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Cited by 54Effects and risks of endocrine disrupting chemicalsNeuroendocrine regulation and behaviorSexual Differentiation and Disorders

Endocrine Disruption of Vasopressin Systems and Related Behaviors

Open access
Patisaul, Heather B.·2017·Frontiers in Endocrinology
DOI 10.3389/fendo.2017.00134PMC PMC5475378
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Abstract

Endocrine disrupting chemicals (EDCs) are chemicals that interfere with the organizational or activational effects of hormones. Although the vast majority of the EDC literature focuses on steroid hormone signaling related impacts, growing evidence from a myriad of species reveals that the nonapeptide hormones vasopressin (AVP) and oxytocin (OT) may also be EDC targets. EDCs shown to alter pathways and behaviors coordinated by AVP and/or OT include the plastics component bisphenol A (BPA), the soy phytoestrogen genistein (GEN), and various flame retardants. Many effects are sex specific and likely involve action at nuclear estrogen receptors. Effects include the elimination or reversal of well-characterized sexually dimorphic aspects of the AVP system, including innervation of the lateral septum and other brain regions critical for social and other non-reproductive behaviors. Disruption of magnocellular AVP function has also been reported in rats, suggesting possible effects on hemodynamics and cardiovascular function.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes evidence that endocrine disrupting chemicals (EDCs) can alter vasopressin (AVP) and oxytocin (OT) pathways and related social, anxiety, and physiological behaviors, often in sex-specific ways. It argues these nonapeptide systems are understudied EDC targets that may contribute to psychosocial and cardiovascular disorders, but causal links remain sparse.

Key findings

  • EDCs including bisphenol A (BPA), genistein (GEN), chlorpyrifos, DDT/p,p′-DDE, methoxychlor, PBDEs, PCBs, and vinclozolin have been reported to alter AVP/OT neuron numbers, innervation, mRNA/protein levels, release, and related behaviors across birds, rodents, voles, and other species.
  • Effects are often sex specific and include elimination or reversal of sexually dimorphic AVP innervation in regions such as the lateral septum, bed nucleus of the stria terminalis, amygdala, and paraventricular nucleus; for example, developmental BPA in prairie voles eliminated or reversed sex differences in PVN TH-ir neuron numbers and social investigation at 5, 50, or 50,000 µg/kg bw.
  • BPA exposure has been linked to anxiogenic phenotypes; in Wistar rats, perinatal BPA via drinking water (1 mg/L) elevated juvenile anxiety-related behaviors, with a soy-rich diet ameliorating the effects, and BPA altered ERβ and Mc4r expression in the amygdala.
  • Magnocellular AVP disruption has also been reported: PCBs/PBDEs reduced AVP release from the supraoptic nucleus in response to dehydration in rats, and perinatal PBDE exposure at 1.7 or 30.6 mg/kg/day elevated systolic blood pressure responses at 3 h post-hyperosmotic challenge.

Methods

  • Narrative review; no primary data collection. It synthesizes published literature and includes tables summarizing EDC effects on AVP/OT pathways and functions attributed to AVP/OT.
  • Evidence is drawn from multiple species, including Japanese quail, rats, mice, prairie and pine voles, hamsters, monkeys, and humans, and uses the Endocrine Society definition of an EDC.
  • Main analysis is qualitative synthesis; no systematic search strategy, inclusion criteria, or meta-analysis is stated.

Limitations

  • The paper states that available data are sparse, the literature on EDCs and AVP/OT pathways remains small, much work is largely descriptive with limited causal understanding, only a handful of compounds have been tested for AVP-related outcomes, and no single chemical has been definitively implicated in a clinical social-brain disorder.
  • The paper notes that some findings are preliminary or unpublished (e.g., AVP mRNA downregulation in BPA-exposed females at p ≤ 0.07 described as unpublished observations) and that work on “natural” EDCs is difficult to fund.
  • Evident from the text: the review is not systematic and lacks quantitative synthesis; reliance on animal models and heterogeneous species, doses, and exposure windows limits comparability and human translation.

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

Integrity signals

Registry

Crossref · 10.3389/fendo.2017.00134

Cites

154 of 154 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

104 of 181 cited sources checked · 28 supported · 4 flagged · accuracy not yet measured

  • Premisecitation

    BPA exposure effects on social behavior (juvenile social recognition and social investigation) were directionally inconsistent across generations.

    “Evidence of effects on social behavior, including juvenile social recognition and social investigation, was reported but directionally inconsistent across generations”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [104] Wolstenholme, 2013, Transgenerational effects of prenatal bisphenol A on social recognition, Horm Behav source

      The Results section reports increased juvenile social investigation in both F1 and F3 BPA-lineage mice, not effects in opposite directions across generations. It also reports impaired responses to a novel female in F3 but not F1; that is a generation-specific difference in social recognition, not a reversal in the direction of social investigation. (LLM, conf=0.87)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    No evidence of disrupted AVP-ir levels was found for the MePD, PVN, LS or BnST in BPA-exposed mice.

    “No evidence of disrupted AVP-ir levels was found for the MePD, PVN, LS or BnST (66).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [66] Goldsby, 2017, Multi- and transgenerational consequences of bisphenol A on sexually dimorphic cell populations in mouse brain, Endocrinology source

      The Results (AVP-ir in F1 brains; page not provided) report reduced AVP immunoreactivity in the MePD after gestational BPA exposure and decreased immunoreactive area in BPA-exposed males in both the MePD and LS. Thus the claim that no disruption was found in any of the four regions contradicts the F1 findings, even though the Results for F3 brains report no diet main effects in those regions. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    NO endocrine disruption by GEN, BPA, and other EDCs has been found in parvocellular aspects of AVP signaling.

    “Concomitant work focused on the parvocellular aspects of AVP signaling has also found evidence of NO endocrine disruption by GEN, BPA, and other EDCs (39, 74, 151).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [39] Frye, 2012, Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behaviour and neuroendocrine systems, J Neuroendocrinol source

      In “EDCs Influence Brain Morphology” (page unavailable), the review reports that embryonic exposure to genistein, DES, or DDE significantly demasculinized the sexually dimorphic parvocellular AVT system in Japanese quail. That is contrary to the claim of no endocrine disruption in this system. The passage concerns avian AVT, the counterpart the review discusses alongside mammalian AVP; it does not establish a BPA effect on parvocellular AVP signaling. (LLM, conf=0.85)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [74] Ponti, 2017, Early postnatal genistein administration permanently affects nitrergic and vasopressinergic systems in a sex-specific way, Neuroscience source

      The Results (Paraventricular nucleus; page unavailable) report that genistein changed AVP-positive cell numbers in the medial parvicellular region, increasing them in females and decreasing them in males. The paper also reports effects on nNOS, a marker of nitric-oxide-producing neurons, but does not show that nitric oxide disruption caused the parvocellular AVP changes. BPA and other EDCs appear to be covered by the sentence’s other citations, not this study’s experiment. (LLM, conf=0.81)

      Experimental — accuracy not yet measured
    • cites [151] Martini, 2010, Effects of perinatal administration of bisphenol A on the neuronal nitric oxide synthase expressing system in the hypothalamus and limbic system of CD1 mice, J Neuroendocrinol source
  • Premisecitation

    The neuroendocrine pathways coordinating numerous social traits are highly conserved, including the coordinating roles of AVP and OT.

