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Cited by 86Circadian rhythm and melatoninBirth, Development, and HealthMaternal Mental Health During Pregnancy and Postpartum

Maternal and Early-Life Circadian Disruption Have Long-Lasting Negative Consequences on Offspring Development and Adult Behavior in Mice

Open access
Smarr, Benjamin L., Grant, Azure D., Perez, Luz, Zucker, Irving, Kriegsfeld, Lance J.·2017·Scientific Reports
DOI 10.1038/s41598-017-03406-4PMC PMC5468226
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Abstract

Modern life involves chronic circadian disruption through artificial light and these disruptions are associated with numerous mental and physical health maladies. Because the developing nervous system is particularly vulnerable to perturbation, we hypothesized that early-life circadian disruption would negatively impact offspring development and adult function. Pregnant mice were subjected to chronic circadian disruption from the time of uterine implantation through weaning. To dissociate in utero from postnatal effects, a subset of litters was cross-fostered at birth from disrupted dams to control dams and vice versa. Postnatal circadian disruption was associated with reduced adult body mass, social avoidance, and hyperactivity. In utero disruption resulted in more pronounced social avoidance and hyperactivity, phenotypes not abrogated by cross-fostering to control mothers. To examine whether circadian disruption affects development by acting as an early life stressor, we examined birthweight, litter size, maternal cannibalism, and epigenetic modifications. None of these variables differed between control and disrupted dams, or resembled patterns seen following early-life stress. Our findings indicate that developmental chronic circadian disruption permanently affects somatic and behavioral development in a stage-of-life-dependent manner, independent of early life stress mechanisms, underscoring the importance of temporal structure during development, both in utero and early postnatal life.

AI snapshot

Written from the paper’s full text.

TL;DR

Chronic circadian disruption during gestation and early postnatal life in mice produced lasting adult somatic and behavioral changes, with effects depending on developmental timing. In utero disruption drove more pronounced social avoidance and hyperactivity, while postnatal disruption more strongly reduced adult body mass, and these effects did not appear to be mediated by early-life stress mechanisms.

Key findings

  • Adult body mass at postnatal day 60 was lower in disrupted offspring: females p = 2.1 × 10−3 and males p = 2.2 × 10−3; cross-fostered litters also showed a group effect (males χ2 = 20.12, p = 0.0012; females χ2 = 11.11, p = 0.049), with rearing shifts more consistently linked to lower adult mass than in utero shifts.
  • Shifted offspring spent significantly less time near a novel mouse in the social approach task (χ2 = 80.99, p = 2.89 × 10−16), and in utero disruption produced more pronounced social avoidance that was not rescued by cross-fostering to control mothers.
  • In the elevated plus maze, groups differed in stereotyped anxiety-like movements (χ2 = 87.35, p = 2.42 × 10−17), with disrupted groups generally showing more such movements, but no significant difference in time in open vs. closed arms and no significant novel object recognition deficits.
  • DCCD did not mimic early-life stress: birth weight, litter size, cannibalism, and methylation at BDNF IV or GR 17 did not differ between control and disrupted groups; SS vs. CC showed non-significant 3% and 11% methylation increases, compared with average ELS-associated increases of 95% and 135% for the same regions.

Methods

  • Pregnant BALB/c mice were exposed to chronic circadian disruption from gestational day 6 through weaning at p22, consisting of 6 h light-cycle advances every 4 days; cross-fostering at birth generated control, shifted, and all in utero/postnatal permutations (C, S, CC, CS, SC, SS).
  • Adult offspring underwent body-weight tracking, puberty onset assessment, and behavioral testing in sequence: elevated plus maze, social approach, short-term novel object recognition, and long-term novel object recognition; maternal nest building and pup retrieval were also assessed.
  • Analyses used Matlab 2016a with Wilcoxon rank-sum or Kruskal-Wallis tests and Dunn’s post hoc comparisons, alpha p < 0.05; methylation was quantified by bisulfite sequencing at NR3C1 promoter 17 and BDNF promoter IV.

Limitations

  • The paper states that it did not examine body composition or food intake, leaving specific metabolic/feeding mechanisms unresolved; it also notes that daytime behavioral testing may mask subtle DCCD-induced learning deficits that might appear in the early dark phase.
  • The paper states that mechanisms remain unclear, that BALB/c mice have markedly attenuated melatonin production, and that whether a dam with robust melatonin rhythms would rescue prenatal DCCD effects is not known.
  • Evident from the text: findings are from a single mouse strain and cannot establish causal effects in humans; methylation analyses focused on selected promoter regions and selected high/low responders, and maternal behavior tests were limited to C and S groups before cross-fostering.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41598-017-03406-4

Cites

88 of 88 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 95 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Postnatal circadian disruption is associated with social avoidance in mice.

