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Cited by 169Heavy Metal Exposure and ToxicityAutism Spectrum Disorder ResearchTrace Elements in Health

Fetal and postnatal metal dysregulation in autism

Open access
Arora, Manish, Reichenberg, Abraham, Willfors, Charlotte, Austin, Christine, Gennings, Chris, Berggren, Steve, Lichtenstein, Paul, Anckarsäter, Henrik +2 more·2017·Nature Communications
DOI 10.1038/ncomms15493PMC PMC5461492
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Abstract

Genetic and environmental factors contribute to the etiologies of autism spectrum disorder (ASD), but evidence of specific environmental exposures and susceptibility windows is limited. Here we study monozygotic and dizygotic twins discordant for ASD to test whether fetal and postnatal metal dysregulation increases ASD risk. Using validated tooth-matrix biomarkers, we estimate pre- and post-natal exposure profiles of essential and toxic elements. Significant divergences are apparent in metal uptake between ASD cases and their control siblings, but only during discrete developmental periods. Cases have reduced uptake of essential elements manganese and zinc, and higher uptake of the neurotoxin lead. Manganese and lead are also correlated with ASD severity and autistic traits. Our study suggests that metal toxicant uptake and essential element deficiency during specific developmental windows increases ASD risk and severity, supporting the hypothesis of systemic elemental dysregulation in ASD. Independent replication in population-based studies is needed to extend these findings.

AI snapshot

Written from the paper’s full text.

TL;DR

In ASD-discordant twins, tooth-matrix biomarkers showed element-specific differences in metal uptake during discrete prenatal and early postnatal windows, with lower manganese and zinc and higher lead in ASD cases. These differences correlated with later ASD severity/traits, but the authors call for independent replication.

Key findings

  • Lead was higher in ASD cases than co-twins from 20 weeks before birth to 30 weeks after birth; after intra-twin correction, this was significant at 10–20 weeks postnatally, greatest at 15 weeks postnatally (1.5 times higher; Holm–Bonferroni 95% CI 0.9–2.5).
  • Manganese was lower in ASD cases in two windows: 10 weeks prenatally to birth and postnatal weeks 5–20; greatest at postnatal week 15 (2.5 times lower; 95% CI 1.1–4.5 times lower). Zinc was lower from 10 weeks prenatally to ∼5 weeks postnatally, with 28% lower levels at 8 weeks prenatally (95% CI 22–65% lower).
  • Manganese was inversely associated with SRS-2 autistic traits (strongest at 15 weeks, r=−0.25, 95% CI −0.40 to −0.10) and ADOS-2 severity (strongest at 12 weeks, r=−0.20, 95% CI −0.35 to −0.05); lead was positively associated with ADOS-2 (strongest 5 weeks prenatally, r=0.40, 95% CI 0.20–0.60).
  • Exploratory analyses found differences for six of ten metals, including higher tin (significant 20–16 weeks before birth), higher strontium (most prominent 22–30 weeks after birth), and lower chromium (greatest 20–15 weeks prenatally).

Methods

  • Study used RATSS twins recruited 2011–2016; primary analysis compared ASD-discordant twin pairs (7 pairs) with non-ASD control twin pairs (19 pairs), with a sensitivity comparison to ASD-concordant pairs (6 pairs) and correlation analyses in all participants (n=76). The sample included 32 complete twin pairs (17 MZ, 15 DZ) plus 12 individuals whose co-twin did not donate a tooth.
  • Naturally shed deciduous teeth were analyzed by laser ablation-inductively coupled plasma mass spectrometry (LA-ICP-MS), using the neonatal line and incremental markings to assign developmental time; on average each tooth was sampled at 152 locations.
  • Distributed lag models estimated differences in metal uptake at discrete developmental stages, adjusted for sex, zygosity, gestational age, average birth weight and within-pair birth weight s.d., with an intra-twin correlation random effect and Holm–Bonferroni correction.