    “Although no animal model can fully capture the sophisticated complexity of human social behavior, the neuroendocrine pathways coordinating numerous social traits are highly conserved (7, 42), including the coordinating roles of AVP and OT.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [7] Albers, 2015, Species, sex and individual differences in the vasotocin/vasopressin system: relationship to neurochemical signaling in the social behavior neural network, Front Neuroendocrinol source
    • cites [42] Adkins-Regan, 2009, Neuroendocrinology of social behavior, ILAR J source
  • Interpretationcitation

    Because AVP/OT and the dopaminergic pathways they feed into are heavily influenced by sex steroids across the lifespan, their sexually dimorphic ontogeny and function may be particularly vulnerable to endocrine disruption.

    “Because AVP/OT and the dopaminergic pathways they feed into are heavily influenced by sex steroids across the lifespan (50–59), it is highly plausible that their sexually dimorphic ontogeny and function may be particularly vulnerable to endocrine disruption.”
    Quote in the paperSubstantial claim5 of 10 sources checked
    • cites [50] Simerly, 1985, Influence of perinatal androgen on the sexually dimorphic distribution of tyrosine hydroxylase-immunoreactive cells and fibers in the anteroventral periventricular nucleus of the rat, Neuroendocrinology source
    • cites [51] Cushing, 2005, Mechanisms underlying epigenetic effects of early social experience: the role of neuropeptides and steroids, Neurosci Biobehav Rev source
    • cites [52] Cushing, 2003, The effects of neonatal castration on the subsequent behavioural response to centrally administered arginine vasopressin and the expression of V1a receptors in adult male prairie voles, J Neuroendocrinol source

      The Discussion reports that early removal of gonadal steroids changes adult male prairie voles’ behavioral response to vasopressin, and the Abstract says steroids maintain the vasopressin system in adult males. This supports steroid influence on AVP across developmental stages, but the paper does not establish the same claim for oxytocin or dopaminergic pathways. The endocrine-disruption inference follows the citation and is the citing authors’ own framing. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [53] Lonstein, 2000, Sex differences in the parental behavior of rodents, Neurosci Biobehav Rev source
    • cites [54] Kabelik, 2011, Estrogenic regulation of dopaminergic neurons in the opportunistically breeding zebra finch, Gen Comp Endocrinol source

      The Introduction reports that sex steroids regulate dopamine activity and synthesis, including effects during specific developmental periods. It does not establish that AVP/OT feeds into those pathways or that both systems are heavily influenced by sex steroids across the lifespan. The proposed vulnerability to endocrine disruption is the citing authors’ inference, not a finding attributed to this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [55] Cavanaugh, 2010, Androgenic and oestrogenic influences on tyrosine hydroxylase-immunoreactive cells of the prairie vole medial amygdala and bed nucleus of the stria terminalis, J Neuroendocrinol source

      The Abstract reports that sex steroids regulate sexually dimorphic tyrosine hydroxylase-immunoreactive cells in adult prairie voles. The Discussion also describes hormone-mediated plasticity in adult cells synthesizing vasopressin. These passages do not establish steroid effects on oxytocin or effects across the lifespan; the endocrine-disruption inference is the citing authors’ own conclusion, not a finding attributed to this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [56] Cushing, 2008, Estrogen receptors in the medial amygdala inhibit the expression of male prosocial behavior, J Neurosci source

      The Discussion (page unavailable) reports that neonatal castration altered adult male prairie voles’ response to vasopressin and that changing estrogen-receptor expression in adults altered social behavior. This supports a link between sex-steroid signaling and some vasopressin-related behavior, but the cited paper does not establish steroid effects on oxytocin or dopaminergic pathways across the lifespan. The endocrine-disruption vulnerability is the citing authors’ inference, not a finding attributed to this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [57] Kramer, 2009, Sex steroids are necessary in the second postnatal week for the expression of male alloparental behavior in prairie voles (Microtus ochragaster), Behav Neurosci source
    • cites [58] Perry, 2015, Effects of postnatal estrogen manipulations on juvenile alloparental behavior, Horm Behav source

      The Abstract and Results report sex-specific effects of postnatal estrogen-receptor activation on ERα expression and alloparental behavior in prairie voles. They do not address whether sex steroids influence AVP/OT and the dopaminergic pathways they feed into across the lifespan; searches for those pathways and endocrine disruption returned no passage establishing that point. The endocrine-disruption inference follows the citation in the citing sentence and is the citing authors’ own framing. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [59] Ploskonka, 2015, Developmental expression of estrogen receptor beta in the brain of prairie voles (Microtus ochrogaster), Dev Psychobiol source
  • May combine two claims. 54
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Premisecitation

    Genetic factors contribute only an estimated 30-40% of ASD heritability, with most of that attributable to common genetic variants.

    “Genetic factors contribute only an estimated 30–40% of ASD heritability, with most of that attributable to common genetic variants (11).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Sandin, 2014, The familial risk of autism, JAMA source

      The Results (Heritability; page unavailable) estimate ASD heritability at 50% in the best-fitting model, not 30–40%; the Discussion likewise says genetic factors explain half of ASD liability. The paper mentions a 38% estimate from a different twin study but does not assess whether common genetic variants account for most of the genetic contribution. (LLM, conf=0.85)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    BPA alters AVP and OT neuron numbers and innervation of sexually dimorphic regions associated with social and aggressive behaviors in multiple species, and is anxiogenic in multiple species.

    “Altered AVP and OT neuron numbers and innervation of sexually dimorphic regions associated with social and aggressive behaviors in multiple species; anxiogenic in multiple species”
    Quote in the paperSubstantial claim6 of 7 sources checked
    • cites [60] Patisaul, 2012, Anxiogenic effects of developmental bisphenol A exposure are associated with gene expression changes in the juvenile rat amygdala and mitigated by soy, PLoS One source

      The Discussion (page unavailable) reports anxiogenic effects of developmental BPA exposure in this rat study and cites similar findings in two mouse species. It discusses oxytocin and vasopressin signaling as a possible mechanism, but does not report altered AVP or OT neuron numbers or innervation of sexually dimorphic regions; it says their gene expression was not significantly altered in the amygdala. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [61] Adewale, 2011, The impact of neonatal bisphenol-A exposure on sexually dimorphic hypothalamic nuclei in the female rat, Neurotoxicology source

      The Results (section 3.3) report that neonatal BPA exposure increased OT neuron numbers in the rostral PVN of female rats. The paper does not report BPA-induced changes in AVP neurons or innervation, or establish these neural effects or anxiogenic effects in multiple species; the Discussion (section 4.1) says the physiological and behavioral significance of the OT finding remains unclear. Page numbers were not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [62] Sullivan, 2014, A novel model for neuroendocrine toxicology: neurobehavioral effects of BPA exposure in a prosocial species, the prairie vole (Microtus ochrogaster), Endocrinology source
    • cites [63] Rissman, 2014, Minireview: transgenerational epigenetic inheritance: focus on endocrine disrupting compounds, Endocrinology source

      The ‘EDCs and Transgenerational Epigenetic Inheritance’ section reports BPA-related changes in social interaction in mice, but does not address AVP or OT neuron numbers, innervation, aggression, or anxiogenic effects across species. Its discussion of anxiety-like behavior concerns vinclozolin, not BPA (pages unavailable in our copy). Searches for AVP/OT innervation and BPA-related anxiety found no passage establishing the attributed claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [64] Wolstenholme, 2011, Gestational exposure to low dose bisphenol A alters social behavior in juvenile mice, PLoS One source

