CoChat
Sign Up
Cited by 69Toxic Organic Pollutants ImpactPesticide Exposure and ToxicityEffects and risks of endocrine disrupting chemicals

Effects of prenatal exposure to a mixture of organophosphate flame retardants on placental gene expression and serotonergic innervation in the fetal rat brain

Open access
Rock, Kylie D, St Armour, Genevieve, Horman, Brian, Phillips, Allison, Ruis, Matthew, Stewart, Allison K, Jima, Dereje, Muddiman, David C +2 more·2020·Toxicological Sciences
DOI 10.1093/toxsci/kfaa046PMC PMC7357193
Open this paper in CoChat — free account

Abstract

There is a growing need to understand the potential neurotoxicity of organophosphate flame retardants (OPFRs) and plasticizers because use and, consequently, human exposure, is rapidly expanding. We have previously shown in rats that developmental exposure to the commercial flame retardant mixture Firemaster 550 (FM 550), which contains OPFRs, results in sex-specific behavioral effects, and identified the placenta as a potential target of toxicity. The placenta is a critical coordinator of fetal growth and neurodevelopment, and a source of neurotransmitters for the developing brain. We have shown in rats and humans that flame retardants accumulate in placental tissue, and induce functional changes, including altered neurotransmitter production. Here, we sought to establish if OPFRs (triphenyl phosphate and a mixture of isopropylated triarylphosphate isomers) alter placental function and fetal forebrain development, with disruption of tryptophan metabolism as a primary pathway of interest. Wistar rat dams were orally exposed to OPFRs (0, 500, 1000, or 2000 μg/day) or a serotonin (5-HT) agonist 5-methoxytryptamine for 14 days during gestation and placenta and fetal forebrain tissues collected for analysis by transcriptomics and metabolomics. Relative abundance of genes responsible for the transport and synthesis of placental 5-HT were disrupted, and multiple neuroactive metabolites in the 5-HT and kynurenine metabolic pathways were upregulated. In addition, 5-HTergic projections were significantly longer in the fetal forebrains of exposed males. These findings suggest that OPFRs have the potential to impact the 5-HTergic system in the fetal forebrain by disrupting placental tryptophan metabolism.

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 · 10.1093/toxsci/kfaa046

Cites

3 of 3 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?

  • FRs can compromise both redox buffering and mitochondrial/metabolic support during synaptic development.

    “These observations indicate that FRs can compromise both redox buffering and mitochondrial/metabolic support during synaptic development (Marinello et al., 2023; Newell et al., 2023a; Rock et al., 2020).”

    From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Rock et al., 2020

    The Results (page unavailable) report reduced placental Sod2 expression after OPFR exposure, and the Discussion identifies altered mitochondrial-dysfunction and energy-production pathways. The study also reports altered fetal forebrain serotonergic projections, but it does not establish that redox buffering or mitochondrial/metabolic support was compromised at developing synapses. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Gestational FireMaster 550 exposure disrupted placental monoamine production, particularly serotonin, and altered fetal-brain genes required for cellular respiration.

    “In a complementary prairie vole model, gestational FireMaster 550 exposure disrupted placental monoamine production, particularly serotonin, and altered fetal-brain genes required for cellular respiration.”

    From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Rock et al., 2020

    The Abstract and Conclusions report that gestational exposure to organophosphate flame retardants disrupted placental serotonin-related metabolism in Wistar rats. The claim instead describes a prairie vole model and exposure to the full FireMaster 550 mixture. The Results place the energy-production gene-expression findings in placental tissue, not the fetal brain; the fetal-brain finding concerned serotonergic projections. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Prenatal exposure to a mixture of OPFRs altered placental gene programs linked to oxidative-stress defense, including downregulation of Sod2.

    “Prenatal exposure to a mixture of OPFRs altered placental gene programs linked to oxidative-stress defense, including downregulation of Sod2, while developmental organophosphate ester exposure in brain produced transcriptomic signatures enriched for mitochondrial transcriptional regulation.”