Limitations

  • Stated: relatively small non-random sample; caution generalizing; need replication in different populations and larger non-twin ASD samples; biomarkers do not measure first-trimester exposure; data do not establish causality; tooth biomarkers do not distinguish exposure routes; need to study metal-mixture kinetics; heterogeneous metal distribution in enamel and dentine can occur.
  • Evident from text: the primary discordant-vs-control DLM analysis relied on only 7 ASD-discordant pairs, and the twin-based design may limit power and generalizability despite controlling for genetic variation.

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

Integrity signals

Registry

Crossref · 10.1038/ncomms15493

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 48 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In non-ASD control MZ twins, lead, manganese and zinc show close concordance.

    “Figure 3a shows close concordance for lead, manganese and zinc in non-ASD control MZ twins (other elements show a similar pattern, Supplementary Fig. 3).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Manganese was inversely associated with ASD severity on ADOS-2 (strongest association at 12 weeks, r=−0.20, 95% CI −0.35 to −0.05).

    “Manganese was inversely associated with autistic traits measured using SRS-2 (strongest association at 15 weeks, r=−0.25, 95% CI −0.40 to −0.10) and ASD severity on ADOS-2 (strongest association at 12 weeks, r=−0.20, 95% CI −0.35 to −0.05).”
    Quote in the paperSubstantial claim
  • Findingown data

    Manganese was inversely associated with autistic traits measured using SRS-2 (strongest association at 15 weeks, r=−0.25, 95% CI −0.40 to −0.10).

    “Manganese was inversely associated with autistic traits measured using SRS-2 (strongest association at 15 weeks, r=−0.25, 95% CI −0.40 to −0.10) and ASD severity on ADOS-2 (strongest association at 12 weeks, r=−0.20, 95% CI −0.35 to −0.05).”
    Quote in the paperSubstantial claim
  • Findingown data

    The association between lead and ADOS-2 was statistically significant from 10 weeks before birth to 30 weeks after birth, with strongest association 5 weeks prenatally (r=0.40, 95% CI 0.20-0.60).

    “The association with ADOS-2 was statistically significant from 10 weeks before birth to 30 weeks after birth, with strongest association 5 weeks prenatally (r=0.40, 95% CI 0.20–0.60).”
    Quote in the paperSubstantial claim
  • Findingown data

    Zinc and other metals analysed under exploratory analysis were not significantly associated with SRS-2 and ADOS-2.

    “Zinc and other metals analysed under exploratory analysis were not significantly associated with SRS-2 and ADOS-2.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 36
  • Classified as probably not a substantial claim. 24

  • May combine two claims.

    Findingown data

    Strontium was higher in cases throughout the period of study and this difference was most prominent during weeks 22-30 after birth.

    “Strontium was higher in cases throughout the period of study and this difference was most prominent during weeks 22–30 after birth.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In sensitivity analyses comparing ASD discordant twin pairs with ASD concordant twins (six pairs), similar patterns were observed, including significantly higher lead levels in cases.

    “Therefore, in a sensitivity analyses, we compared ASD discordant twin pairs with ASD concordant twins (six pairs) and observed similar patterns to our comparison of ASD discordant versus control pairs, including significantly higher lead levels in cases (Fig. 5).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Concordant ASD twin pairs are more alike in their metal status than discordant pairs.

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

    Findingcitation

    A total of 154 twin pairs had participated in RATSS as of September 2016, which includes 11.3% of all ASD discordant twins in Sweden in the specified age range.

    “A total of 154 twin pairs had participated in RATSS as of September 2016, which includes 11.3% of all ASD discordant twins in Sweden in the specified age range13.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Lichtenstein, P., Carlstrom, E., Rastam, M., Gillberg, C. & Anckarsater, H. The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am. J. Psychiatry 167, 1357–1363 (2010). source

      Not checked in the free run.

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

    Findingcitation

    The observed metal distributions were in agreement with previous studies using tooth-matrix biomarkers.