    “Postnatal circadian disruption was associated with reduced adult body mass, social avoidance, and hyperactivity.”
    Quote in the paperSubstantial claim
  • Findingown data

    In utero circadian disruption results in more pronounced hyperactivity than postnatal disruption in mice.

    “In utero disruption resulted in more pronounced social avoidance and hyperactivity, phenotypes not abrogated by cross-fostering to control mothers.”
    Quote in the paperSubstantial claim
  • Findingown data

    The social avoidance and hyperactivity phenotypes resulting from in utero disruption are not abrogated by cross-fostering to control mothers.

    “In utero disruption resulted in more pronounced social avoidance and hyperactivity, phenotypes not abrogated by cross-fostering to control mothers.”
    Quote in the paperSubstantial claim
  • Findingown data

    Postnatal circadian disruption is associated with reduced adult body mass in mice.

    “Postnatal circadian disruption was associated with reduced adult body mass, social avoidance, and hyperactivity.”
    Quote in the paperSubstantial claim
  • Findingown data

    In utero circadian disruption results in more pronounced social avoidance than postnatal disruption in mice.

    “In utero disruption resulted in more pronounced social avoidance and hyperactivity, phenotypes not abrogated by cross-fostering to control mothers.”
    Quote in the paperSubstantial claim
  • May combine two claims. 26
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 26

  • May combine two claims.

    Findingown data

    Birthweight, litter size, maternal cannibalism, and epigenetic modifications did not differ between control and disrupted dams.

    “None of these variables differed between control and disrupted dams, or resembled patterns seen following early-life stress.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Birthweight, litter size, maternal cannibalism, and epigenetic modifications did not resemble patterns seen following early-life stress.

    “None of these variables differed between control and disrupted dams, or resembled patterns seen following early-life stress.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    DCCD caused lower adult weights in males at p60.

    “DCCD did not induce significant differences in body weight by p33 for either sex (females: p = 0.59, males: p = 0.53), but did cause lower adult weights in both females and males (p = 2.1 × 10−3, p = 2.2 × 10−3, respectively) (Fig. 4).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Females weighed less than males regardless of condition at p33 and in adulthood.

    “As expected, females weighed less than males regardless of condition both at p33 (p = 2.4 × 10−4) and in adulthood (p = 7.0 × 10−11).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    33% of shifted dams did not use all nesting material provided, but this difference was not significant.

    “Whereas all C animals built complete nests and used all nesting material, 75% of S dams built incomplete nests (p = 9.3 × 10−3) and 33% did not use all the nesting material provided (p = 0.3, not significant) (Fig. 3a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    All control dams built complete nests and used all nesting material.

    “Whereas all C animals built complete nests and used all nesting material, 75% of S dams built incomplete nests (p = 9.3 × 10−3) and 33% did not use all the nesting material provided (p = 0.3, not significant) (Fig. 3a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both sexes were examined, and no sex differences were apparent in the methylation analysis.

    “Both sexes were examined, and no sex differences were apparent.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SS shows non-significant median increases of 3% and 11% in methylation of BDNF IV and GR17, respectively, compared to CC.

    “Specifically, SS shows non-significant 3% and 11% increases from CC, respectively”
    • Also stated in: § DCCD Does Not Mimic Early Life Stress · plain
      “with non-significant median changes of 3% and 11% overall”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    During both days of novel object recognition, all groups attended to the novel object more than 50% of the trial.

    “Finally, during both days of novel object recognition, all groups attended to the novel object more than 50% of the trial, and no effect of group or sex reached significance (% time near novel object: mean +/− s.d., Day 1: C: 63 +/− 18, S: 63 +/− 25; Day 2: C: 73 +/− 11, S: 67 +/− 17, Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No effect of group or sex reached significance in novel object recognition.

    “Finally, during both days of novel object recognition, all groups attended to the novel object more than 50% of the trial, and no effect of group or sex reached significance (% time near novel object: mean +/− s.d., Day 1: C: 63 +/− 18, S: 63 +/− 25; Day 2: C: 73 +/− 11, S: 67 +/− 17, Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Birth weight, number of pups per litter, number of pups cannibalized, and cannibalization rate did not differ between C and S dams.