    From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Rock et al., 2020

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: 111

  1. Abdallah M. A., Covaci A. (2014). Organophosphate flame retardants in indoor dust from Egypt: Implications for human exposure. Environ. Sci. Technol. 48, 4782–4789. [DOI] [PubMed] [Google Scholar]
  2. Aldridge J. E., Levin E. D., Seidler F. J., Slotkin T. A. (2005). Developmental exposure of rats to chlorpyrifos leads to behavioral alterations in adulthood, involving serotonergic mechanisms and resembling animal models of depression. Environ. Health Perspect. 113, 527–531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anders S., Pyl P. T., Huber W. (2015). HTSeq—A python framework to work with high-throughput sequencing data. Bioinformatics (Oxford) 31, 166–169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bailey J. M., Levin E. D. (2015). Neurotoxicity of Firemaster 550® in zebrafish (Danio rerio): Chronic developmental and acute adolescent exposures. Neurotoxicol. Teratol. 52, 210–219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Baldwin K. R., Phillips A. L., Horman B., Arambula S. E., Rebuli M. E., Stapleton H. M., Patisaul H. B. (2017). Sex specific placental accumulation and behavioral effects of developmental Firemaster® 550 exposure in Wistar rats. Sci. Rep. 7, 7118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Behl M., Hsieh J.-H., Shafer T. J., Mundy W. R., Rice J. R., Boyd W. A., Freedman J. H., Hunter E. S., Jarema K. A., Padilla S., et al. (2015). Use of alternative assays to identify and prioritize organophosphorus flame retardants for potential developmental and neurotoxicity. Neurotoxicol. Teratol. 52, 181–193. [DOI] [PubMed] [Google Scholar]
  7. Belcher S. M., Cookman C. J., Patisaul H. B., Stapleton H. M. (2014). In vitro assessment of human nuclear hormone receptor activity and cytotoxicity of the flame retardant mixture fm 550 and its triarylphosphate and brominated components. Toxicol. Lett. 228, 93–102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Benediktsson R., Calder A. A., Edwards C. R., Seckl J. R. (1997). Placental 11 beta-hydroxysteroid dehydrogenase: A key regulator of fetal glucocorticoid exposure. Clin. Endocrinol. (Oxf.) 46, 161–166. [DOI] [PubMed] [Google Scholar]
  9. Benjamini Y., Hochberg Y. (1995). Controlling the false discovery rate: A practical and powerful approach to multiple testing. J. R. Stat. Soc. 57, 289–300. [Google Scholar]
  10. Bennett D., Bellinger D. C., Birnbaum L. S., Bradman A., Chen A., Cory-Slechta D. A., Engel S. M., Fallin M. D., Halladay A., Hauser R., et al. (2016). Project TENDR: Targeting environmental neuro-developmental risks the TENDR consensus statement. Environ. Health Perspect. 124, A118–122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Bjelakovic G., Beninati S., Pavlovic D., Kocic G., Jevtovic T., Kamenov B., Saranac L. J., Bjelakovic B., Stojanovic I., Basic J. (2007). Glucocorticoids and oxidative stress. J. Basic Clin. Physiol. Pharmacol. 18, 115–127. [DOI] [PubMed] [Google Scholar]
  12. Bonnin A., Goeden N., Chen K., Wilson M. L., King J., Shih J. C., Blakely R. D., Deneris E. S., Levitt P. (2011). A transient placental source of serotonin for the fetal forebrain. Nature 472, 347–350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Bonnin A., Levitt P. (2011). Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain. Neuroscience 197, 1–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Brommer S., Harrad S., Van den Eede N., Covaci A. (2012). Concentrations of organophosphate esters and brominated flame retardants in German indoor dust samples. J. Environ. Monit. 14, 2482–2487. [DOI] [PubMed] [Google Scholar]