      The Results ('BPA exposure affects gene expression'; page unavailable) report altered oxytocin-receptor mRNA, not altered AVP or OT neuron numbers or innervation. The Discussion (page unavailable) reports that a 40-fold higher BPA dose increased anxiety-related behavior in mice, whereas the current low-dose study found no anxiety effect. The paper does not establish that BPA is anxiogenic in multiple species. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [65] Wolstenholme, 2012, Gestational exposure to bisphenol a produces transgenerational changes in behaviors and gene expression, Endocrinology source

      The gene-expression results report altered Avp and Oxt mRNA in mouse brains, but the Discussion says the authors were still assessing which neuron subpopulations BPA affects; it does not establish changes in neuron numbers or innervation. The background mentions anxiety findings in mice and children, but the paper’s own elevated-plus-maze results state that gestational BPA did not alter anxiety-like behavior in any generation. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [66] Goldsby, 2017, Multi- and transgenerational consequences of bisphenol A on sexually dimorphic cell populations in mouse brain, Endocrinology source

      The Results (AVP-ir in F1 brains; page unavailable) report reduced AVP immunoreactivity in sexually dimorphic regions of BPA-exposed male mice, and the Discussion links the AVP circuit to social behavior. The Methods (Image analysis; page unavailable) specify that immunoreactive area was measured without distinguishing cells from fibers. The paper does not establish altered OT neuron numbers or innervation, aggressive behavior, or anxiogenic effects in multiple species; its BPA findings here are primarily in mice. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    GEN alters AVP and OT neuron numbers and innervation of sexually dimorphic regions associated with social and aggressive behaviors in multiple species, and is anxiogenic in males of multiple species.

    “Altered AVP and OT neuron numbers and innervation of sexually dimorphic regions associated with social and aggressive behaviors in multiple species; anxiogenic in males of multiple species”
    Quote in the paperSubstantial claim1 of 6 sources checked
    • cites [69] Viglietti-Panzica, 2007, Effects of early embryonic exposure to genistein on male copulatory behavior and vasotocin system of Japanese quail, Horm Behav source
    • cites [70] Panzica, 2005, Early embryonic administration of xenoestrogens alters vasotocin system and male sexual behavior of the Japanese quail, Domest Anim Endocrinol source
    • cites [71] Hartley, 2003, The soya isoflavone content of rat diet can increase anxiety and stress hormone release in the male rat, Psychopharmacology (Berl) source
    • cites [72] Moore, 2004, The neurobehavioral effects of phytoestrogens in male Syrian hamsters, Brain Res source
    • cites [73] Scallet, 2003, Dietary exposure to genistein increases vasopressin but does not alter beta-endorphin in the rat hypothalamus, Toxicol Sci source
    • cites [74] Ponti, 2017, Early postnatal genistein administration permanently affects nitrergic and vasopressinergic systems in a sex-specific way, Neuroscience source

      The Paraventricular nucleus results (page unavailable) report that genistein increased AVP-positive cell numbers in female mice and decreased them in males; the figure caption also reports increased AVP immunoreactivity in the female bed nucleus of the stria terminalis. The paper does not establish changes in OT neurons or effects across multiple species. Its Introduction mentions altered anxiety behavior in male mice from an earlier study, but does not specify an anxiogenic effect or establish one in multiple species. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Differences in the region-specific distribution of AVPRs and/or OTRs have been linked to individual and species variation in prosocial phenotypes including social attachment, parental behavior, and social anxiety, as have genetic polymorphisms in AVP, OT, and/or their receptors.

    “Differences in the region-specific distribution of AVPRs and/or OTRs have been linked to individual and species variation in prosocial phenotypes including social attachment, parental behavior, and social anxiety, as have genetic polymorphisms in AVP, OT, and/or their receptors.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [5] Johnson, 2017, Oxytocin and vasopressin neural networks: implications for social behavioral diversity and translational neuroscience, Neurosci Biobehav Rev source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Direct evidence linking any specific EDC to a clearly defined clinical disorder involving the social brain is sparse, and no single chemical has yet been definitively implicated.

    “Direct evidence linking any specific EDC to a clearly defined clinical disorder involving the social brain is sparse, and no single chemical has yet been definitively implicated (18, 21–25).”
    Quote in the paperSubstantial claim6 of 6 sources checked
    • cites [18] Landrigan, 2012, A research strategy to discover the environmental causes of autism and neurodevelopmental disabilities, Environ Health Perspect source
    • cites [21] Kalkbrenner, 2014, Environmental chemical exposures and autism spectrum disorders: a review of the epidemiological evidence, Curr Probl Pediatr Adolesc Health Care source
    • cites [22] Grandjean, 2014, Neurobehavioural effects of developmental toxicity, Lancet Neurol source

      In “Other suspected developmental neurotoxicants” (page unavailable), the paper links phthalates to impaired social interactions and says their effects could relate to endocrine disruption. In “Developmental neurotoxicity and clinical neurology” (page unavailable), it links phthalates to ADHD risk and autism-like behaviours. These are qualified associations, but the paper does not establish that direct evidence is sparse overall or state that no individual EDC has been definitively implicated in a clinical disorder involving the social brain. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [23] Fujiwara, 2016, Chemicals, nutrition, and autism spectrum disorder: a mini-review, Front Neurosci source
    • cites [24] Aguiar, 2010, Attention deficit/hyperactivity disorder: a focused overview for children’s environmental health researchers, Environ Health Perspect source

      The Conclusion says ADHD’s etiology remains poorly understood and calls for further research on environmental chemical exposures, supporting the claim’s general caution about definitive links. It does not assess endocrine-disrupting chemicals (EDCs) as a class or disorders involving the “social brain,” so it cannot support those specific parts of the claim. No page number is available in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [25] Eubig, 2010, Lead and PCBs as risk factors for attention deficit/hyperactivity disorder, Environ Health Perspect source

      In “Lead and ADHD” (page not specified), the paper says the evidence linking lead exposure to ADHD is insufficient to infer causality. Its PCB discussion (page not specified) says the relationship between PCB exposure and an ADHD diagnosis remains essentially unexplored. These passages support uncertainty about those chemicals and ADHD, but the paper does not establish the broader claim about any specific EDC and clinical disorders involving the social brain. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    OT binds to the OT receptor (OTR), and AVP binds to one of two AVP receptor (AVPR) subtypes: AVPR1A or AVPR1B, the central distribution of which can differ substantially by sex, age, and species.

    “OT binds to the OT receptor (OTR), and AVP binds to one of two AVP receptor (AVPR) subtypes: AVPR1A or AVPR1B, the central distribution of which can differ substantially by sex, age, and species (5).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [5] Johnson, 2017, Oxytocin and vasopressin neural networks: implications for social behavioral diversity and translational neuroscience, Neurosci Biobehav Rev source

      The OT/AVP-like receptors section (page unavailable) identifies OTR, V1aR and V1bR as the principal receptors studied in mammalian nervous tissue and describes differences in central receptor expression by sex and species. It does not establish that receptor distribution differs by age. It also notes that OT- and AVP-like ligands can bind across receptor types, so the claim's binding description is simplified. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PBDEs impair AVP release from the SON in response to dehydration and disrupt nitric oxide release related to AVP function in rats.

