016/j.biopsych.2010.05.036
Franklin TB, Linder N, Russig H et al (2011) Influence of early stress on social abilities and serotonergic functions across generations in mice. PLoS ONE. https://doi.org/10.1371/journal.pone.0021842
Fritz MS, MacKinnon DP (2007) Required sample size to detect the mediated effect. Psychol Sci. https://doi.org/10.1111/j.1467-9280.2007.01882.x
Gershoff ET (2002) Corporal punishment by parents and associated child behaviors and experiences: a meta-analytic and theoretical review. Psychol Bull 128:539–579. https://doi.org/10.1037/0033-2909.128.4.539
Gershoff ET (2010) More harm than good: a summary of scientific research on the intended and unintended effects of corporal punishment on children. Law Contemp Probl 73:31–56. https://doi.org/10.1525/sp.2007.54.1.23
Gershoff ET, Grogan-kaylor A, Lansford JE et al (2011) NIH Public Access. Child Dev 81:487–502. https://doi.org/10.1111/j.1467-8624.2009.01409.x.Parent
Gershoff ET, Lansford JE, Sexton HR et al (2012) Longitudinal links between spanking and children’s externalizing behaviors in a national sample of White, Black, Hispanic, and Asian American Families and Arnold. Child Dev 83:838–843
Gershoff ET, Grogan-kaylor A, Gershoff ET, Grogan-kaylor A (2016) Spanking and child outcomes: old controversies and new meta-analyses. J Fam Pshycol 30:453–469. https://doi.org/10.1037/fam0000191
Granger DA, Fortunato CK, Beltzer EK et al (2012) Focus on methodology: salivary bioscience and research on adolescence: an integrated perspective. J Adolesc. https://doi.org/10.1016/j.adolescence.2012.01.005
Grasso D, Boonsiri J, Lipschitz D et al (2009) Posttraumatic stress disorder: The missed diagnosis. Child Welfare 88:157
Hecker T, Radtke KM, Hermenau K et al (2016) Associations among child abuse, mental health, and epigenetic modifications in the proopiomelanocortin gene (POMC): A study with children in Tanzania. Dev Psychopathol 28:1401–1412. https://doi.org/10.1017/S0954579415001248
Heim C, Nemeroff CB (2001) The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry 49:1023–1039
Houseman EA, Accomando WP, Koestler DC et al (2012) DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics. https://doi.org/10.1186/1471-2105-13-86
Jackson AP, Choi J, Preston KSJ (2019) Harsh Parenting and Black Boys’ Behavior Problems: Single Mothers’ Parenting Stress and Nonresident Fathers’ Involvement. Fam Relat. https://doi.org/10.1111/fare.12373
Kelley ML, Lawrence HR, Milletich RJ et al (2015) Modeling risk for child abuse and harsh parenting in families with depressed and substance-abusing parents. Child Abus Negl. https://doi.org/10.1016/j.chiabu.2015.01.017
Klengel T, Mehta D, Anacker C et al (2013) Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci 16:33–41. https://doi.org/10.1038/nn.3275
Kundakovic M, Champagne FA (2015) Early-life experience, Epigenetics, and the developing brain. Neuropsychopharmacology 40:141–153. https://doi.org/10.1038/npp.2014.140
Labonte B, Yerko V, Gross J et al (2012) Differential glucocorticoid receptor exon 1(B), 1(C), and 1(H) expression and methylation in suicide completers with a history of childhood abuse. Biol Psychiatry 72:41–48. https://doi.org/10.1016/j.biopsych.2012.01.034
Lee Y (2013) Adolescent motherhood and capital: Interaction effects of race/ethnicity on harsh parenting. J Community Psychol. https://doi.org/10.1002/jcop.21517
Lee SJ, Altschul I, Gershoff ET (2013) Does warmth moderate longitudinal associations between maternal spanking and child aggression in early childhood? Dev Psychol. https://doi.org/10.1037/a0031630
Lemery-Chalfant K, Clifford S, McDonald K et al (2013) Arizona twin project: A focus on early resilience. Twin Res Hum Genet. https://doi.org/10.1017/thg.2012.107
Lewis CR, Olive MF (2014) Early-life stress interactions with the epigenome: potential mechanisms driving vulnerability toward psychiatric illness. Behav Pharmacol. https://doi.org/10.1097/FBP.0000000000000057
Lewis CR, Bastle RM, Manning TB et al (2016) Interactions between early life stress, nucleus accumbens MeCP2 expression, and methamphetamine self-administration in male rats. Neuropsychopharmacology. https://doi.org/10.1038/npp.2016.96
Lewis CR, Henderson-Smith A, Breitenstein RS et al (2019) Dopaminergic gene methylation is associated with cognitive performance in a childhood monozygotic twin study. Epigenetics. https://doi.org/10.1080/15592294.2019.1583032
Liu J, Morgan M, Hutchison K, Calhoun VD (2010) A study of the influence of sex on genome wide methylation. PLoS ONE. https://doi.org/10.1371/journal.pone.0010028