  15. Bronson S. L., Bale T. L. (2014). Prenatal stress-induced increases in placental inflammation and offspring hyperactivity are male-specific and ameliorated by maternal antiinflammatory treatment. Endocrinology 155, 2635–2646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Bronson S. L., Bale T. L. (2016). The placenta as a mediator of stress effects on neurodevelopmental reprogramming. Neuropsychopharmacology 41, 207–218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Butt C. M., Congleton J., Hoffman K., Fang M., Stapleton H. M. (2014). Metabolites of organophosphate flame retardants and 2-ethylhexyl tetrabromobenzoate in urine from paired mothers and toddlers. Environ. Sci. Technol. 48, 10432–10438. [DOI] [PubMed] [Google Scholar]
  18. Butt C. M., Miranda M. L., Stapleton H. M. (2016). Development of an analytical method to quantify PBDEs, OH-BDEs, HBCDs, 2,4,6-TBP, EH-TBB, and BEH-TEBP in human serum. Anal. Bioanal. Chem. 408, 2449–2459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Carr R. L., Graves C. A., Mangum L. C., Nail C. A., Ross M. K. (2014). Low level chlorpyrifos exposure increases anandamide accumulation in juvenile rat brain in the absence of brain cholinesterase inhibition. Neurotoxicology 43, 82–89. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Cequier E., Sakhi A. K., Marce R. M., Becher G., Thomsen C. (2015). Human exposure pathways to organophosphate triesters—A biomonitoring study of mother-child pairs. Environ. Int. 75, 159–165. [DOI] [PubMed] [Google Scholar]
  21. Chan S. Y., Vasilopoulou E., Kilby M. D. (2009). The role of the placenta in thyroid hormone delivery to the fetus. Nat. Clin. Pract. Endocrinol. Metab. 5, 45–54. [DOI] [PubMed] [Google Scholar]
  22. Charil A., Laplante D. P., Vaillancourt C., King S. (2010). Prenatal stress and brain development. Brain Res. Rev. 65, 56–79. [DOI] [PubMed] [Google Scholar]
  23. Charnay Y., Leger L. (2010). Brain serotonergic circuitries. Dialogues Clin. Neurosci. 12, 471–487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Chen A., Yolton K., Rauch S. A., Webster G. M., Hornung R., Sjodin A., Dietrich K. N., Lanphear B. P. (2014). Prenatal polybrominated diphenyl ether exposures and neurodevelopment in U.S. children through 5 years of age: The home study. Environ. Health Perspect. 122, 856–862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Chen G., Jin Y., Wu Y., Liu L., Fu Z. (2015). Exposure of male mice to two kinds of organophosphate flame retardants (OPFRs) induced oxidative stress and endocrine disruption. Environ. Toxicol. Pharmacol. 40, 310–318. [DOI] [PubMed] [Google Scholar]
  26. Coelho S. D., Sousa A. C. A., Isobe T., Kim J. W., Kunisue T., Nogueira A. J. A., Tanabe S. (2016). Brominated, chlorinated and phosphate organic contaminants in house dust from Portugal. Sci. Total Environ. 569–570, 442–449. [DOI] [PubMed] [Google Scholar]
  27. Cooper E. M., Covaci A., van Nuijs A. L., Webster T. F., Stapleton H. M. (2011). Analysis of the flame retardant metabolites bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and diphenyl phosphate (DPP) in urine using liquid chromatography-tandem mass spectrometry. Anal. Bioanal. Chem. 401, 2123–2132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Deverman B. E., Patterson P. H. (2009). Cytokines and CNS development. Neuron 64, 61–78. [DOI] [PubMed] [Google Scholar]
  29. Dishaw L. V., Powers C. M., Ryde I. T., Roberts S. C., Seidler F. J., Slotkin T. A., Stapleton H. M. (2011). Is the pentabde replacement, tris(1,3-dichloro-2-propyl) phosphate (TDCPP), a developmental neurotoxicant? Studies in PC12 cells. Toxicol. Appl. Pharmacol. 256, 281–289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Dodson R. E., Van den Eede N., Covaci A., Perovich L. J., Brody J. G., Rudel R. A. (2014). Urinary biomonitoring of phosphate flame retardants: Levels in California adults and recommendations for future studies. Environ. Sci. Technol. 48, 13625–13633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Gaspar P., Cases O., Maroteaux L. (2003). The developmental role of serotonin: News from mouse molecular genetics. Nat. Rev. Neurosci. 4, 1002–1012. [DOI] [PubMed] [Google Scholar]