    “Impaired AVP release from the SON in response to dehydration; disruption of nitric oxide release related to AVP function in rats”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [76] Coburn, 2005, Dietary exposure to aroclor 1254 alters central and peripheral vasopressin release in response to dehydration in the rat, Toxicol Sci source
    • cites [77] Coburn, 2007, Polybrominated diphenyl ethers and ortho-substituted polychlorinated biphenyls as neuroendocrine disruptors of vasopressin release: effects during physiological activation in vitro and structure-activity relationships, Toxicol Sci source

      The Discussion reports that the PBDE mixture DE-71 significantly reduced vasopressin (AVP) release from rat SON tissue punches during hyperosmotic stimulation, an in vitro model of the response to dehydration. It discusses nitric oxide as a possible mechanism but does not report measuring nitric oxide release or showing that PBDEs disrupt it. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [78] Shah, 2011, Altered cardiovascular reactivity and osmoregulation during hyperosmotic stress in adult rats developmentally exposed to polybrominated diphenyl ethers (PBDEs), Toxicol Appl Pharmacol source

  • May combine two claims.

    Premisecitation

    The parvocellular AVP/OT system is sexually dimorphic, steroid hormone sensitive, and fundamental for the coordination of affiliative and social behaviors including courtship, pair bonding, empathy, reciprocity, trust, and context-specific aggression.

    “The parvocellular system sends projections to the median eminence and throughout the brain and is sexually dimorphic, steroid hormone sensitive, and fundamental for the coordination of affiliative and social behaviors including courtship, pair bonding, empathy, reciprocity, trust, and context-specific aggression (1–4).”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [1] Caldwell, 2016, Oxytocin, vasopressin, and the motivational forces that drive social behaviors, Curr Top Behav Neurosci source
    • cites [2] Ross, 2009, Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior, Front Neuroendocrinol source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [3] Young, 2011, The neurobiology of pair bonding: insights from a socially monogamous rodent, Front Neuroendocrinol source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [4] Rood, 2011, Vasopressin innervation of the mouse (Mus musculus) brain and spinal cord, J Comp Neurol source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Exposure significantly increased OT-immunoreactive neuron numbers, but only in the anterior PVN.

    “Exposure significantly increased OT-immunoreactive (-ir) neuron numbers, but only in the anterior PVN, a result interpreted to potentially indicate sequestration of OT and reduced release from nerve terminals.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [61] Adewale, 2011, The impact of neonatal bisphenol-A exposure on sexually dimorphic hypothalamic nuclei in the female rat, Neurotoxicology source

  • May combine two claims.

    Premisecitation

    In C57BL/6J mice, gestational BPA exposure (dams on approximately 170 μg/kg bw diet) produced social deficits, particularly in females, coinciding with decreased AVP mRNA in whole embryonic brains of ED18.5 siblings of both sexes.

    “Mice reared on a diet delivering approximately 170 µg/kg bw BPA (to the dams) during gestation displayed social deficits, particularly in females, that coincided with a decrease in AVP mRNA expression levels in whole embryonic brains obtained from their ED18.5 siblings (both sexes).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [64] Wolstenholme, 2011, Gestational exposure to low dose bisphenol A alters social behavior in juvenile mice, PLoS One source

      The Methods (Animals) identify C57BL/6J mice and gestational exposure through BPA-supplemented chow, while the Discussion reports altered juvenile social behavior, especially in females. But the Discussion describes increased female social interactions, not social deficits. The Results (BPA exposure affects gene expression) report reduced oxytocin-receptor (Oxtr) mRNA in exposed male E18.5 brains; the paper does not report decreased AVP mRNA in both sexes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [65] Wolstenholme, 2012, Gestational exposure to bisphenol a produces transgenerational changes in behaviors and gene expression, Endocrinology source

      The Animals section (page unavailable) identifies C57BL/6J mice given 5 mg BPA/kg diet, and the qPCR results report lower Avp mRNA in E18.5 embryonic brains without a sex effect. The paper does not give the claimed approximately 170 µg/kg body-weight dose. Its juvenile social-interaction results find no sex-by-diet interaction, while its social-preference results show reduced preference in BPA-exposed males rather than females; thus “particularly in females” is not supported. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The CPF-induced decrease in hypothalamic AVP and increase in OT was more pronounced in males than females and following pre- rather than postnatal exposure.

    “This outcome was more pronounced in males than females and following pre-, rather than post-, natal exposure.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [67] Tait, 2009, Long-term effects on hypothalamic neuropeptides after developmental exposure to chlorpyrifos in mice, Environ Health Perspect source

  • May combine two claims.

    Premisecitation

    In CD1 mice, oral intake of 50 μg/kg GEN in the first week of life slightly but significantly increased AVP-ir in the female BnST but did not impact sexually dimorphic AVP innervation of the LS.

    “For example, in CD1 mice, oral intake of 50 µg/kg GEN in the first week of life slightly, but significantly increased AVP-ir in the female BnST but did not impact the sexually dimorphic AVP innervation of the LS (74).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [74] Ponti, 2017, Early postnatal genistein administration permanently affects nitrergic and vasopressinergic systems in a sex-specific way, Neuroscience source

      The Animals and treatment sections (page unavailable) describe CD-1 mice fed GEN from postnatal day 1 to 8. The AVP results report a significant increase in female BST AVP immunoreactivity and no treatment effect on sexually dimorphic LS innervation. However, the treatment section specifies 50 mg/kg GEN, not the claimed 50 µg/kg; 50 µg/kg was the estradiol dose. (LLM, conf=0.93)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In both studies, CPF-exposed mice displayed altered social and exploratory behaviors, with specific outcomes differing by sex.

    “In both studies CPF-exposed mice displayed altered social and exploratory behaviors, with the specific outcomes differing by sex.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [67] Tait, 2009, Long-term effects on hypothalamic neuropeptides after developmental exposure to chlorpyrifos in mice, Environ Health Perspect source
    • cites [68] Venerosi, 2015, Effects of maternal chlorpyrifos diet on social investigation and brain neuroendocrine markers in the offspring – a mouse study, Environ Health source

      The Results (Social recognition; page unavailable) report altered social investigation in CPF-exposed offspring, with different patterns in males and females. But the Results (Open field; page unavailable) report no CPF effect on spontaneous behavior, so this study does not support the claim that exploratory behavior was altered. This paper also cannot establish what occurred in the other study referenced by “both studies.” (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    F1 male mice exposed to BPA had fewer AVP-ir in the MePD than unexposed males, while females were unaffected.

    “F1 males had fewer AVP-ir in the MePD than unexposed males, but females were unaffected.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [66] Goldsby, 2017, Multi- and transgenerational consequences of bisphenol A on sexually dimorphic cell populations in mouse brain, Endocrinology source

  • May combine two claims.

    Premisecitation

    Evidence of endocrine disrupting properties of GEN dates back decades, and soy is well recognized as a hormonally active food.

    “Evidence of the endocrine disrupting properties of GEN dates back decades, and soy is so well recognized as a hormonally active food, that it is frequently advertised and promoted as such (15, 111–115).”
    Quote in the paperNot a substantial claim4 of 6 sources checked
    • cites [15] Patisaul, 2010, The pros and cons of phytoestrogens, Front Neuroendocrinol source

      Section 7.4 reports endocrine-disrupting effects of genistein in rodents, and section 4.1 describes the popular use of soy phytoestrogens as a hormone-replacement alternative. But section 3 dates the historical evidence to clover-associated phytoestrogens, primarily coumestrol, in the 1940s—not specifically to genistein. The paper also discusses soy marketing, but does not establish that soy is frequently advertised specifically as a hormonally active food. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [111] Patisaul, 2004, Dietary phytoestrogens source
    • cites [112] Patisaul, 2016, Endocrine disruption by dietary phyto-oestrogens: impact on dimorphic sexual systems and behaviours, Proc Nutr Soc source
    • cites [113] Jefferson, 2012, Reproductive consequences of developmental phytoestrogen exposure, Reproduction source
    • cites [114] Barrett, 1996, Phytoestrogens. Friends or foes?, Environ Health Perspect source

      The historical discussion (p. 478) says estrogen-like compounds in soybeans were identified in the early 1930s, and the discussion of human studies (p. 480) reports that a soy diet altered menstrual cycles. These passages support the longstanding evidence of hormonal activity, but they do not establish that evidence about genistein specifically dates back decades or that soy is frequently advertised for that activity. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [115] McCarrison, 1933, The goitrogenic action of soya-bean and ground-nut, Indian J Med Res

  • May combine two claims.