    “Birth weight, number of pups per litter, number of pups cannibalized, and cannibalization rate did not differ between C and S dams (p = 0.80, p = 0.86, p = 0.70, and p = 0.69, respectively).”
    • Also stated in: § Discussion · plain
      “DCCD dams did not have smaller or underweight litters and did not cannibalize their pups at an increased rate.”
    • Also stated in: § DCCD Does Not Mimic Early Life Stress · plain
      “Birthweight for S and C litters do not differ (A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Post hoc analysis indicated that CC mice were not significantly separable from C mice, but CS, SC, SS, and S were all in significantly separate clusters from C mice (p < 0.05).

    “Probing this effect with a post hoc analysis indicated that CC mice were not significantly separable from C mice, but CS, SC, SS, and S were all in significantly separate clusters from C mice (p < 0.05) (Fig. 5d)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CS offspring were significantly more social than S, but less than C or CC.

    “Post hoc analysis reveals that CS offspring were significantly more social than S, but less than C or CC (p < 0.05).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    High and low responders were chosen from each group, and no apparent effect of phenotype on methylation rates.

    “High and low responders were chosen from each group, and no apparent effect of phenotype on methylation rates.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Hippocampal clock gene rhythms are disrupted after gestation in constant light, and timed infusions of melatonin delivered to the dam prevent these deficits in adult offspring.

    “For instance, hippocampal clock gene rhythms are disrupted after gestation in constant light, and timed infusions of melatonin delivered to the dam prevent these deficits in adult offspring15.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Vilches, N. et al. Gestational chronodisruption impairs hippocampal expression of NMDA receptor subunits Grin1b/Grin3a and spatial memory in the adult offspring. PloS One 9, e91313 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In adult mammals, chronic circadian disruption has diverse negative impacts on physical and mental health, including a shortened lifespan.

    “In adult mammals, chronic circadian disruption has diverse negative impacts on physical and mental health6, 7, including a shortened lifespan8.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [6] Karatsoreos, I. N. Effects of circadian disruption on mental and physical health. Curr. Neurol. Neurosci. Rep. 12, 218–225 (2012). source

      Not checked in the free run.

    • cites [7] Karatsoreos, I. N., Bhagat, S., Bloss, E. B., Morrison, J. H. & McEwen, B. S. Disruption of circadian clocks has ramifications for metabolism, brain, and behavior. Proc. Natl. Acad. Sci. USA 108, 1657–1662 (2011). source

      Not checked in the free run.

    • cites [8] Froy, O. Circadian Rhythms, Aging, and Life Span in Mammals. Physiology 26, 225–235 (2011). source

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    Premisecitation

    Circadian oscillations are ubiquitous in cells throughout the brain and body and their coordinated daily activity is essential for normal health.

    “Circadian oscillations are ubiquitous in cells throughout the brain and body and their coordinated daily activity is essential for normal health1–3.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Smarr, B. L. & Kriegsfeld, L. J. In APA Handbook of Comparative Psychology (ed. Call, J.) 1, (Amer Psychological Assn, 2017).

      Not checked in the free run.

    • cites [2] Evans, J. A. & Davidson, A. J. Health consequences of circadian disruption in humans and animal models. Prog. Mol. Biol. Transl. Sci. 119, 283–323 (2013). source

      Not checked in the free run.

    • cites [3] Moore-Ede, M. C., Czeisler, C. A. & Richardson, G. S. Circadian timekeeping in health and disease. Part 1. Basic properties of circadian pacemakers. N. Engl. J. Med. 309, 469–476 (1983).

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    Premisecitation

    Organisms across taxa exhibit daily rhythms in behavior and physiology generated by endogenous ~24 h circadian oscillations that facilitate synchronization to the day-night cycle.

    “Organisms across taxa exhibit daily rhythms in behavior and physiology generated by endogenous ~24 h oscillations (circadian rhythms) that facilitate synchronization to the day-night cycle1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Smarr, B. L. & Kriegsfeld, L. J. In APA Handbook of Comparative Psychology (ed. Call, J.) 1, (Amer Psychological Assn, 2017).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Exposing pregnant mice and rats to constant light produces mixed results in learning tasks and associated hippocampal functions.