  32. Gillera S. E. A., Marinello W. P., Horman B. M., Phillips A. L., Ruis M. T., Stapleton H. M., Reif D. M., Patisaul H. B. (2019). Sex-specific effects of perinatal Firemaster® 550 (FM 550) exposure on socioemotional behavior in prairie voles. Neurotoxicol. Teratol. 106840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Goeden N., Notarangelo F. M., Pocivavsek A., Beggiato S., Bonnin A., Schwarcz R. (2017). Prenatal dynamics of kynurenine pathway metabolism in mice: Focus on kynurenic acid. Dev. Neurosci. 39, 519–528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Hammel S. C., Hoffman K., Webster T. F., Anderson K. A., Stapleton H. M. (2016). Measuring personal exposure to organophosphate flame retardants using silicone wristbands and hand wipes. Environ. Sci. Technol. 50, 4483–4491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Hoffman K., Daniels J. L., Stapleton H. M. (2014). Urinary metabolites of organophosphate flame retardants and their variability in pregnant women. Environ. Int. 63, 169–172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Hoffman K., Webster T. F., Sjodin A., Stapleton H. M. (2017). Toddler’s behavior and its impacts on exposure to polybrominated diphenyl ethers. J. Expo. Sci. Environ. Epidemiol. 27, 193–197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Holland O. J., Hickey A. J. R., Alvsaker A., Moran S., Hedges C., Chamley L. W., Perkins A. V. (2017). Changes in mitochondrial respiration in the human placenta over gestation. Placenta 57, 102–112. [DOI] [PubMed] [Google Scholar]
  38. Hou R., Xu Y., Wang Z. (2016). Review of OPFRs in animals and humans: Absorption, bioaccumulation, metabolism, and internal exposure research. Chemosphere 153, 78–90. [DOI] [PubMed] [Google Scholar]
  39. Hunt P. A., Susiarjo M., Rubio C., Hassold T. J. (2009). The bisphenol a experience: A primer for the analysis of environmental effects on mammalian reproduction. Biol. Reprod. 81, 807–813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Jarema K. A., Hunter D. L., Shaffer R. M., Behl M., Padilla S. (2015). Acute and developmental behavioral effects of flame retardants and related chemicals in zebrafish. Neurotoxicol. Teratol. 52, 194–209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Jensen Pena C., Monk C., Champagne F. A. (2012). Epigenetic effects of prenatal stress on 11beta-hydroxysteroid dehydrogenase-2 in the placenta and fetal brain. PLoS One 7, e39791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Jones M. L., Mark P. J., Lewis J. L., Mori T. A., Keelan J. A., Waddell B. J. (2010). Antioxidant defenses in the rat placenta in late gestation: Increased labyrinthine expression of superoxide dismutases, glutathione peroxidase 3, and uncoupling protein 2. Biol. Reprod. 83, 254–260. [DOI] [PubMed] [Google Scholar]
  43. Kepser L. J., Homberg J. R. (2015). The neurodevelopmental effects of serotonin: A behavioural perspective. Behav. Brain Res. 277, 3–13. [DOI] [PubMed] [Google Scholar]
  44. Kilkenny C., Browne W. J., Cuthill I. C., Emerson M., Altman D. G. (2010). Improving bioscience research reporting: The arrive guidelines for reporting animal research. PLoS Biol. 8, e1000412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Kim S., Jung J., Lee I., Jung D., Youn H., Choi K. (2015). Thyroid disruption by triphenyl phosphate, an organophosphate flame retardant, in zebrafish (Danio rerio) embryos/larvae, and in GH3 and FRTL-5 cell lines. Aquat. Toxicol. 160, 188–196. [DOI] [PubMed] [Google Scholar]