    Premisecitation

    Postnatal GEN eliminated the sexually dimorphic density of AVP-ir neurons in the medial parvicellular part of the PVN (PaMP), with higher numbers in females and lower numbers in males.

    “Notably, the sexually dimorphic density of AVP-ir neurons in the medial parvicellular part of the PVN (PaMP) was eliminated by postnatal GEN, with higher numbers in females and lower numbers in males.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [74] Ponti, 2017, Early postnatal genistein administration permanently affects nitrergic and vasopressinergic systems in a sex-specific way, Neuroscience source

      The Paraventricular nucleus results report that postnatal GEN increased AVP-positive cell numbers in female PaMP and decreased them in male PaMP; the Discussion describes an inverted phenotype. But the paper does not establish a pre-treatment PaMP sex dimorphism that GEN eliminated, and the difference between GEN-treated females and males fell just short of significance (p=0.054). (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In the transgenerational mouse model, disrupted ERα-ir was found in F3 females from the BPA-exposed lineage, with higher levels in the AVPV and lower levels in the BnST.

    “Moreover, in the transgenerational mouse model, one of the most striking findings was disrupted ERα-ir in the F3 females from the BPA-exposed lineage, with higher levels in the AVPV and lower levels in the BnST (66).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [66] Goldsby, 2017, Multi- and transgenerational consequences of bisphenol A on sexually dimorphic cell populations in mouse brain, Endocrinology source

  • May combine two claims.

    Premisecitation

    By this model, estradiol simultaneously acts through ERβ in the PVN to increase OT, and ERα in the amygdala to increase OTR expression.

    “By this model, estradiol simultaneously acts through ERβ in the PVN to increase OT, and ERα in the amygdala to increase OTR expression.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [7] Albers, 2015, Species, sex and individual differences in the vasotocin/vasopressin system: relationship to neurochemical signaling in the social behavior neural network, Front Neuroendocrinol source

      Section 5.1 discusses estradiol’s effects on the AVP system, while section 9.1.5 discusses OT receptors in the central amygdala; neither describes the proposed estradiol–ERβ–PVN–OT and estradiol–ERα–amygdala–OTR pathways. Searches for ERβ, estrogen receptor alpha, and the proposed pathways found no passage addressing that model. Page numbers were not available in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [131] Choleris, 2003, An estrogen-dependent four-gene micronet regulating social recognition: a study with oxytocin and estrogen receptor-alpha and -beta knockout mice, Proc Natl Acad Sci U S A source

  • May combine two claims.

    Premisecitation

    These AVP neurons receive osmosensitive inputs from the organum vasculosum lamina terminalis via glutamatergic synapses and are modulated by nitric oxide (NO) signaling pathways.

    “These AVP neurons receive osmosensitive inputs from the organum vasculosum lamina terminalis via glutamatergic synapses and are modulated by nitric oxide (NO) signaling pathways (146–148).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [146] Trudel, 2012, Circadian modulation of osmoregulated firing in rat supraoptic nucleus neurones, J Neuroendocrinol source
    • cites [147] Silva, 2014, Effects of nitric oxide on magnocellular neurons of the supraoptic nucleus involve multiple mechanisms, Braz J Med Biol Res source

      The Abstract (page not provided) says vasopressin-producing supraoptic neurons receive synaptic input from circumventricular organs containing osmosensitive neurons. The Concluding remarks (page not provided) describe NO modulation of these neurons and a role for glutamatergic neurotransmission during osmotic stress. Our copy does not identify the organum vasculosum of the lamina terminalis as the input source or establish that its inputs use glutamatergic synapses. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [148] Gillard, 2007, Vasopressin autoreceptors and nitric oxide-dependent glutamate release are required for somatodendritic vasopressin release from rat magnocellular neuroendocrine cells responding to osmotic stimuli, Endocrinology source

  • May combine two claims.

    Premisecitation

    Manipulation of OT/AVP levels via direct exposures to exogenous hormones, agonists, or alteration of the social environment can significantly modify the number of OT, AVP, and TH neurons in the PVN, resulting in anxiety-like behavior and alterations of prototypical male and female sociosexual behavior.

    “Manipulation of OT/AVP levels via direct exposures to exogenous hormones, agonists, or alteration of the social environment can significantly modify the number of OT, AVP, and TH neurons in the PVN, thereby resulting in anxiety-like behavior and alterations of prototypical male and female sociosexual behavior (123–127).”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [123] Yamamoto, 2004, Neonatal manipulations of oxytocin alter expression of oxytocin and vasopressin immunoreactive cells in the paraventricular nucleus of the hypothalamus in a gender-specific manner, Neuroscience source
    • cites [124] Martin, 2012, Developmental exposure to a serotonin agonist produces subsequent behavioral and neurochemical changes in the adult male prairie vole, Physiol Behav source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [125] Ahern, 2009, The impact of early life family structure on adult social attachment, alloparental behavior, and the neuropeptide systems regulating affiliative behaviors in the monogamous prairie vole (Microtus ochrogaster), Front Behav Neurosci source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [126] Curtis, 2003, Differential effects of intraspecific interactions on the striatal dopamine system in social and non-social voles, Neuroscience source
    • cites [127] Lieberwirth, 2012, Social isolation impairs adult neurogenesis in the limbic system and alters behaviors in female prairie voles, Horm Behav source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Pathways coordinating social recognition are regulated by estrogen, with both ERα and ERβ knockout mice showing social impairments, and ERβ knockout females failing to generate OT or AVP mRNA expression in response to exogenous estrogen.

    “Pathways coordinating social recognition are well known to be regulated by estrogen, with both ERα and ERβ knockout mice showing social impairments (130, 131), and ERβ knockout females failing to generate OT or AVP mRNA expression in response to exogenous estrogen administration (132, 133).”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [130] Choleris, 2008, Steroidal/neuropeptide interactions in hypothalamus and amygdala related to social anxiety, Prog Brain Res source
    • cites [131] Choleris, 2003, An estrogen-dependent four-gene micronet regulating social recognition: a study with oxytocin and estrogen receptor-alpha and -beta knockout mice, Proc Natl Acad Sci U S A source
    • cites [132] Patisaul, 2003, Oxytocin, but not oxytocin receptor, is regulated by oestrogen receptor beta in the female mouse hypothalamus, J Neuroendocrinol source
    • cites [133] Nomura, 2002, Estrogen receptor-β regulates transcript levels for oxytocin and arginine vasopressin in the hypothalamic paraventricular nucleus of male mice, Mol Brain Res source

  • May combine two claims.

    Premisecitation

    Neonatal manipulation of estradiol or testosterone alters prairie vole affiliative behaviors later in life, and estradiol administration during adulthood alters estrus and locomotor activity.