    “The observed metal distributions were in agreement with previous studies using tooth-matrix biomarkers1419.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Arora, M. & Austin, C. Teeth as a biomarker of past chemical exposure. Curr. Op. Peds. 25, 261–267 (2013). source

      Not checked in the free run.

    • cites [19] Austin, C. et al. Barium distributions in teeth reveal early-life dietary transitions in primates. Nature 498, 216–219 (2013). source

      Not checked in the free run.

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

    Findingown data

    Out of the 32 complete twin pairs, 17 were MZ pairs and 15 DZ pairs including two opposite-sex pairs.

    “Out of the 32 complete twin pairs, 17 were MZ pairs and 15 DZ pairs including two opposite-sex pairs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In exploratory analysis, levels of tin were higher in ASD cases and this difference was statistically significant between 20 and 16 weeks before birth.

    “Levels of tin were higher in ASD cases and this difference was statistically significant between 20 and 16 weeks before birth (Supplementary Fig. 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Lead levels were generally higher in the affected twin and this difference was greatest after birth.

    “Lead levels were generally higher in the affected twin and this difference was greatest after birth.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    This study included 32 complete twin pairs and 12 individuals from twin pairs whose sibling did not donate a tooth.

    “From those participants, this study included 32 complete twin pairs and 12 individuals from twin pairs whose sibling did not donate a tooth.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Chromium was lower in cases than their control co-twins, with differences being greatest from 20 to 15 weeks prenatally.

    “Chromium was lower in cases than their control co-twins, with differences being greatest from 20 to 15 weeks prenatally.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Manganese levels declined rapidly over the prenatal period to birth and continued to decrease at a slower rate postnatally.

    “Specifically, manganese levels declined rapidly over the prenatal period to birth and continued to decrease at a slower rate postnatally.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Zinc levels were steady prenatally in our sample teeth with a marked decrease around birth.

    “Zinc levels were steady prenatally in our sample teeth with a marked decrease around birth.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Manganese levels were consistently lower in ASD cases, statistically significant between 10 weeks prenatally to birth and postnatal weeks 5-20.

    “Manganese levels were consistently lower in ASD cases, and this was statistically significant over two critical windows; between 10 weeks prenatally to birth and subsequently postnatal weeks 5–20.”
    • Also stated in: § Discussion · plain
      “Manganese levels were consistently lower in cases both pre- and postnatally, and this deficiency was highest 4 months after birth.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    We adjusted our analysis for important covariates and applied two levels of stringent corrections: adjustment for intra-twin correlations and Holm-Bonferroni correction for multiple comparisons.

    “We adjusted our analysis for important covariates and also applied two levels of stringent corrections. First, we adjusted for intra-twin correlations and second, we used a Holm–Bonferroni correction to account for multiple comparisons (Methods section).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    The tooth-matrix biomarkers are recently developed and rigorously validated, and objectively reconstruct fetal and early postnatal exposure to multiple metals with detailed temporal resolution.

    “The teeth samples we collected from the twins were analysed using recently developed and rigorously validated tooth-matrix biomarkers, which objectively reconstruct fetal and early postnatal exposure to multiple metals with detailed temporal resolution141516171819.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] Arora, M. & Austin, C. Teeth as a biomarker of past chemical exposure. Curr. Op. Peds. 25, 261–267 (2013). source

      Not checked in the free run.

    • cites [15] Arora, M. et al. Determining prenatal, early childhood and cumulative long-term lead exposure using micro-spatial deciduous dentine levels. PLoS ONE 9, e97805 (2014). source

      Not checked in the free run.

    • cites [16] Arora, M. et al. Determining fetal manganese exposure from mantle dentine of deciduous teeth. Environ. Sci. Technol. 46, 5118–5125 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Taken together, the findings support the hypothesis that prenatal and early childhood disruption (excess or deficiency) of multiple metals during critical developmental windows is associated with ASD, and suggest a role for elemental dysregulation in the etiology of ASD.