    “In previous studies, exposing pregnant mice and rats to constant light produced lasting increases in anxiety-like behavior13–15, with mixed results in learning tasks14–16 and associated hippocampal functions15, 16.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [14] Roman, E. & Karlsson, O. Increased anxiety-like behavior but no cognitive impairments in adult rats exposed to constant light conditions during perinatal development. Ups. J. Med. Sci. 118, 222–227 (2013). source

      Not checked in the free run.

    • cites [15] Vilches, N. et al. Gestational chronodisruption impairs hippocampal expression of NMDA receptor subunits Grin1b/Grin3a and spatial memory in the adult offspring. PloS One 9, e91313 (2014). source

      Not checked in the free run.

    • cites [16] Fujioka, A. et al. Effects of a constant light environment on hippocampal neurogenesis and memory in mice. Neurosci. Lett. 488, 41–44 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Acute circadian disruptions, such as a single jet lag, allow adults to achieve internal realignment with limited negative impact to health.

    “When these disruptions are acute (e.g., in the case of a single ‘jet lag’), adults can achieve internal realignment with limited negative impact to health4.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Gibson, E. M., Wang, C., Tjho, S., Khattar, N. & Kriegsfeld, L. J. Experimental ‘jet lag’ inhibits adult neurogenesis and produces long-term cognitive deficits in female hamsters. PloS One 5, e15267 (2010). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Perturbed maternal melatonin signaling is a proposed mechanism by which circadian disruption negatively impacts development.

    “Previous studies have proposed that perturbed maternal melatonin signaling is a mechanism by which circadian disruption negatively impacts development15, 17, 20–25.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [15] Vilches, N. et al. Gestational chronodisruption impairs hippocampal expression of NMDA receptor subunits Grin1b/Grin3a and spatial memory in the adult offspring. PloS One 9, e91313 (2014). source

      Not checked in the free run.

    • cites [17] Torres-Farfan, C. et al. Maternal melatonin selectively inhibits cortisol production in the primate fetal adrenal gland. J. Physiol. 554, 841–856 (2004). source

      Not checked in the free run.

    • cites [20] Illnerová, H., Buresová, M. & Presl, J. Melatonin rhythm in human milk. J. Clin. Endocrinol. Metab. 77, 838–841 (1993).

      Not checked in the free run.

    • cites [21] Nowak, R., Young, I. R. & McMillen, I. C. Emergence of the diurnal rhythm in plasma melatonin concentrations in newborn lambs delivered to intact or pinealectomized ewes. J. Endocrinol. 125, 97–102 (1990). source

      Not checked in the free run.

    • cites [22] Cohen Engler, A., Hadash, A. & Shehadeh, N. & Pillar, G. Breastfeeding may improve nocturnal sleep and reduce infantile colic: potential role of breast milk melatonin. Eur. J. Pediatr. 171, 729–732 (2012). source

      Not checked in the free run.

    • cites [23] Okatani, Y. et al. Maternal-fetal transfer of melatonin in pregnant women near term. J. Pineal Res. 25, 129–134 (1998). source

      Not checked in the free run.

    • cites [24] Deguchi, T. Ontogenesis of a biological clock for serotonin:acetyl coenzyme A N-acetyltransferase in pineal gland of rat. Proc. Natl. Acad. Sci. USA 72, 2814–2818 (1975). source

      Not checked in the free run.

    • cites [25] Kennaway, D. J., Stamp, G. E. & Goble, F. C. Development of melatonin production in infants and the impact of prematurity. J. Clin. Endocrinol. Metab. 75, 367–369 (1992).

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Early life stress, often transmitted to offspring through dams' poor maternal care, has lasting developmental effects that vary depending on the life stage in which the stress is experienced.

    “ELS, often transmitted to offspring through dams’ poor maternal care, has lasting developmental effects that vary depending on the life stage in which the stress is experienced29.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Weaver, I. C. G. et al. Epigenetic programming by maternal behavior. Nat. Neurosci. 7, 847–854 (2004). source

      Not checked in the free run.

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    Premisecitation

    Maternal stress and early life stress are associated with decreases in birth weight and litter size, and increases in maternal cannibalism of pups.

    “Along with hypermethylation of stress-related genes, maternal stress and ELS are associated with decreases in birth weight35, 36 and litter size37, and increases in maternal cannibalism of pups38, 39.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [35] Diego, M. A. et al. Maternal psychological distress, prenatal cortisol, and fetal weight. Psychosom. Med. 68, 747–753 (2006). source

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    • cites [36] Cheong, J. N. et al. Sex-specific metabolic outcomes in offspring of female rats born small or exposed to stress during pregnancy. Endocrinology en. 2016–1335 (2016). source

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    • cites [37] Geraghty, A. C. et al. Knockdown of hypothalamic RFRP3 prevents chronic stress-induced infertility and embryo resorption. eLife 4. source

      Not checked in the free run.