    “Similarly, neonatal manipulation of estradiol or testosterone alters prairie vole affiliative behaviors later in life, and estradiol administration during adulthood alters estrus and locomotor activity (57, 128, 129).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [57] Kramer, 2009, Sex steroids are necessary in the second postnatal week for the expression of male alloparental behavior in prairie voles (Microtus ochragaster), Behav Neurosci source
    • cites [128] Roberts, 1997, Sexual differentiation in prairie voles: the effects of corticosterone and testosterone, Physiol Behav source
    • cites [129] Lonstein, 2005, Unexpected effects of perinatal gonadal hormone manipulations on sexual differentiation of the extrahypothalamic arginine-vasopressin system in prairie voles, Endocrinology source

      The introductory passage (page unavailable) reports that neonatal castration changes later parental responsiveness in male prairie voles, supporting a limited link between neonatal hormone manipulation and affiliative behavior. It also says perinatal testosterone propionate does not masculinize parental responsiveness in females. The paper examines hormone effects on vasopressin expression; it does not report that adult estradiol administration alters estrus or locomotor activity. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Interpretationreasoning

    BPA may cause homeostatic disruptions including cardiovascular effects and hypertension, and by extension other EDCs may do so.

    “This would suggest an avenue for homeostatic disruptions including cardiovascular effects and hypertension associated with BPA and, by extension, other EDCs (142, 143).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [142] Shankar, 2012, Urinary bisphenol A and hypertension in a multiethnic sample of US adults, J Environ Public Health source

      The Discussion reports an association between higher urinary BPA and hypertension and describes biologically plausible mechanisms; the Introduction also notes studies linking BPA to self-reported cardiovascular disease. The paper does not establish that BPA causes these effects—the Discussion says its cross-sectional design precludes causal conclusions—and it does not extend its findings to other endocrine-disrupting chemicals. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [143] Melzer, 2010, Association of urinary bisphenol a concentration with heart disease: evidence from NHANES 2003/06, PLoS One source

      The Discussion (page unavailable) reports an association between urinary BPA and heart disease and considers possible cardiovascular mechanisms, while cautioning that the cross-sectional findings do not establish causation. It links hypertension to lead, not BPA; its discussion of other contaminants does not establish that other endocrine-disrupting chemicals share BPA’s effects. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The density of ERα markedly differs across prosocial and asocial species and is directly related to the degree to which individuals and species are prosocial.

    “This view is consistent with the observation that the density of ERα markedly differs across prosocial and asocial species and is directly related to the degree to which individuals and species are prosocial (3, 137, 138).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [3] Young, 2011, The neurobiology of pair bonding: insights from a socially monogamous rodent, Front Neuroendocrinol source

      Section 7 reports that increased ERα expression in male prairie voles was associated with reduced social affiliation and describes an inverse relationship between regional ERα expression and social behavior. It does not report marked ERα-density differences between prosocial and asocial species; the cross-species receptor comparisons in Section 3 concern other receptors. Page numbers are unavailable in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [137] Cushing, 2006, Estrogen receptor-alpha distribution in male rodents is associated with social organization, J Comp Neurol source
    • cites [138] Lei, 2010, Estrogen receptor-alpha in the bed nucleus of the stria terminalis regulates social affiliation in male prairie voles (Microtus ochrogaster), PLoS One source

      The Introduction (page not provided) says highly social males of several species have low ERα levels in the BST and MeA, and the Discussion reports a strong correlation between low ERα expression and high male prosocial behavior. The paper also finds that increasing ERα in male prairie voles reduces heterosexual affiliation. These passages support an inverse association, but do not establish the claimed marked density difference between prosocial and asocial species or a relationship across degrees of prosociality in both individuals and species. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A subpopulation of parvocellular PVN OT and AVP neurons, along with ERβ and coordinating input from the BnST, is thought to be involved in the stress response, supporting the possibility that EDCs may influence the hypothalamic-pituitary-adrenal axis.

    “Finally, a subpopulation of parvocellular PVN OT and AVP neurons, along with ERβ and coordinating input from the BnST, is thought to be involved in the stress response (135, 139, 140) supporting the possibility that EDCs may influence the hypothalamic–pituitary–adrenal axis.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [135] Kudwa, 2014, Estrogen receptor beta and oxytocin interact to modulate anxiety-like behavior and neuroendocrine stress reactivity in adult male and female rats, Physiol Behav source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [139] Herman, 1994, Involvement of the bed nucleus of the stria terminalis in tonic regulation of paraventricular hypothalamic CRH and AVP mRNA expression, J Neuroendocrinol source
    • cites [140] Dabrowska, 2011, Neuroanatomical evidence for reciprocal regulation of the corticotrophin-releasing factor and oxytocin systems in the hypothalamus and the bed nucleus of the stria terminalis of the rat: implications for balancing stress and affect, Psychoneuroendocrinology source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The phytoestrogen coumestrol and GEN upregulate ERβ mRNA expression in the PVN, an effect opposite to that of 17β-estradiol.

    “The phytoestrogen coumestrol (found in clover and other pasture legumes) and GEN upregulate ERβ mRNA expression in the PVN, an effect opposite to that of 17β-estradiol (119, 120).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [119] Patisaul, 1999, Regulation of estrogen receptor beta mRNA in the brain: opposite effects of 17β-estradiol and the phytoestrogen, coumestrol, Brain Res Mol Brain Res source
    • cites [120] Patisaul, 2002, Genistein affects ERβ- but not ERα-dependent gene expression in the hypothalamus, Endocrinology source

  • May combine two claims.

    Premisecitation

    The assays within the EDSP are reasonably effective at targeting sex steroid hormone disruptors but ineffective at identifying non-steroidal endocrine disrupting activity including OT and AVP disruption.

    “The assays within the EDSP are reasonably effective at targeting sex steroid hormone disruptors but ineffective at identifying non-steroidal endocrine disrupting activity including OT and AVP disruption (152) leaving a desperate need for improvement.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [152] Filer, 2014, Test driving ToxCast: endocrine profiling for 1858 chemicals included in phase II, Curr Opin Pharmacol source

      The Updated EDC ToxPi Findings section reports extensive estrogen-assay coverage and says coverage for oxytocin and vasopressin was inadequate for confident results. But those findings concern the ToxCast/ToxPi analyses, not an evaluation of EDSP assays. The section also does not establish that screening is ineffective for all non-steroidal endocrine activity. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Disruption of pBnST TH-ir neuron numbers occurred at the lowest dose, but not the higher two.

    “Disruption of pBnST TH-ir neuron numbers also occurred at the lowest dose, but not the higher two making that outcome somewhat more difficult to interpret.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Sullivan, 2014, A novel model for neuroendocrine toxicology: neurobehavioral effects of BPA exposure in a prosocial species, the prairie vole (Microtus ochrogaster), Endocrinology source

  • May combine two claims.

    Findingcitation

    At the two lower doses, BPA eliminated the sex difference in social investigation and at the highest dose, reversed it.

    “At the two lower doses, BPA eliminated this sex difference and at the highest dose, reversed it.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Sullivan, 2014, A novel model for neuroendocrine toxicology: neurobehavioral effects of BPA exposure in a prosocial species, the prairie vole (Microtus ochrogaster), Endocrinology source

  • May combine two claims.

    Findingcitation

    In prairie voles, females in the highest exposure group had fewer OT-ir neurons in the posterior PVN but more AVP-ir neurons in the anterior PVN.

    “Females in the highest exposure group had fewer OT-ir neurons in the posterior PVN but more AVP-ir neurons in the anterior PVN.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Sullivan, 2014, A novel model for neuroendocrine toxicology: neurobehavioral effects of BPA exposure in a prosocial species, the prairie vole (Microtus ochrogaster), Endocrinology source

  • May combine two claims.