    “Taken together, this supports the hypothesis that prenatal and early childhood disruption (excess or deficiency) of multiple metals during critical developmental windows is associated with ASD, and suggests a role for elemental dysregulation in the etiology of ASD.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    One study that compared hair metal concentrations of ASD cases with literature reference values was suggestive of reduced zinc and magnesium and elevated levels of toxicants including lead.

    “For example, one study that compared hair metal concentrations of ASD cases with literature reference values was suggestive of reduced zinc and magnesium and elevated levels of toxicants including lead26.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Yasuda, H., Yasuda, Y. & Tsutsui, T. Estimation of autistic children by metallomics analysis. Sci. Rep. 3, 1199 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Animal studies have demonstrated that the effects of various metals on brain development could be mediated through dysregulation in neurotransmission, and alterations in frontal and subcortical brain structures.

    “Animal studies have demonstrated that the effects of various metals on brain development could be mediated through dysregulation in neurotransmission, and alterations in frontal and subcortical brain structures8, several of which have also been implicated in ASD9.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Modabbernia, A., Arora, M. & Reichenberg, A. Exposure to metals and Psychosis. Curr. Op. Peds. 28, 243–249 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisereasoning

    Assessing the contribution of environmental factors in the etiology of ASD needs control for genetic factors.

    “Third, assessing the contribution of environmental factors in the etiology of ASD needs control for genetic factors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The influence of common genetic factors in ASD is estimated to be at least 50%, however currently etiologic genetic variants can be found in ∼16 to 50% of affected children, suggesting important roles for environmental factors that have not yet been confirmed.

    “The influence of common genetic factors in ASD is estimated to be at least 50% (ref. 4), however currently etiologic genetic variants can be found in ∼16 to 50% of affected children, suggesting important roles for environmental factors that have not yet been confirmed46.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Sandin, S. et al. The familial risk of autism. JAMA 311, 1770–1777 (2014). source

      Not checked in the free run.

    • cites [46] Dunn, L. M. & Dunn, L. M. Peabody Picture Vocabulary Test-III American Guidance Service (1997). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Manganese is an essential nutrient with emerging evidence of neurotoxicity.

    “Our primary focus was on lead, an established neurotoxicant that has been implicated in ASD20, and manganese, an essential nutrient with emerging evidence of neurotoxicity21.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Zoni, S. & Lucchini, R. G. Manganese exposure: cognitive, motor and behavioral effects on children: a review of recent findings. Curr. Op. Peds. 25, 255–260 (2013). source

      Not checked in the free run.

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

    Premisecitation

    Zinc is an essential element that is critical for the maintenance of health and central to the regulation of many metal transport mechanisms.

    “We also examined zinc, an essential element that is critical for the maintenance of health and central to the regulation of many metal transport mechanisms22.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Kambe, T., Tsuji, T., Hashimoto, A. & Itsumura, N. The physiological, biochemical, and molecular roles of zinc transporters in zinc homeostasis and metabolism. Physiol. Rev. 95, 749–784 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lead is an established neurotoxicant that has been implicated in ASD.

    “Our primary focus was on lead, an established neurotoxicant that has been implicated in ASD20, and manganese, an essential nutrient with emerging evidence of neurotoxicity21.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Canfield, R. L. et al. Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter. N. Eng. J. Med. 348, 1517–1526 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies of toxic metals and nutritional elements in ASD have yielded mixed results, with some reporting higher concentrations of toxic metals including lead and others finding no association.

    “Studies of toxic metals and nutritional elements in ASD have yielded mixed results. Although several studies reported higher concentrations of toxic metals in ASD, including the neurotoxin lead, others found no association10.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Rossignol, D. A., Genuis, S. J. & Frye, R. E. Environmental toxicants and autism spectrum disorders: a systematic review. Transl. Psych. 4, e360 (2014). source

      Not checked in the free run.

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

    Premisecitation

    Heritable factors account for at least 50% of ASD risk, with the remainder attributable to environmental factors acting alone or through interaction with genetics.