  46. Kim U. J., Wang Y., Li W., Kannan K. (2019). Occurrence of and human exposure to organophosphate flame retardants/plasticizers in indoor air and dust from various microenvironments in the United States. Environ. Int. 125, 342–349. [DOI] [PubMed] [Google Scholar]
  47. Kojima H., Takeuchi S., Itoh T., Iida M., Kobayashi S., Yoshida T. (2013). In vitro endocrine disruption potential of organophosphate flame retardants via human nuclear receptors. Toxicology 314, 76–83. [DOI] [PubMed] [Google Scholar]
  48. Konkel L. (2016). Lasting impact of an ephemeral organ: The role of the placenta in fetal programming. Environ. Health Perspect. 124, A124129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Lefebvre P., Benomar Y., Staels B. (2010). Retinoid X receptors: Common heterodimerization partners with distinct functions. Trends Endocrinol. Metab. 21, 676–683. [DOI] [PubMed] [Google Scholar]
  50. Li A. A., Baum M. J., McIntosh L. J., Day M., Liu F., Gray L. E. Jr (2008). Building a scientific framework for studying hormonal effects on behavior and on the development of the sexually dimorphic nervous system. Neurotoxicology 29, 504–519. [DOI] [PubMed] [Google Scholar]
  51. Lips K. S., Bruggmann D., Pfeil U., Vollerthun R., Grando S. A., Kummer W. (2005). Nicotinic acetylcholine receptors in rat and human placenta. Placenta 26, 735–746. [DOI] [PubMed] [Google Scholar]
  52. Liu C., Wang Q., Liang K., Liu J., Zhou B., Zhang X., Liu H., Giesy J. P., Yu H. (2013. a). Effects of tris(1,3-dichloro-2-propyl) phosphate and triphenyl phosphate on receptor-associated mRNA expression in zebrafish embryos/larvae. Aquat. Toxicol. 128–129, 147–157. [DOI] [PubMed] [Google Scholar]
  53. Liu X., Ji K., Choi K. (2012). Endocrine disruption potentials of organophosphate flame retardants and related mechanisms in H295R and MVLN cell lines and in zebrafish. Aquat. Toxicol. 114–115, 173–181. [DOI] [PubMed] [Google Scholar]
  54. Liu X., Ji K., Jo A., Moon H. B., Choi K. (2013. b). Effects of TDCPP or TPP on gene transcriptions and hormones of HPG axis, and their consequences on reproduction in adult zebrafish (Danio rerio). Aquat. Toxicol. 134–135, 104–111. [DOI] [PubMed] [Google Scholar]
  55. Livak K. J., Schmittgen T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25, 402–408. [DOI] [PubMed] [Google Scholar]
  56. Lugo-Huitron R., Ugalde Muniz P., Pineda B., Pedraza C. J., Rios C., Perez-de la Cruz V. (2013). Quinolinic acid: An endogenous neurotoxin with multiple targets. Oxid. Med. Cell. Longev. 2013, 1–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Mairesse J., Lesage J., Breton C., Breant B., Hahn T., Darnaudery M., Dickson S. L., Seckl J., Blondeau B., Vieau D., et al. (2007). Maternal stress alters endocrine function of the feto-placental unit in rats. Am. J. Physiol. Endocrinol. Metab. 292, E1526–1533. [DOI] [PubMed] [Google Scholar]
  58. Martin M. M., Liu Y., Wang Z. (2012). Developmental exposure to a serotonin agonist produces subsequent behavioral and neurochemical changes in the adult male prairie vole. Physiol. Behav. 105, 529–535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Meeker J. D., Cooper E. M., Stapleton H. M., Hauser R. (2013). Urinary metabolites of organophosphate flame retardants: Temporal variability and correlations with house dust concentrations. Environ. Health Perspect. 121, 580–585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Mendelsohn E., Hagopian A., Hoffman K., Butt C. M., Lorenzo A., Congleton J., Webster T. F., Stapleton H. M. (2016). Nail polish as a source of exposure to triphenyl phosphate. Environ. Int. 86, 45–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Messer A. (2010). Mini-review: Polybrominated diphenyl ether (PBDE) flame retardants as potential autism risk factors. Physiol. Behav. 100, 245–249. [DOI] [PubMed] [Google Scholar]
  62. Nakanishi T. (2008). Endocrine disruption induced by organotin compounds; organotins function as a powerful agonist for nuclear receptors rather than an aromatase inhibitor. J. Toxicol. Sci. 33, 269–276. [DOI] [PubMed] [Google Scholar]