Lowe R, Gemma C, Beyan H et al (2013) Buccals are likely to be a more informative surrogate tissue than blood for epigenome-wide association studies. Epigenetics. https://doi.org/10.4161/epi.24362
Lutz P-E, Turecki G (2013) DNA methylation and childhood maltreatment: from animal models to human studies. Neuroscience. https://doi.org/10.1016/j.neuroscience.2013.07.069
Masterpasqua F (2009) Psychology and epigenetics. Rev Gen Psychol. https://doi.org/10.1037/a0016301
McGowan PO, Sasaki A, D’Alessio AC et al (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12:342–348. https://doi.org/10.1038/nn.2270
McLoyd VC, Kaplan R, Hardaway CR, Wood D (2007) Does endorsement of physical discipline matter? Assessing moderating influences on the maternal and child psychological correlates of physical discipline in african american families. J Fam Psychol. https://doi.org/10.1037/0893-3200.21.2.165
Meaney MJ, Szyf M (2005) Environmental programming of stress responses through DNA methylation: Life at the interface between a dynamic environment and a fixed genome. Dialogues Clin Neurosci. https://doi.org/10.1523/JNEUROSCI.3652-05.2005
Michels N, Sioen I, Huybrechts I et al (2012) Negative life events, emotions and psychological difficulties as determinants of salivary cortisol in Belgian primary school children. Psychoneuroendocrinology. https://doi.org/10.1016/j.psyneuen.2012.02.004
Mitchell C, Schneper LM, Notterman DA (2016) DNA methylation, early life environment, and health outcomes. Pediatr Res 79:211–219
Model F, Adorján P, Olek A, Piepenbrock C (2001) Feature selection for DNA methylation based cancer classification. Bioinformatics. https://doi.org/10.1093/bioinformatics/17.suppl_1.S157
Moore LD, Le T, Fan G (2013) DNA methylation and its basic function. Neuropsychopharmacology 38:23
Murgatroyd C, Spengler D (2014) Polycomb binding precedes early-life stress responsive DNA methylation at the Avp enhancer. PLoS ONE 9:1–9. https://doi.org/10.1371/journal.pone.0090277
Murgatroyd C, Patchev AV, Wu Y et al (2009) Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci 12:1559–1566. https://doi.org/10.1038/nn.2436
Neppl TK, Senia JM, Donnellan MB (2016) Effects of economic hardship: Testing the Family Stress Model over time. J Fam Psychol. https://doi.org/10.1037/fam0000168
O’Brien Caughy M, Miller TL, Genevro JL et al (2003) The effects of Healthy Steps on discipline strategies of parents of young children. J Appl Dev Psychol. https://doi.org/10.1016/j.appdev.2003.08.004
Oberlander TF, Weinberg J, Papsdorf M et al (2008) Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 3:97–106. https://doi.org/10.4161/epi.3.2.6034
Perroud N, Paoloni-Giacobino A, Prada P et al (2011) Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma. Transl Psychiatry 1:e59. https://doi.org/10.1038/tp.2011.60
Perroud N, Dayer A, Piguet C et al (2014) Childhood maltreatment and methylation of the glucocorticoid receptor gene NR3C1 in bipolar disorder. Br J Psychiatry. https://doi.org/10.1192/bjp.bp.112.120055
Repetti RL, Taylor SE, Seeman TE (2002) Risky families: Family social environments and the mental and physical health of offspring. Psychol Bull 128:330
Rodriguez CM (2003) Parental discipline and abuse potential affects on child depression, anxiety, and attributions. J Marriage Fam. https://doi.org/10.1111/j.1741-3737.2003.00809.x
Romens SE, McDonald J, Svaren J, Pollak SD (2014) Associations between early life stress and gene methylation in children. Child Dev 00:1–7. https://doi.org/10.1111/cdev.12270
Romens SE, Mcdonald J, Svaren J, Pollak SD (2015) Associations between early life stress and gene methylation in children. Child Dev 86:303–309. https://doi.org/10.1111/cdev.12270
Roth TL, Lubin FD, Funk AJ, Sweatt JD (2009) Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry 65:760–769. https://doi.org/10.1016/j.biopsych.2008.11.028
Schofield TJ, Conger RD, Gonzales JA, Merrick MT (2016) Harsh parenting, physical health, and the protective role of positive parent-adolescent relationships. Soc Sci Med. https://doi.org/10.1016/j.socscimed.2016.03.027
Sheehan MJ, Watson MW (2008) Reciprocal influences between maternal discipline techniques and aggression in children and adolescents. Aggress Behav. https://doi.org/10.1002/ab.20241
Shonkoff JP, Boyce WT, McEwen BS (2009) Neuroscience, molecular biology, and the childhood roots of health disparities: building a new framework for health promotion and disease prevention. JAMA 301:2252
Shonkoff JP, Garner AS, Siegel BS et al (2012) The lifelong effects of early childhood adversity and toxic stress. Pediatrics. https://doi.org/10.1542/peds.2011-2663