    “Heritable factors account for at least 50% of ASD risk with the remainder attributable to environmental factors acting alone or through interaction with genetics45.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Sandin, S. et al. The familial risk of autism. JAMA 311, 1770–1777 (2014). source

      Not checked in the free run.

    • cites [5] Hallmayer, J. et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch. Gen. Psych. 68, 1095–1102 (2011). source

      Not checked in the free run.

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

    Premisecitation

    Higher blood lead levels have been reported in ASD cases, but in those studies it is possible that the uptake of metal toxicants or nutritional deficiencies are a consequence of autism-related behaviours and do not necessarily reflect a causal exposure prior to the onset of autism symptoms.

    “Similarly, higher blood lead levels have been reported in ASD cases11, but in those studies it is possible that the uptake of metal toxicants or nutritional deficiencies are a consequence of autism-related behaviours and do not necessarily reflect a causal exposure prior to the onset of autism symptoms27.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Cohen, D. J., Paul, R., Anderson, G. M. & Harcherik, D. F. Blood lead in autistic children. Lancet 2, 94–95 (1982). source

      Not checked in the free run.

    • cites [27] Kinnell, H. G. Pica as a feature of autism. Br. J. Psych. 147, 80–82 (1985). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Upstream factors such as placental insufficiency and epigenetic alterations of metal transporters may disrupt zinc homeostasis initiating a cascade of elemental dysregulation which, in the presence of genetic predisposition, raises the risk of ASD.

    “Therefore, upstream factors such as placental insufficiency and epigenetic alterations of metal transporters may disrupt zinc homeostasis initiating a cascade of elemental dysregulation which, in the presence of genetic predisposition, raises the risk of ASD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Early signs of ASD first manifest 6-12 months after birth, suggesting a narrow window for environmental factors to contribute to ASD risk.

    “Early signs of ASD first manifest 6–12 months after birth29, suggesting a narrow window for environmental factors to contribute to ASD risk.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Ozonoff, S. et al. A prospective study of the emergence of early behavioral signs of autism. J. Am. Acad. Child Adol. Psych. 49, 256–266 e1-2 (2010).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many of the genes associated with ASD are also linked with elemental homeostasis, and genes implicated in ASD converge to specific neuronal co-expression networks especially during the same critical early developmental periods observed in this study.

    “Notably, many of the genes associated with ASD are also linked with elemental homeostasis930, and it is intriguing that genes implicated in ASD converge to specific neuronal co-expression networks especially during the same critical early developmental periods we have observed in this study313233.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] Grabrucker, A. M. Environmental factors in autism. Front. Psych. 3, 118–122 (2012).

      Not checked in the free run.

    • cites [30] Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012). source

      Not checked in the free run.

    • cites [31] Uddin, M. et al. Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder. Nat. Genet. 46, 742–747 (2014). source

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

    Premisecitation

    Transcriptional alterations in response to chemical exposures that mimic changes seen in brain samples from autism patients have also been reported recently.

    “Transcriptional alterations in response to chemical exposures that mimic changes seen in brain samples from autism patients have also been reported recently34.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Pearson, B. L. et al. Identification of chemicals that mimic transcriptional changes associated with autism, brain ageing and neurodegeneration. Nat. Commun. 7, 11173 (2016). source

      Not checked in the free run.

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

    Study design and conductcitation

    Clinical severity of ASD symptoms was determined by ADOS comparison scores, and autistic traits were measured by parent reported SRS-2 total raw scores.

    “Clinical severity of ASD symptoms was determined by ADOS comparison scores, and autistic traits were measured by parent reported Social Responsiveness Scale-2 (SRS-2)45 total raw scores.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Constantino, J. N. & Gruber, C. P. Social Responsiveness Scale, 2nd edn (SRS-2) Western Psychological Services (2012).

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    Prenatal lead levels in teeth were validated with maternal blood lead measured during the second and third trimesters of pregnancy, and birth and childhood measures of tooth lead with lead concentrations in umbilical cord blood and serial childhood blood measures.