    • cites [38] Busnel, R. G. & Lehmann, A. Acoustic signals in mouse maternal behavior: retrieving and cannibalism. Z. Für Tierpsychol. 45, 321–324 (1977). source

      Not checked in the free run.

    • cites [39] Bellisario, V. et al. Maternal high-fat diet acts as a stressor increasing maternal glucocorticoids’ signaling to the fetus and disrupting maternal behavior and brain activation in C57BL/6J mice. Psychoneuroendocrinology 60, 138–150 (2015). source

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  • Classified as probably not a substantial claim.

    Premisecitation

    When disruptions occur in utero, this epigenotype is rescued by cross-fostering pups to an unstressed dam.

    “When disruptions occur in utero, this epigenotype is rescued by cross-fostering pups to an unstressed dam29.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Weaver, I. C. G. et al. Epigenetic programming by maternal behavior. Nat. Neurosci. 7, 847–854 (2004). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    All relevant behaviors were recorded for scoring in vCode, validated by at least two independent scorers.

    “A video camera was suspended above the center of the testing areas and all relevant behaviors recorded for scoring in vCode, validated by at least two independent scorers.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Only samples with a conversion efficiency >88% were included in the methylation analysis.

    “Only samples with a conversion efficiency >88% were included in the analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    S and SS pups are negatively impacted by both circadian disruption in utero and poorer maternal care in early life.

    “Pups from control mothers eventually experience longer retrieval times if exposed to DCCD early in postnatal life, indicating that S and SS pups are negatively impacted by both circadian disruption in utero and poorer maternal care in early life.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Early-life stress is reported to increase methylation of the same BDNF IV and GR17 regions by 95% and 135%, respectively.

    “as compared to average reported increases for the same regions resulting from early-life stress of 95%32–34 and 135%29, 30, 47, respectively”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [32] Roth, T. L., Lubin, F. D., Funk, A. J. & Sweatt, J. D. Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol. Psychiatry 65, 760–769 (2009). source

      Not checked in the free run.

    • cites [33] Unternaehrer, E. et al. Childhood maternal care is associated with DNA methylation of the genes for brain-derived neurotrophic factor (BDNF) and oxytocin receptor (OXTR) in peripheral blood cells in adult men and women. Stress Amst. Neth. 18, 451–461 (2015). source

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    • cites [34] Blaze, J., Asok, A. & Roth, T. L. Long-term effects of early-life caregiving experiences on brain-derived neurotrophic factor histone acetylation in the adult rat mPFC. Stress Amst. Neth. 18, 607–615 (2015). source

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    • cites [29] Weaver, I. C. G. et al. Epigenetic programming by maternal behavior. Nat. Neurosci. 7, 847–854 (2004). source

      Not checked in the free run.

    • cites [30] Palma-Gudiel, H., Córdova-Palomera, A., Leza, J. C. & Fañanás, L. Glucocorticoid receptor gene (NR3C1) methylation processes as mediators of early adversity in stress-related disorders causality: A critical review. Neurosci. Biobehav. Rev. 55, 520–535 (2015). source

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    • cites [47] McGowan, P. O. et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat. Neurosci. 12, 342–348 (2009). source

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  • Classified as probably not a substantial claim.

    Premisecitation

    In these cases, testing was conducted at variable times of day.

    “In these cases, testing was conducted at variable times of day.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Vilches, N. et al. Gestational chronodisruption impairs hippocampal expression of NMDA receptor subunits Grin1b/Grin3a and spatial memory in the adult offspring. PloS One 9, e91313 (2014). source

      Not checked in the free run.

    • cites [16] Fujioka, A. et al. Effects of a constant light environment on hippocampal neurogenesis and memory in mice. Neurosci. Lett. 488, 41–44 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many types of learning show circadian modulation.

    “Many types of learning show circadian modulation49.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Smarr, B. L., Jennings, K. J., Driscoll, J. R. & Kriegsfeld, L. J. A time to remember: the role of circadian clocks in learning and memory. Behav. Neurosci. 128, 283–303 (2014). source

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    Premisecitation

    Other studies have found learning deficits following gestation under constant light.