    Findingown data

    There was some evidence for downregulation of AVP mRNA in BPA-exposed females, but the effect did not quite reach statistical significance (p ≤ 0.07), and no effect on OT, AVP1aR, OTR, or Mc4R expression was observed in either sex.

    “There was some evidence for downregulation of AVP mRNA in BPA-exposed females, but the effect did not quite reach statistical significance (p ≤ 0.07), and no effect on OT, AVP1aR, OTR, or Mc4R expression was observed in either sex (unpublished observations).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    At the lower two doses, BPA eliminated the well-characterized sex difference in PVN TH-ir neuron numbers and reversed it at the highest dose.

    “At the lower two doses, BPA eliminated the well-characterized sex difference in PVN TH-ir neuron numbers and reversed it at the highest dose.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Sullivan, 2014, A novel model for neuroendocrine toxicology: neurobehavioral effects of BPA exposure in a prosocial species, the prairie vole (Microtus ochrogaster), Endocrinology source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    AVP and OT are found only in mammals, are structurally similar, and evolutionarily derived from the pituitary hormone vasotocin (VT).

    “Broadly, AVP and OT are found only in mammals, are structurally similar, and evolutionarily derived from the pituitary hormone, vasotocin (VT).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Magnocellular AVP and OT are axonally released into the periphery from the paraventricular and supraoptic nuclei (PVN and SON) via the neurohypophysis and coordinate a range of physiological processes, including uterine contractions, milk letdown, blood pressure, thermoregulation, and osmotic balance.

    “Magnocellular AVP and OT are axonally released into the periphery from the paraventricular and supraoptic nuclei (PVN and SON) via the neurohypophysis and coordinate a range of physiological processes, including uterine contractions, milk letdown, blood pressure, thermoregulation, and osmotic balance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In general, central OT is anxiolytic, antidepressive, and prosocial, whereas AVP is anxiogenic and can heighten depressive-type behaviors.

    “In general, central OT is anxiolytic, antidepressive, and prosocial, whereas AVP is anxiogenic and can heighten depressive-type behaviors (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Neumann, 2012, Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors, Trends Neurosci source

  • May combine two claims.

    Interpretationreasoning

    Endocrine disruption of central AVP and/or OT function could adversely impact emotional control, and possibly heighten risk of psychosocial disorders.

    “Consequently, there is concern that endocrine disruption of central AVP and/or OT function could adversely impact emotional control, and possibly heighten risk of psychosocial disorders.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    OTR binding was unchanged in LS but reduced in the cingulate of methoxychlor-exposed females compared to unexposed controls.

    “OTR binding was unchanged in LS but reduced in the cingulate of the exposed females compared to unexposed controls.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Engell, 2006, Perinatal exposure to endocrine disrupting compounds alters behavior and brain in the female pine vole, Neurotoxicol Teratol source

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

    Interpretationreasoning

    These data are not in complete directional accord with the rat study, an outcome that could result from different exposure window, doses used, or species differences in OT/AVP pathways.

    “These data are not in complete directional accord with our rat study, an outcome that could result from the different exposure window, doses used, or species differences in OT/AVP pathways.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    The literature on EDCs and AVP/OT pathways remains small, and work has primarily focused on a small subset of high priority chemicals, most of which are known disruptors of estrogen signaling pathways.

    “Overall, the literature on EDCs and AVP/OT pathways remains small, and work has primarily focused on a small subset of high priority chemicals, most of which are known disruptors of estrogen signaling pathways.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    BPA is present in polycarbonate plastics, the epoxy lining of canned foods, thermal paper, and other common household products; it is classified as a high volume production compound and continuous low level exposure is virtually ubiquitous and unavoidable.

    “Present in polycarbonate plastics, the epoxy lining of canned foods, thermal paper, and other common household products, BPA is classified as a “high volume production” compound and continuous low level (resulting in mean blood levels of 4 ng/ml or lower) exposure is virtually ubiquitous and unavoidable (85).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Bergman, 2012 source

  • May combine two claims.

    Premisecitation

    Exogenous administration of estrogen, DES, or an aromatase inhibitor during incubation fully blocked male copulatory behavior at puberty and induced the complete sex reversal of VT-ir in the preoptic area, BnST, and lateral septum.

    “Exogenous administration of estrogen, diethylstilbestrol (DES), or an aromatase inhibitor during incubation fully blocked male copulatory behavior at puberty and induced the complete sex reversal of VT-ir in the preoptic area, BnST, and lateral septum (LS) (70, 81).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [70] Panzica, 2005, Early embryonic administration of xenoestrogens alters vasotocin system and male sexual behavior of the Japanese quail, Domest Anim Endocrinol source
    • cites [81] Panzica, 1998, Organizational effects of estrogens on brain vasotocin and sexual behavior in quail, J Neurobiol source

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

    Interpretationnone given

    Sex-specific isoflavone-related effects on the rodent AVP/OT system have been sporadically shown by multiple laboratories, but work in this area remains limited and incomplete.

    “Although sex-specific isoflavone-related effects on the rodent AVP/OT system have been sporadically shown by multiple laboratories, including my own, work in this area remains limited and incomplete.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Male rats maintained on a diet containing 150 μg/g GEN and daidzein displayed increased anxiety and elevated stress-induced plasma AVP and corticosterone levels.

    “Similarly, male rats maintained on a diet containing 150 µg/g GEN and daidzein displayed increased anxiety and elevated stress-induced plasma AVP and corticosterone levels (71).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Hartley, 2003, The soya isoflavone content of rat diet can increase anxiety and stress hormone release in the male rat, Psychopharmacology (Berl) source

  • May combine two claims.

    Premisecitation

    Two dietary isoflavone supplements produced anxiolytic elevated plus maze behavior in proestrus female rats, but anxiogenic responses in gonadally intact males.

    “My lab has also shown that two dietary isoflavone supplements produced anxiolytic elevated plus maze behavior in proestrus female rats, but anxiogenic responses in gonadally intact males (118).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] Patisaul, 2005, Dietary soy supplements produce opposite effects on anxiety in intact male and female rats in the elevated plus-maze, Behav Neurosci source

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Specific outcomes of BPA exposure likely differ between sex and species depending on the degree to which they are prosocial.

    “They also suggest, unsurprisingly, that specific outcomes likely differ between sex and species depending on the degree to which they are prosocial.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Data in support of CPF as a peptidergic disruptor are sparse but suggestive of sex-specific vulnerability.

    “Data in support of CPF as a peptidergic disruptor are sparse but suggestive of sex-specific vulnerability.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    CPF is a developmental neurotoxin and endocrine disruptor, and a likely environmental contributor to ASD, ADHD, and other behavioral disorders.

    “Collectively, these data are consistent with a robust body of evidence showing that CPF is a developmental neurotoxin and endocrine disruptor, and a likely environmental contributor to ASD, ADHD, and other behavioral disorders.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Additional environmental factors, including diet, may modify outcomes and contribute to discordance across studies on BPA.

    “Additional environmental factors, including diet, may modify outcomes and contribute to discordance across studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Long-term consumption of soy-rich diets enhances aggression in Syrian hamsters, which also had lower AVP1A expression in the LS but higher AVP1A expression in lateral hypothalamus.

    “and Syrian hamsters (72), the latter of which also had lower AVP1A expression in the LS but higher AVP1A expression in lateral hypothalamus.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Moore, 2004, The neurobehavioral effects of phytoestrogens in male Syrian hamsters, Brain Res source

  • May combine two claims.

    Premisecitation

    Daily exposure to EDCs is virtually silent and unceasingly increasing.