    “For example, earlier we validated prenatal lead levels in teeth with maternal blood lead measured during the second and third trimesters of pregnancy, and birth and childhood measures of tooth lead with lead concentrations in umbilical cord blood and serial childhood blood measures, respectively15.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Arora, M. et al. Determining prenatal, early childhood and cumulative long-term lead exposure using micro-spatial deciduous dentine levels. PLoS ONE 9, e97805 (2014). source

      Not checked in the free run.

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

    Study design and conductnone given

    Our tooth-biomarkers measure uptake of metals from all sources but do not distinguish specific routes of exposure such as diet.

    “Our tooth-biomarkers measure uptake of metals from all sources but do not distinguish specific routes of exposure such as diet.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    While the differences we observe between cases and controls precede the onset of ASD symptoms, these data do not establish causality.

    “Furthermore, while the differences we observe between cases and controls precede the onset of ASD symptoms, these data do not establish causality.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Recent evidence from human and animal studies suggests that under stress, placental transfer of nutrients to the fetus is disrupted, and factors such as prenatal stress and placental inflammation increase hyperactivity in offspring.

    “Recent evidence from human and animal studies suggests that under stress, placental transfer of nutrients to the fetus is disrupted, and factors such as prenatal stress and placental inflammation increase hyperactivity in offspring3536.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Bronson, S. L. & Bale, T. L. Prenatal stress-induced increases in placental inflammation and offspring hyperactivity are male-specific and ameliorated by maternal anti-inflammatory treatment. Endocrinology 155, 2635–2646 (2014). source

      Not checked in the free run.

    • cites [36] Walker, C. K. et al. Preeclampsia, placental insufficiency, and autism spectrum disorder or developmental delay. JAMA Ped. 169, 154–162 (2015). source

      Not checked in the free run.

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

    Study design and conductreasoning

    This study has multiple strengths, such as the inclusion of an informative twin sample recruited from population-based cohorts, a rigorous diagnostic assessment, and the use of direct fetal biomarkers.

    “This study has multiple strengths, such as the inclusion of an informative twin sample recruited from population-based cohorts, a rigorous diagnostic assessment, and the use of direct fetal biomarkers.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    General cognitive ability was assessed using the Wechsler Intelligence Scales for Children or Adults (Fourth Editions) or the Leiter Scales and the Peabody Picture Vocabulary Test (Third Edition) in cases of low verbal abilities.

    “General cognitive ability was assessed using the Wechsler Intelligence Scales for Children or Adults (Fourth Editions) or the Leiter Scales and the Peabody Picture Vocabulary Test (Third Edition) in cases of low verbal abilities464748.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 464748

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Our sample included MZ and DZ twins and substantially more detailed family data, and our tooth-matrix biomarkers allowed us to investigate the timing of exposure during discrete developmental periods over the pre- and postnatal periods.

    “Our sample included MZ and DZ twins and substantially more detailed family data, and our tooth-matrix biomarkers also allowed us to investigate the timing of exposure during discrete developmental periods over the pre-and postnatal periods.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These differences at specific developmental periods in early life for a range of toxic and essential elements suggest that there are multiple mechanisms leading to dysregulation, and endorse the higher vulnerability of the mid- to late-fetal period to the pathophysiological mechanisms underlying ASD.

    “These differences at specific developmental periods in early life for a range of toxic and essential elements suggest that there are multiple mechanisms leading to dysregulation, and endorse the higher vulnerability of the mid- to late-fetal period to the pathophysiological mechanisms underlying ASD.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    ASD was diagnosed according to DSM-5 criteria based on clinical experts consensus and corroborated by results from the Autism Diagnostic Interview-Revised and the ADOS-2.

