CoChat
Sign Up
Cited by 68Effects and risks of endocrine disrupting chemicalsBarrier Structure and Function StudiesPesticide Exposure and Toxicity

Disruption of the blood-brain barrier and its close environment following adult exposure to low doses of di(2-ethylhexyl)phthalate alone or in an environmental phthalate mixture in male mice

Open access
Ahmadpour, Delnia, Mhaouty-Kodja, Sakina, Grange-Messent, Valérie·2021·Chemosphere
DOI 10.1016/j.chemosphere.2021.131013
Open this paper in CoChat — free accountOpen PDF

Abstract

We have previously shown that adult male mice exposure to low doses of di(2-ethylhexyl)phthalate (DEHP) alters neural function and behaviour. Whether such exposure also affects the integrity and function of the blood-brain barrier (BBB) remained to be explored. The impact of adult exposure to low doses of DEHP alone or in an environmental phthalate mixture on the BBB integrity and surrounding parenchyma was studied in male mice. Two-month-old C57BL/6J males were orally exposed for 6 weeks to DEHP alone (5, and 50 μg/kg/day) or to DEHP (5 μg/kg/day) in an environmental phthalate mixture. BBB permeability, glial activation and neuroinflammation were investigated in the hypothalamic medial preoptic area (mPOA) and hippocampus involved, respectively on the reproductive and cognitive functions. Exposure to DEHP alone or in a phthalate mixture increased BBB permeability and affected the endothelial accessory tight junction protein zona occludens-1 and caveolae protein Cav-1 in the mPOA and the hippocampal CA1 and CA3 areas. This was associated with an inflammatory profile including astrocyte activation accompanied by enhanced expression of inducible nitric oxide synthase in the mPOA, and a microglial activation in the mPOA and the hippocampal CA1 and CA3 areas. The protein levels of the inflammatory molecule cyclooxygenase-2 were increased in activated microglial cells of the exposed mPOA. None of the major effects induced by DEHP alone or in a mixture was detected in the hippocampal dendate gyrus. The data highlight that environmental exposure to endocrine disruptors such as phthalates, could represent a risk factor for the cerebrovascular function.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.chemosphere.2021.131013

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Barrier impairment facilitates the entry of peripheral immune mediators and other harmful substances into vulnerable brain regions, reinforcing neuroinflammatory and neurotoxic cascades.

    “Such barrier impairment is mechanistically significant because it facilitates the entry of peripheral immune mediators and other harmful substances into vulnerable brain regions, thereby reinforcing neuroinflammatory and neurotoxic cascades (Ahmadpour et al., 2021; Damiano et al., 2025).”

    From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Ahmadpour et al., 2021

    The Introduction says the BBB limits entry of circulating substances, and the Results (§3.1; page unavailable) show circulating IgG entering the brain parenchyma after phthalate exposure. The Discussion (§4; page unavailable) reports associated neuroinflammation but explicitly leaves open whether BBB dysfunction causes or follows it. The paper therefore does not establish the claimed cascade in which entry of peripheral immune mediators reinforces neuroinflammation and neurotoxicity. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In adult male mice, six-week oral exposure to low doses of DEHP alone or in an environmental phthalate mixture increased BBB permeability in the hypothalamic medial preoptic area and in the hippocampal CA1 and CA3 regions, accompanied by altered expression of zona occludens-1 and Cav-1, as well as local glial activation.

    “In adult male mice, six-week oral exposure to low doses of DEHP alone or in an environmental phthalate mixture increased BBB permeability in the hypothalamic medial preoptic area and in the hippocampal CA1 and CA3 regions, accompanied by altered expression of the tight-junction-associated protein zona occludens-1 and caveolae protein Cav-1, as well as local glial activation (Ahmadpour et al., 2021”