    “Consequently, daily exposure is virtually silent and unceasingly increasing (12).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Patisaul, 2017 source

  • May combine two claims.

    Premisecitation

    In humans, BPA exposure has been tentatively linked with cardiovascular disease and hypertension, but causal mechanisms remain uncharacterized.

    “Intriguingly, in humans, BPA exposure has been tentatively linked with cardiovascular disease and hypertension, but the causal mechanisms remain to be characterized (144).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Han, 2016, Bisphenol A, hypertension, and cardiovascular diseases: epidemiological, laboratory, and clinical trial evidence, Curr Hypertens Rep source

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Only a handful of compounds have been tested for AVP-related outcomes at all.

    “Moreover, only a handful of compounds have been tested for AVP-related outcomes at all.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Magnocellular AVP neurons in the PVN and SON release AVP both centrally and systemically in response to dehydration, hemorrhage, and stress and are primary physiological regulators of water-electrolyte balance.

    “Magnocellular AVP neurons in the PVN and SON release AVP both centrally and systemically in response to dehydration, hemorrhage, and stress and are known to be one of the primary physiological regulators of water-electrolyte balance (145).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Sivukhina, 2016, Magnocellular hypothalamic system and its interaction with the hypothalamo-pituitary-adrenal axis, Steroids source

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

    Interpretationreasoning

    The possibility that BPA alters the density and function of magnocellular neurons could not be ruled out.

    “Although we surmised that the populations of OT-ir and AVP-ir neurons impacted by BPA are primarily parvocellular, the possibility that BPA alters the density and function of magnocellular neurons could not be ruled out.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Rising rates of behavioral, hypertensive, and other disorders for which AVP are known to play a coordinating role suggest a causal role for environmental factors, including chemical exposures, but which specific ones remains elusive.

    “Rising rates of behavioral, hypertensive, and other disorders for which AVP are known to play a coordinating role suggest a causal role for environmental factors, including chemical exposures, but which specific ones remains elusive.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Perinatal oral exposure to 1.7 or 30.6 mg/kg/day resulted in elevated systolic blood pressure responses at 3 h post-hyperosmotic challenge, possibly attributable to decreased plasma AVP levels.

    “Subsequent work revealed that perinatal oral exposure to 1.7 or 30.6 mg/kg/day resulted in elevated systolic blood pressure responses at 3 h post-hyperosmotic challenge, an effect the authors interpreted as possibly attributable to decreased plasma AVP levels (78).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Shah, 2011, Altered cardiovascular reactivity and osmoregulation during hyperosmotic stress in adult rats developmentally exposed to polybrominated diphenyl ethers (PBDEs), Toxicol Appl Pharmacol source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    There is an ever-churning conveyer belt of worrying chemical replacements such that when EDCs such as PBDEs, DDT, and BPA are phased out, they are rapidly replaced by structurally similar compounds.

    “Moreover, there is an ever-churning conveyer belt of worrying chemical replacements such that when EDCs, such as the PBDEs, DDT, and BPA, are finally phased out, they are rapidly replaced by structurally similar compounds.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    How estrogens and androgens contribute to the sexual differentiation and function of the AVP/OT system are sex and species dependent and associated with functional differences in prosociality.

    “How estrogens and androgens contribute to the sexual differentiation and function of the AVP/OT system are sex and species dependent and associated with functional differences in prosociality (121, 122).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [121] Plumari, 2002, Changes in the arginine-vasopressin immunoreactive systems in male mice lacking a functional aromatase gene, J Neuroendocrinol source
    • cites [122] Han, 2003, Organizational effects of testosterone, estradiol, and dihydrotestosterone on vasopressin mRNA expression in the bed nucleus of the stria terminalis, J Neurobiol source

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Much EDC work, particularly on social and other non-reproductive behaviors, remains largely descriptive with limited understanding of causal relationships.

    “Much EDC work, particularly on social and other non-reproductive behaviors, remains largely descriptive with limited understanding of causal relationships.”
    Quote in the paperNot a substantial claim
59 of 59

  • The paper relies on this without support.

    Environmental factors, including chemical exposures, are contributing to the rising rates of psychosocial disorders such as autism spectrum disorders (ASDs).

    “Growing recognition that environmental factors are likely contributing to rapidly rising rates of psychosocial disorders in which neuropeptides are thought to play a central role, including autism spectrum disorders (ASDs), has ignited greater interest in understanding how EDCs might impact targets outside of the reproductive axis.”

  • The paper relies on this without support.

    A “perfect storm” of genetic predispositions and environmental insults manifests as clinical disease.

    “The challenge is figuring out which chemicals, and how a “perfect storm” of genetic predispositions and environmental insults manifests as clinical disease.”

  • The paper relies on this without support.

    Rodent social behaviors and AVP/OT systems are predictive of human social behaviors and AVP/OT systems.

    “Experiments with a greater emphasis on linking cause and effect are greatly needed to estimate the degree to which BPA may affect AVP/OT systems in humans.”

  • The authors state this as an assumption.

    The EPA’s endocrine disruptor screening program (EDSP) was slated for elimination as the paper went to press.

    “As this paper went to press the EPA’s endocrine disruptor screening program (EDSP), an effort that took more than two decades to construct, and only recently reached the capacity to effectively identify any chemical as a purported EDC, was slated for elimination.”

  • The authors state this as an assumption.

    Within the USA there is no federal-level mechanism in place to evaluate where EDCs are found, let alone regulate their use in common items such as cosmetics, personal care products, food containers or durable goods.

    “Within the USA there is absolutely no federal-level mechanism in place to evaluate where EDCs are found, let alone regulate their use in common items such as cosmetics, personal care products, food containers or durable goods.”
5 of 5

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.

  • MePD AVP-ir effect is both reported and denied

    Minor

    The text reports fewer MePD AVP-ir cells in F1 males, then states without a generation qualifier that no disrupted MePD AVP-ir levels were found. The latter may have been intended to refer only to F3 mice, but as written it contradicts the F1 result.

  • Methoxychlor-exposed vole species differs between table and text

    Minor

    Table 2 identifies prairie voles as the species with disrupted female affiliative behavior, whereas the corresponding discussion identifies pine voles.

2 of 2

Cites

Flagged first, then by citations

1 of the 155 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. 2011, Toxicological and Health Aspects of Bisphenol A: Report of Joint FAO/WHO Expert Meeting and Report of Stakeholder Meeting on Bisphenol A
  2. Whitten, 1997, Isoflavonoids, 117
  3. Whitten, 1991, Dietary plant estrogens: a biologically active background for estrogen action, 155

Cited by

Sorted by citations

Related

Authors
Patisaul, H. B.
Affiliations
North Carolina State University (US)
Corresponding author
Patisaul, Heather B.
ORCID
Patisaul, Heather B.
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2017-06-19
Volume
8
Pages
134-134
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2017.00134
PMC
PMC5475378
OpenAlex
W2720273963
Semantic Scholar
518804e86fca9264d1a73dc1b3a64f282732bd22
Cited by
54
References
155
Citations by year
2026: 6 · 2025: 5 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 11 · 2020: 5 · 2019: 6 · 2018: 5 · 2017: 2 · 2015: 1
FWCI
2.47
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Environmental Health Sciences (P30ES025128, R21ES021233)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
Keywords
endocrine disruptors, vasopressin, oxytocin, bisphenol A, genistein, flame retardants, estrogen receptor, lateral septum, social behavior, cardiovascular function

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 2026-10-12.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-12.

Cited sources are checked by gpt-6-sol.

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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