    “ASD was diagnosed according to DSM-5 criteria based on clinical experts consensus and corroborated by results from the Autism Diagnostic Interview—Revised43 and the ADOS-2 (ref. 44).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Rutter, M., Le Couteur, A. & Lord, C. Autism Diagnostic Interview Revised Western Psychological Services (2003). source

      Not checked in the free run.

    • cites [44] Lord, C. et al. Autism Diagnostic Observation Schedule, 2nd edn (ADOS-2) Manual (Part 1). Western Psychological Services (2012).

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    All pairs of DNA samples showing ≥0.99 identity by descent were considered monozygotic.

    “All pairs of DNA samples showing ≥0.99 were considered as monozygotic pairs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007). source

      Not checked in the free run.

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

    Study design and conductcitation

    RATSS includes 11.3% of all ASD discordant twins in Sweden in the specified age range.

    “Currently, RATSS includes 11.3% of all ASD discordant twins in Sweden in the specified age range13.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Lichtenstein, P., Carlstrom, E., Rastam, M., Gillberg, C. & Anckarsater, H. The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am. J. Psychiatry 167, 1357–1363 (2010). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All models were adjusted for covariates including sex, zygosity, gestational age, the average birth weight of the twin pairs and the s.d. of the birth weight within the twin pair.

    “All models were adjusted for covariates including sex, zygosity, gestational age, the average birth weight of the twin pairs and the s.d. of the birth weight within the twin pair.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Heterogeneous distribution of metals in enamel and dentine can occur in response to variable environmental exposures, changes in diet and due to age-dependent metabolic changes, and has been observed in humans and other mammals.

    “Heterogeneous distribution of metals in enamel and dentine can occur in response to variable environmental exposures, changes in diet and due to age-dependent metabolic changes, and has been observed in humans and other mammals38.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Kohn, M. J., Morris, J. & Olin, P. Trace element concentrations in teeth–a modern Idaho baseline with implications for archeometry, forensics, and palaeontology. J. Archaeol. Sci. 40, 1689–1699 (2013). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The analysis adjusted for intra-twin correlations through a random effect term per twin pair.

    “first, we adjusted for intra-twin correlations through a random effect term per twin pair”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    Limitations of the study are a relatively small non-random sample, although the sample size was adequate to uncover significant associations after stringent statistical adjustments.

    “Limitations of the study are a relatively small non-random sample, although the sample size was adequate to uncover significant associations after stringent statistical adjustments, and our twin sample represented a significant subsample (11.3%) of the total population of twins discordant for ASD in Sweden in the examined age range13.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Lichtenstein, P., Carlstrom, E., Rastam, M., Gillberg, C. & Anckarsater, H. The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am. J. Psychiatry 167, 1357–1363 (2010). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The analysis used a Holm-Bonferroni correction to account for multiple comparisons.

    “second, we used a Holm–Bonferroni correction to account for multiple comparisons.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Data were analysed as metal to calcium ratios to control for any variations in mineral content within a tooth and between samples.

    “Data were analysed as metal to calcium ratios (for example, 208Pb:43Ca) to control for any variations in mineral content within a tooth and between samples.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    Metal levels in teeth were validated against environmental samples and animal studies with controlled exposures.

    “We have similarly validated metal levels in teeth against environmental samples (house dust concentrations and distance to exposure source, for example)1617, and also undertaken detailed animal studies with controlled exposures1819.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1617]

      Not checked in the free run.

    • cites [1819]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Caution should be exercised when generalizing our findings to other populations.

    “Nevertheless, caution should be exercised when generalizing our findings, and additional studies are needed in different populations, particularly larger non-twin ASD samples to corroborate our findings, and differentiate genetic and non-genetic contributions in understanding the relation between metals and ASD.”
    Quote in the paperNot a substantial claim
49 of 49

  • The paper relies on this without support.

    Concordant ASD twin pairs are more alike in their metal status than discordant pairs.

    “Concordant pairs, where both twins have ASD, are expected to be more alike in their metal status than discordant pairs.”

  • The paper relies on this without support.

    Most previous studies recruited patient series rather than enroling participants from the population.