    From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Ahmadpour et al., 2021

Self-check

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

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 36

  1. Abbott, N.J., Patabendige, A.A.K., Dolman, D.E.M., Yusof, S.R., Begley, D.J., 2010. Structure and function of the blood-brain barrier. Neurobiol. Dis. 37, 13-25. https://doi.org/10.1016/j.nbd.2009.07.030 · DOI · Paper page
  2. Adam, N, Brusamonti, L, Mhaouty-Kodja, S., 2021. Exposure of adult female mice to low doses of di(2 ethylhexyl)phthalate alone or in an environmental phthalate mixture: Evaluation of reproductive behavior and underlying neural mechanisms. Environ Health Perspect, 129 (1). https://doi.org/10.1289/EHP7662 · DOI
  3. Ahmadpour, D., Grange-Messent, V., 2020. Involvement of testosterone signaling in the integrity of the neurovascular unit in the male: review of evidence, contradictions and hypothesis. Neuroendocrinology. https://doi.org/10.1159/000509218 Anses. 2015. Connaissances relatives à la réglementation, à l'identification, aux propriétés chimiques, à la production et aux usages des composés de la famille des Phtalates (Tome3). https://www.anses.fr/fr/system/files/SUBCHIM2009sa0331Ra-106.pdf · DOI
  4. Atallah, A., Mhaouty-Kodja, S., Grange-Messent, V., 2017. Chronic depletion of gonadal testosterone leads to blood-brain barrier dysfunction and inflammation in male mice. J. Cereb. Blood Flow Metab. 37, 3161-3175. https://doi.org/10.1177/0271678X16683961 · DOI
  5. Barakat, R., Lin, P.-C., Park, C.J., Best-Popescu, C., Bakry, H.H., Abosalem, M.E., Abdelaleem, N.M., Flaws, J.A., Ko, C., 2018. Prenatal Exposure to DEHP Induces Neuronal Degeneration and Neurobehavioral Abnormalities in Adult Male Mice. Toxicol. Sci. Off. J. Soc. Toxicol. 164, 439-452. https://doi.org/10.1093/toxsci/kfy103 · DOI
  6. Barreto, G., Veiga, S., Azcoitia, I., Garcia-Segura, L.M., Garcia-Ovejero, D., 2007. Testosterone decreases reactive astroglia and reactive microglia after brain injury in male rats: role of its metabolites, oestradiol and dihydrotestosterone: Testosterone down regulates reactive gliosis. Eur. J. Neurosci. 25, 3039-3046. https://doi.org/10.1111/j.1460- 9568.2007.05563.x · DOI
  7. Capela, D., Mhaouty-Kodja, S., 2021. Effects of pubertal exposure to low doses of di-(2- ethylexyl)phthalate on reproductive behaviors in male mice. Chemosphere 263, 128191. https://doi.org/10.1016/j.chemosphere.2020.128191 · DOI
  8. Cheema, U.B., Most, E., Eder, K., Ringseis, R., 2019. Effect of lifelong carnitine supplementation on plasma and tissue carnitine status, hepatic lipid metabolism and stress signalling pathways and skeletal muscle transcriptome in mice at advanced age. Br. J. Nutrition 121 (12), 1323-1333. https://doi.org/10.1017/S0007114519000709 Directive 2013/39/EU of the European Parliament and of the Council amending Directives 428 2000/60/EC and 2008/105/EC as regards priority substances in the field of water policy. Available 429 at: https://www.ecolex.org/details/legislation/directive-201339eu-of-the- european-parliament-and430 of-the-council-amending-directives-200060ec-and-2008105ec- as-regards-priority-substances-in-the431 field-of-water-policy-lex-faoc127344/. · DOI
  9. Dewalque, L., Charlier, C., Pirard, C., 2014. Estimated daily intake and cumulative risk assessment of phthalate diesters in a Belgian general population. Toxicol. Lett. 231, 161- 168. https://doi.org/10.1016/j.toxlet.2014.06.028 · DOI
  10. Dombret, C., Capela, D., Poissenot, K., Parmentier, C., Bergsten, E., Pionneau, C., Chardonnet, S., Hardin-Pouzet, H., Grange-Messent, V., Keller, M., Franceschini, I., Mhaouty-Kodja, S., 2017. Neural Mechanisms Underlying the Disruption of Male Courtship Behavior by Adult Exposure to Di(2-ethylhexyl) Phthalate in Mice. Environ. Health Perspect. 125, 097001. https://doi.org/10.1289/EHP1443 EFSA (European Food Safety Authority). 2005. Opinion of the Scientific Panel on food additives, flavourings, processing aids and materials in contact with food (AFC) on a request from the Commission related to bis(2-ethylhexyl)phthalate (DEHP) for use in food contact materials. EFSA Journal 3:243; doi: 10.2903/j.efsa.2005.243 · DOI
  11. EFSA (European Food Safety Authority). 2019. Update of the risk assessment of di- butylphthalate (DBP), butyl-benzyl-phthalate (BBP), bis(2-ethylhexyl)phthalate (DEHP), di- isononylphthalate (DINP) and di-isodecylphthalate (DIDP) for use in food contact materials. EFSA Journal, 17:5838; doi: 10.2903/j.efsa.2019.5838 · DOI
  12. Erdő, F., Denes, L., de Lange, E., 2017. Age-associated physiological and pathological changes at the blood-brain barrier: A review. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 37, 4-24. https://doi.org/10.1177/0271678X16679420 · DOI · Paper page
  13. Gao, D.-W., Wen, Z.-D., 2016. Phthalate esters in the environment: A critical review of their occurrence, biodegradation, and removal during wastewater treatment processes. Sci. Total Environ. 541, 986-1001. https://doi.org/10.1016/j.scitotenv.2015.09.148 · DOI
  14. Hajszan, T., Milner, T.A., Leranth, C., 2007. Sex Steroids and the Dentate Gyrus. Prog. Brain Res. 163C, 399-816. https://doi.org/10.1016/S0079-6123(07)63023-4 · DOI
  15. Heneka, M.T., Feinstein, D.L., 2001. Expression and function of inducible nitric oxide synthase in neurons. J. Neuroimmunol. 114, 8-18. https://doi.org/10.1016/s0165- 5728(01)00246-6 · DOI