    “Other studies have found learning deficits following gestation under constant light15, 16.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Vilches, N. et al. Gestational chronodisruption impairs hippocampal expression of NMDA receptor subunits Grin1b/Grin3a and spatial memory in the adult offspring. PloS One 9, e91313 (2014). source

      Not checked in the free run.

    • cites [16] Fujioka, A. et al. Effects of a constant light environment on hippocampal neurogenesis and memory in mice. Neurosci. Lett. 488, 41–44 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Our findings establish that DCCD leads to lasting changes in somatic development and adult behavior.

    “Our findings establish that DCCD leads to lasting changes in somatic development and adult behavior.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several physiological systems exhibit ultradian rhythms in the 1-3 h range, including the HPG axis, HPA axis, and suprachiasmatic nucleus.

    “Several physiological systems exhibit ultradian rhythms (URs) in the 1–3 h range, including the HPG axis60–65, the HPA axis66–72, and the suprachiasmatic nucleus73, 74 – the principal orchestrating brain area for circadian rhythms.”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [60] Sanchez-Alavez, M., Alboni, S. & Conti, B. Sex- and age-specific differences in core body temperature of C57Bl/6 mice. Age Dordr. Neth. 33, 89–99 (2011). source

      Not checked in the free run.

    • cites [61] Mauvais-Jarvis, F. Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity. Trends Endocrinol. Metab. TEM 22, 24–33 (2011). source

      Not checked in the free run.

    • cites [62] Marrone, B. L., Thomas Gentry, R. & Wade, G. N. Gonadal hormones and body temperature in rats: Effects of estrous cycles, castration and steroid replacement. Physiol. Behav. 17, 419–425 (1976). source

      Not checked in the free run.

    • cites [63] Rance, N. E., Dacks, P. A., Mittelman-Smith, M. A., Romanovsky, A. A. & Krajewski-Hall, S. J. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. Front. Neuroendocrinol. 34, 211–227 (2013). source

      Not checked in the free run.

    • cites [64] de la Iglesia, H. O. & Schwartz, W. J. Minireview: timely ovulation: circadian regulation of the female hypothalamo-pituitary-gonadal axis. Endocrinology 147, 1148–1153 (2006). source

      Not checked in the free run.

    • cites [65] Wang, Z. Y., Cable, E. J., Zucker, I. & Prendergast, B. J. Pregnancy-induced changes in ultradian rhythms persist in circadian arrhythmic Siberian hamsters. Horm. Behav. 66, 228–237 (2014). source

      Not checked in the free run.

    • cites [66] Smarr, B., Burnett, D., Mesri, S., Pister, K. & Kriegsfeld, L. A Wearable Sensor System with Circadian Rhythm Stability Estimation for Prototyping Biomedical Studies. IEEE Trans. Affect. Comput. PP, 1–1 (2015).

      Not checked in the free run.

    • cites [67] Fulkerson, W. J. & Tang, B. Y. Ultradian and circadian rhythms in the plasma concentration of cortisol in sheep. J. Endocrinol. 81, 135–141 (1979). source

      Not checked in the free run.

    • cites [68] Young, E. A., Abelson, J. & Lightman, S. L. Cortisol pulsatility and its role in stress regulation and health. Front. Neuroendocrinol. 25, 69–76 (2004). source

      Not checked in the free run.

    • cites [69] Qian, X., Droste, S. K., Lightman, S. L., Reul, J. M. H. M. & Linthorst, A. C. E. Circadian and ultradian rhythms of free glucocorticoid hormone are highly synchronized between the blood, the subcutaneous tissue, and the brain. Endocrinology 153, 4346–4353 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Temporal structure governing behavior in the mother, and likely in the fetus, is provided by ultradian as well as circadian mechanisms.

    “Importantly, temporal structure governing behavior in the mother, and likely in the fetus, is provided by ultradian (rhythms < 24 h) as well as circadian mechanisms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Together, these findings suggest that the nature of the circadian disruption applied developmentally, and the time of day of testing, may influence those deficits that manifest.

    “Together, these findings suggest that the nature of the circadian disruption applied developmentally, and the time of day of testing, may influence those deficits that manifest.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Sleep disruption in adolescents is associated with attention deficit hyperactivity disorder and autism spectrum disorder.

    “Sleep disruption in adolescents is associated with attention deficit hyperactivity disorder84 and autism spectrum disorder85.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [84] Lunsford-Avery, J. R., Krystal, A. D. & Kollins, S. H. Sleep disturbances in adolescents with ADHD: A systematic review and framework for future research. Clin. Psychol. Rev. 50, 159–174 (2016). source

      Not checked in the free run.