    “Second, most previous studies recruited patient series rather than enroling participants from the population.”

  • The paper relies on this without support.

    Metal deposits in teeth are stable at room temperature.

    “Metal deposits in teeth are stable at room temperature”

  • The paper relies on this without support.

    Children only shed teeth until the age of 12 years.

    “children only shed teeth until the age of 12 years”
4 of 4

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?

  • In a twin-cotwin design using a validated tooth matrix, significant divergences in metal uptake between ASD cases and control twins occurred during discrete developmental periods, and reduced zinc uptake correlated with ASD severity and autistic traits.

    “Findings revealed significant divergences in metal uptake between ASD cases and their control twins during discrete developmental periods, and correlations between reduced zinc uptake and ASD severity and autistic traits [175].”

    From The contribution of environmental exposure to the etiology of autism spectrum disorder (2019) · cites this paper as [175]

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.

  • Zinc percentage and fold decrease are not equivalent

    Minor

    A level 28% lower is 72% of the comparison level, or about 1.39-fold lower. A level 1.28-fold lower is about 22% lower, not 28%.

1 of 1

Cites

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Related

Authors
Arora, M., Reichenberg, A., Willfors, C., Austin, C., Gennings, C., Berggren, S., Lichtenstein, P., Anckarsäter, H., Tammimies, K., & Bölte, S.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • Region Stockholm (SE)
  • Karolinska Institutet (SE)
  • University of Gothenburg (SE)
Corresponding author
  • Arora, Manish
  • Bölte, Sven
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-06-01
Volume
8
Issue
1
Pages
15493-15493
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms15493
PMC
PMC5461492
OpenAlex
W2620629113
Semantic Scholar
e6c7953b451b6c4bd9ac19797e86afd0c1c0440f
Cited by
169
References
45
Citations by year
2026: 9 · 2025: 18 · 2024: 11 · 2023: 16 · 2022: 18 · 2021: 25 · 2020: 29 · 2019: 16 · 2018: 24 · 2017: 3
FWCI
10.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eSpace (Curtin University) (submittedVersion, cc-by)
Funders
  • Icahn School of Medicine at Mount Sinai (P30ES023515)
  • Beatrice and Samuel A. Seaver Foundation
  • European Federation of Pharmaceutical Industries and Associations (FP7/20072013)
  • European Commission (2007–2013, FP7 2007-2013, 115300, FP7/2007)
  • Stiftelsen för Strategisk Forskning
  • VINNOVA (259‐2012‐24, P30ES023515, 115300)
  • Svenska Forskningsrådet Formas (259-2012-24, P30ES023515, 115300, 523-2009-7054)
  • Knut och Alice Wallenbergs Stiftelse (P30ES023515, 115300)
  • Stockholms Läns Landsting
  • Vetenskapsrådet (FP7/2007-2013, 521-2013-2531, 523‐2009‐7054, 523-2009-7054; 521-2013-2531, 115300, 259-2012-24, P30ES023515)
  • Forskningsrådet om Hälsa, Arbetsliv och Välfärd (115300, 259-2012-24, P30ES023515)
  • Science for Life Laboratory
  • National Institutes of Health (FP7/2007-2013)
  • Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai
  • National Institute of Mental Health (MH097849, R01MH097849, R56MH097849, 115300)
  • National Institute of Environmental Health Sciences (R00ES019597, DP2ES025453, P30ES023515)
  • National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01HD073978, HD073978)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
Keywords
autism spectrum disorder, essential trace elements, manganese, zinc, lead exposure, toxic metals, monozygotic and dizygotic twins, developmental windows, ASD severity, autistic traits, prenatal and postnatal exposure
MeSH terms
Adolescent, Attention Deficit Disorder with Hyperactivity, Autistic Disorder, Child, Female, Fetus, Humans, Male, Metals, Severity of Illness Index, Sweden, Tooth, Biomarkers, Case-Control Studies, Twin Studies as Topic

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 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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