  16. Kabir, E.R., Rahman, M.S., Rahman, I., 2015. A review on endocrine disruptors and their possible impacts on human health. Environ. Toxicol. Pharmacol. 40, 241-258. https://doi.org/10.1016/j.etap.2015.06.009 · DOI · Paper page
  17. Kassab, R.B., Lokman, M.S., Essawy, E.A., 2019. Neurochemical alterations following the exposure to di-n-butyl phthalate in rats. Metab. Brain Dis. 34, 235-244. https://doi.org/10.1007/s11011-018-0341-0 · DOI
  18. Kerr, J.E., Allore, R.J., Beck, S.G., Handa, R.J., 1995. Distribution and hormonal regulation of androgen receptor (AR) and AR messenger ribonucleic acid in the rat hippocampus. Endocrinology 136, 3213-3221. https://doi.org/10.1210/endo.136.8.7628354 · DOI
  19. Lin, K., Yin, A., Yao, L., Li, Y., 2015. N-myc downstream-regulated gene 2 in the nervous system: from expression pattern to function. Acta Biochim. Biophys. Sin. 47, 761-766. https://doi.org/10.1093/abbs/gmv082 · DOI
  20. Lu, M.L., Schneider, M.C., Zheng, Y., Zhang, X., Richie, J.P., 2001. Caveolin-1 Interacts with Androgen Receptor A POSITIVE MODULATOR OF ANDROGEN RECEPTOR MEDIATED TRANSACTIVATION. J. Biol. Chem. 276, 13442-13451. https://doi.org/10.1074/jbc. · DOI
  21. Martine, B., Marie-Jeanne, T., Cendrine, D., Fabrice, A., Marc, C., 2013. Assessment of Adult Human Exposure to Phthalate Esters in the Urban Centre of Paris (France). Bull. Environ. Contam. Toxicol. 90, 91-96. https://doi.org/10.1007/s00128-012-0859-5 · DOI
  22. Mhaouty-Kodja, S., 2018. Role of the androgen receptor in the central nervous system. Mol. Cell. Endocrinol. 465, 103-112. https://doi.org/10.1016/j.mce.2017.08.001 · DOI
  23. Picot, M., Billard, J.-M., Dombret, C., Albac, C., Karameh, N., Daumas, S., Hardin-Pouzet, H., Mhaouty-Kodja, S., 2016. Neural Androgen Receptor Deletion Impairs the Temporal Processing of Objects and Hippocampal CA1-Dependent Mechanisms. PLoS ONE 11. https://doi.org/10.1371/journal.pone.0148328 · DOI
  24. Ran, D., Luo, Y., Gan, Z., Liu, J., Yang, J., 2019. Neural mechanisms underlying the deficit of learning and memory by exposure to Di(2-ethylhexyl) phthalate in rats. Ecotoxicol. Environ. Saf. 174, 58-65. https://doi.org/10.1016/j.ecoenv.2019.02.043 · DOI
  25. Raponi, E., Agenes, F., Delphin, C., Assard, N., Baudier, J., Legraverend, C., Deloulme, J.- C., 2007. S100B expression defines a state in which GFAP-expressing cells lose their neural stem cell potential and acquire a more mature developmental stage. Glia 55, 165-177. https://doi.org/10.1002/glia.20445 · DOI
  26. Raskin, K., de Gendt, K., Duittoz, A., Liere, P., Verhoeven, G., Tronche, F., Mhaouty-Kodja, S., 2009. Conditional inactivation of androgen receptor gene in the nervous system: effects on male behavioral and neuroendocrine responses. J. Neurosci. Off. J. Soc. Neurosci. 29, 4461-4470. https://doi.org/10.1523/JNEUROSCI.0296-09.2009 · DOI · Paper page
  27. Robison, L.S., Gannon, O.J., Salinero, A.E., Zuloaga, K.L., 2019. Contributions of sex to cerebrovascular function and pathology. Brain Res. 1710, 43-60. https://doi.org/10.1016/j.brainres.2018.12.030 · DOI
  28. Saha, R.N., Pahan, K., 2006. Signals for the induction of nitric oxide synthase in astrocytes. Neurochem. Int. 49, 154-163. https://doi.org/10.1016/j.neuint.2006.04.007 · DOI
  29. Sandoval, K.E., Witt, K.A., 2011. Age and 17β-estradiol effects on blood-brain barrier tight junction and estrogen receptor proteins in ovariectomized rats. Microvasc. Res. 81, 198-205. https://doi.org/10.1016/j.mvr.2010.12.007 · DOI
  30. Saunders, N.R., Dziegielewska, K.M., Møllgård, K., Habgood, M.D., 2015. Markers for blood- brain barrier integrity: how appropriate is Evans blue in the twenty-first century and what are the alternatives? Front. Neurosci. 9. https://doi.org/10.3389/fnins.2015.00385 · DOI
  31. Sierra, A., Navascués, J., Cuadros, M.A., Calvente, R., Martín-Oliva, D., Ferrer-Martín, R.M., Martín-Estebané, M., Carrasco, M.-C., Marín-Teva, J.L., 2014. Expression of Inducible Nitric Oxide Synthase (iNOS) in Microglia of the Developing Quail Retina. PLoS ONE 9. https://doi.org/10.1371/journal.pone.0106048 · DOI
  32. Steinwall, O., Klatzo, I., 1966. Selective vulnerability of the blood brain barrier in chemically induced lesions. J. Neuropath. Exp. Neurol. 25,: 542-559. https://doi.org/10.1097/00005072- 196610000-00004 · DOI
  33. Vijitruth, R., Liu, M., Choi, D.-Y., Nguyen, X.V., Hunter, R.L., Bing, G., 2006. Cyclooxygenase-2 mediates microglial activation and secondary dopaminergic cell death in the mouse MPTP model of Parkinson's disease. J. Neuroinflammation 3, 6. https://doi.org/10.1186/1742-2094-3-6 · DOI
  34. Villaseñor, R., Lampe, J., Schwaninger, M., Collin, L., 2019. Intracellular transport and regulation of transcytosis across the blood-brain barrier. Cell. Mol. Life Sci. 76, 1081-1092. https://doi.org/10.1007/s00018-018-2982-x · DOI
  35. Vodo, S., Bechi, N., Petroni, A., Muscoli, C., Aloisi, A.M., 2013. Testosterone-Induced Effects on Lipids and Inflammation [WWW Document]. Mediators Inflamm. https://doi.org/10.1155/2013/183041 · DOI
  36. Weiss, N., Miller, F., Cazaubon, S., Couraud, P.-O., 2009. The blood-brain barrier in brain homeostasis and neurological diseases. Biochim. Biophys. Acta BBA -Biomembr., Apical Junctional Complexes Part II 1788, 842-857. https://doi.org/10.1016/j.bbamem.2008.10.022 · DOI · Paper page