    • cites [85] Cohen, S., Conduit, R., Lockley, S. W., Rajaratnam, S. M. & Cornish, K. M. The relationship between sleep and behavior in autism spectrum disorder (ASD): a review. J. Neurodev. Disord. 6 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mothers communicate rhythmic information to developing pups through melatonin in their milk.

    “Mothers communicate rhythmic information to developing pups through melatonin in their milk20, 22.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Illnerová, H., Buresová, M. & Presl, J. Melatonin rhythm in human milk. J. Clin. Endocrinol. Metab. 77, 838–841 (1993).

      Not checked in the free run.

    • cites [22] Cohen Engler, A., Hadash, A. & Shehadeh, N. & Pillar, G. Breastfeeding may improve nocturnal sleep and reduce infantile colic: potential role of breast milk melatonin. Eur. J. Pediatr. 171, 729–732 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Circadian disruptions are ubiquitous in modern society, affected by the modern lighting environment and negatively impacting health from in utero development through old age.

    “Circadian disruptions are ubiquitous in modern society, affected by the modern lighting environment and negatively impacting health from in utero development through old age79–81.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [79] Borniger, J. C., McHenry, Z. D., Abi Salloum, B. A. & Nelson, R. J. Exposure to dim light at night during early development increases adult anxiety-like responses. Physiol. Behav. 133, 99–106 (2014). source

      Not checked in the free run.

    • cites [80] Cissé, Y. M., Peng, J. & Nelson, R. J. Dim light at night prior to adolescence increases adult anxiety-like behaviors. Chronobiol. Int. 0, 1–8 (2016).

      Not checked in the free run.

    • cites [81] Hofman, M. A. & Swaab, D. F. Alterations in circadian rhythmicity of the vasopressin-producing neurons of the human suprachiasmatic nucleus (SCN) with aging. Brain Res. 651, 134–142 (1994). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    As of 2004, 12.6% of women over the age of 16 in the US work force were shift workers.

    “As of 2004, 12.6% of women over the age of 16 in the US work force were shift workers82.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] McMenamin, T. M. A time to work: Recent trends in shift work and flexible schedules. Mon. Labor Rev. (2007).

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Diagnoses for both ADHD and autism have been on the rise over the past several decades.

    “Diagnoses for both have been on the rise over the past several decades86–88.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [86] Olfson, M., Gameroff, M. J., Marcus, S. C. & Jensen, P. S. National Trends in the Treatment of Attention Deficit Hyperactivity Disorder. Am. J. Psychiatry 160, 1071–1077 (2003). source

      Not checked in the free run.

    • cites [87] Giacobini, M., Medin, E., Ahnemark, E., Russo, L. J. & Carlqvist, P. Prevalence, Patient Characteristics, and Pharmacological Treatment of Children, Adolescents, and Adults Diagnosed With ADHD in Sweden. J. Atten. Disord. 1087054714554617 (2014). source

      Not checked in the free run.

    • cites [88] Mandell, D. S., Thompson, W. W., Weintraub, E. S., DeStefano, F. & Blank, M. B. Trends in Diagnosis Rates for Autism and ADHD at Hospital Discharge in the Context of Other Psychiatric Diagnoses. Psychiatr. Serv. 56, 56–62 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Both in utero and early life development are uniquely vulnerable, with different downstream consequences.

    “The present findings also indicate that both in utero and early life development are uniquely vulnerable, with different downstream consequences.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Early postnatal circadian disruption induces nearly equivalent behavioral changes and a more marked body mass deficit.

    “by contrast, early postnatal circadian disruption induces nearly equivalent behavioral changes and a more marked body mass deficit.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The central dopaminergic axis exhibits ultradian rhythms in the 1-3 h range.

    “The central dopaminergic axis exhibits URs in the 1–3 h range75”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Blum, I. D. et al. A highly tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal. eLife 3 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Fetal ultradian rhythms exist.

    “Fetal URs are understudied but do exist77”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Pillai, M., James, D. K. & Parker, M. The development of ultradian rhythms in the human fetus. Am. J. Obstet. Gynecol. 167, 172–177 (1992). source

      Not checked in the free run.

44 of 44

  • The paper relies on this without support.

    The repeated phase-shift design mimics the type of circadian disruptions experienced by pregnant women under rotating shift schedules.