Sigel IE, McGillicuddy-DeLisi AV, Goodnow JJ (1992) Parental belief systems: psychological consequences for children. In: Dix T (ed) Parenting on behalf of the child: empathic goals in the regulation of responsive parenting. Psychology Press, London
Stonawski V, Frey S, Golub Y et al (2018) Associations of prenatal depressive symptoms with DNA methylation of HPA axis-related genes and diurnal cortisol profiles in primary school-aged children. Dev Psychopathol 31:419
Taylor SE, Way BM, Seeman TE (2011) Early adversity and adult health outcomes. Dev Psychopathol. https://doi.org/10.1017/S0954579411000411
Te WM, Kenny S (2014) Longitudinal links between fathers’ and mothers’ harsh verbal discipline and adolescents’ conduct problems and depressive symptoms. Child Dev. https://doi.org/10.1111/cdev.12143
Teschendorff AE, Breeze CE, Zheng SC, Beck S (2017) A comparison of reference-based algorithms for correcting cell-type heterogeneity in Epigenome-Wide Association Studies. BMC Bioinform. https://doi.org/10.1186/s12859-017-1511-5
Turney K (2014) The intergenerational consequences of mass incarceration: implications for children’s co-residence and contact with grandparents. Soc Forces. https://doi.org/10.1093/sf/sou062
Tyrka AR, Price LH, Marsit C et al (2012) Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: preliminary findings in healthy adults. PLoS ONE 7:e30148. https://doi.org/10.1371/journal.pone.0030148
Tyrka AR, Ridout KK, Parade SH et al (2015) Childhood maltreatment and methylation of FK506 binding protein 5 gene (FKBP5). Dev Psychopathol. https://doi.org/10.1017/S0954579415000991
Vaiserman AM, Koliada AK (2017) Early-life adversity and long-term neurobehavioral outcomes: epigenome as a bridge? Hum Genomics 11:34
Van Bodegom M, Homberg JR, Henckens MJAG (2017) Modulation of the hypothalamic–pituitary–adrenal axis by early life stress exposure. Front Cell Neurosci 11:87
van der Knaap LJ, Riese H, Hudziak JJ et al (2014) Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study. Transl Psychiatry 4:e381. https://doi.org/10.1038/tp.2014.22
van der Knaap LJ, Oldehinkel AJ, Verhulst FC et al (2015) Glucocorticoid receptor gene methylation and HPA-axis regulation in adolescents: The TRAILS study. Psychoneuroendocrinology 58:46–50. https://doi.org/10.1016/j.psyneuen.2015.04.012
Wang W, Feng J, Ji C et al (2017) Increased methylation of glucocorticoid receptor gene promoter 1Fin peripheral blood of patients with generalized anxiety disorder. J Psychiatr Res 91:18–25. https://doi.org/10.1016/j.jpsychires.2017.01.019
Weaver ICG, Diorio J, Seckl JR et al (2004) Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites. Ann N Y Acad Sci 1024:182–212. https://doi.org/10.1196/annals.1321.099
Weder N, Zhang H, Jensen K et al (2014) Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry. J Am Acad Child Adolesc Psychiatry. https://doi.org/10.1016/j.jaac.2013.12.025
Wu Y, Patchev AV, Daniel G et al (2014) Early-Life stress reduces dna methylation of the pomc gene in male mice. Endocrinology 155:1751–1762. https://doi.org/10.1210/en.2013-1868
Zhang T-Y, Hellstrom IC, Bagot RC et al (2010) Maternal care and DNA methylation of a glutamic acid decarboxylase 1 promoter in rat hippocampus. J Neurosci 30:13130–13137. https://doi.org/10.1523/JNEUROSCI.1039-10.2010
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This work was financially supported by Grants from R01 HD079520, R01 HD086085, and Science Foundation Arizona. The funding sources played no role in the design of the study or the collection, analysis, and interpretation of data, or the writing of the manuscript.
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CL designed the study, performed the microarrays, analyses, and was the primary writer of the manuscript. RB collected participant data and samples. AH assisted in microarrays and data preparation. HS ran analyses and assisted in manuscript preparation. IP assisted in data analysis and manuscript preparation. MH provided genomic and methodological expertise. LD was in charge of cortisol collection, measurement, and analysis. KL was in charge of collection and maintenance of longitudinal behavioral data, and provided assistance in writing the manuscript.
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Lewis, C.R., Breitenstein, R.S., Henderson, A. et al. Harsh Parenting Predicts Novel HPA Receptor Gene Methylation and NR3C1 Methylation Predicts Cortisol Daily Slope in Middle Childhood. Cell Mol Neurobiol 41, 783–793 (2021). https://doi.org/10.1007/s10571-020-00885-4
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DOI: https://doi.org/10.1007/s10571-020-00885-4