Cited by

Sorted by citations

Authors
Ahmadpour, D., Mhaouty-Kodja, S., & Grange-Messent, V.
Affiliations
Centre National de la Recherche Scientifique (FR)
Venue
Chemosphere
Publisher
Elsevier BV
Published
2021-11
Volume
282
Pages
131013
ISSN
0045-6535 (ISSN-L)
DOI
10.1016/j.chemosphere.2021.131013
OpenAlex
W3166363738
Cited by
68
References
2
Citations by year
2026: 10 · 2025: 15 · 2024: 12 · 2023: 15 · 2022: 13 · 2021: 3
FWCI
4.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Chemosphere (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • HAL (submittedVersion)
Funders
ANR
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Pesticide Exposure and Toxicity
Keywords
DEHP, phthalate mixtures, blood-brain barrier permeability, endocrine disruptors, hippocampus, astrocyte activation, microglial activation, neuroinflammation, tight junctions, zona occludens-1, caveolin-1, inducible nitric oxide synthase, cyclooxygenase-2, reproductive function, cognitive function, cerebrovascular function
MeSH terms
Animals, Blood-Brain Barrier, Diethylhexyl Phthalate, Environmental Exposure, Male, Mice, Inbred C57BL, Phthalic Acids, Mice, Endocrine Disruptors

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.

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.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review