    “In addressing this question, we elected to employ manipulations that would mimic the type of disruptions – phase shifts – experienced by pregnant women under rotating shift schedules.”

  • The paper relies on this without support.

    BALB/c mice's markedly attenuated melatonin production eliminates any effects of circadian disruption resulting from dysregulated melatonin.

    “In the present study, we used BALB/c mice that have markedly attenuated melatonin production26, 27 to eliminate any effects of circadian disruption resulting from dysregulated melatonin.”

  • The paper relies on this without support.

    The examined variables (birthweight, litter size, maternal cannibalism, and epigenetic modifications) are sufficient to rule out early life stress mechanisms for DCCD effects.

    “To examine whether circadian disruption affects development by acting as an early life stressor, we examined birthweight, litter size, maternal cannibalism, and epigenetic modifications.”

  • The authors state this as an assumption.

    The relative contributions of in utero circadian disruption and altered maternal care to adult outcomes have not been disambiguated.

    “Whether these outcomes are a consequence of circadian disruptions in utero or from alterations in maternal care by circadian-disrupted mothers has not been disambiguated.”

  • The paper relies on this without support.

    Circadian disruptions can activate the stress axis.

    “Given that circadian disruptions can activate the stress axis, we speculated that ELS mechanisms may contribute to any observed changes.”

  • The paper relies on this without support.

    The early-life stress markers used (birth weight, litter size, cannibalization, BDNF IV and GR17 methylation) would show detectable changes if ELS were present.

    “To explore this possibility, we examined markers of ELS in dams and offspring, but detected no signs of stress in any of the markers in any condition.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Gestational circadian disruption promotes social avoidance and hyperactivity behaviours in pups, even when they are cross-fostered by non-disrupted mothers.

    “Gestational circadian disruption also promotes social avoidance and hyperactivity behaviours in pups, even when they are cross-fostered by non-disrupted mothers48, further highlighting the importance of circadian stability during pregnancy on the mother and offspring.”

    From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [48]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Figure 4 caption reverses the reported sex difference in body mass

    Minor

    The Results report that females weighed significantly less than males at p33, whereas the Figure 4 caption says the sexes did not differ halfway through postnatal development.

  • Novel-object results claim every group exceeded 50%

    Minor

    Table 3 lists several sex-by-group means at or below 50%, including 38% for CC males on day 2. This conflicts with the statement that all groups attended to the novel object more than 50% on both days.

  • Cross-fostered offspring have conflicting weighing schedules

    Minor

    The Methods state that all mice were weighed at birth, on several postnatal days, at p33, and at p60. The Results instead state that cross-fostered offspring were weighed only at p60.

  • Figure 6 names a different BDNF region

    Minor

    The Results and Methods identify the examined BDNF promoter as region IV, but the Figure 6 caption calls it BDNF V.

  • SC dams are assigned the wrong fostering condition

    Minor

    The group definition makes SC pups shifted in utero and reared by control dams. The Results instead describe SC dams as shifted mothers fostering pups from control mothers, which describes CS.

5 of 5

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Authors
Smarr, B. L., Grant, A. D., Perez, L., Zucker, I., & Kriegsfeld, L. J.
Affiliations
University of California, Berkeley (US)
Corresponding author
Kriegsfeld, Lance J.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-06-12
Volume
7
Issue
1
Pages
3326-3326
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-017-03406-4
PMC
PMC5468226
OpenAlex
W2621586893
Semantic Scholar
f474ed5882365e2bb017335c67529db7e48ca3a9
Cited by
86
References
88
Citations by year
2026: 8 · 2025: 12 · 2024: 13 · 2023: 8 · 2022: 14 · 2021: 11 · 2020: 10 · 2019: 6 · 2018: 4
FWCI
3.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institute of Child Health and Human Development (HD‐050470, HD081957)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD081957, R01HD050470)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
Keywords
circadian rhythm disruption, artificial light exposure, prenatal development, early life stress, offspring development, social avoidance, hyperactivity, body mass, cross-fostering, maternal cannibalism, birth weight, litter size, epigenetic modifications, developmental timing, adult behavior, mice
MeSH terms
Animals, Anxiety, Behavior, Animal, Circadian Rhythm, Female, Light, Male, Mice, Inbred BALB C, Phenotype, Pregnancy, Prenatal Exposure Delayed Effects, Receptors, Glucocorticoid, Social Behavior, DNA Methylation, Brain-Derived Neurotrophic Factor

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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