  63. Notarangelo F. M., Schwarcz R. (2016). Restraint stress during pregnancy rapidly raises kynurenic acid levels in mouse placenta and fetal brain. Dev. Neurosci. 38, 458–468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Nugent B. M., Bale T. L. (2015). The omniscient placenta: Metabolic and epigenetic regulation of fetal programming. Front. Neuroendocrinol. 39, 28–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. O’Donnell K. J., Bugge Jensen A., Freeman L., Khalife N., O’Connor T. G., Glover V. (2012). Maternal prenatal anxiety and downregulation of placental 11beta-HSD2. Psychoneuroendocrinology 37, 818–826. [DOI] [PubMed] [Google Scholar]
  66. Parrott J. M., Redus L., Santana-Coelho D., Morales J., Gao X., O'Connor J. C. (2016). Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation. Transl. Psychiatry 6, e918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Patisaul H. B., Fortino A. E., Polston E. K. (2008). Sex differences in serotonergic but not {gamma}-aminobutyric acidergic (GABA) projections to the rat ventromedial nucleus of the hypothalamus. Endocrinology 149, 397–408. [DOI] [PubMed] [Google Scholar]
  68. Patisaul H. B., Roberts S. C., Mabrey N., McCaffrey K. A., Gear R. B., Braun J., Belcher S. M., Stapleton H. M. (2013). Accumulation and endocrine disrupting effects of the flame retardant mixture Firemaster® 550 in rats: An exploratory assessment. J. Biochem. Mol. Toxicol. 27, 124–136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Patisaul H. B., Sullivan A. W., Radford M. E., Walker D. M., Adewale H. B., Winnik B., Coughlin J. L., Buckley B., Gore A. C. (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 7, e43890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Patisaul H. B., Todd K. L., Mickens J. A., Adewale H. B. (2009). Impact of neonatal exposure to the ERalpha agonist PPT, bisphenol-A or phytoestrogens on hypothalamic kisspeptin fiber density in male and female rats. Neurotoxicology 30, 350–357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Paxinos G., Ashwell K. (2018). Atlas of the Developing Rat Nervous System. 4th ed. Academic Press, San Diego.
  72. Peters D. A. (1990). Maternal stress increases fetal brain and neonatal cerebral cortex 5-hydroxytryptamine synthesis in rats: A possible mechanism by which stress influences brain development. Pharmacol. Biochem. Behav. 35, 943–947. [DOI] [PubMed] [Google Scholar]
  73. Phillips A. L., Hammel S. C., Hoffman K., Lorenzo A. M., Chen A., Webster T. F., Stapleton H. M. (2018). Children’s residential exposure to organophosphate ester flame retardants and plasticizers: Investigating exposure pathways in the TESIE study. Environ. Int. 116, 176–185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Phillips A. L., Hammel S. C., Konstantinov A., Stapleton H. M. (2017). Characterization of individual isopropylated and tert-butylated triarylphosphate (ITP and TBPP) isomers in several commercial flame retardant mixtures and house dust standard reference material SRM 2585. Environ. Sci. Technol. 51, 13443–13449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Poletti A., Celotti F., Rumio C., Rabuffetti M., Martini L. (1997). Identification of type 1 5alpha-reductase in myelin membranes of male and female rat brain. Mol. Cell. Endocrinol. 129, 181–190. [DOI] [PubMed] [Google Scholar]
  76. Polston E. K., Gu G., Simerly R. B. (2004). Neurons in the principal nucleus of the bed nuclei of the stria terminalis provide a sexually dimorphic GABAergic input to the anteroventral periventricular nucleus of the hypothalamus. Neuroscience 123, 793–803. [DOI] [PubMed] [Google Scholar]
  77. Puzianowska-Kuznicka M., Pietrzak M., Turowska O., Nauman A. (2006). Thyroid hormones and their receptors in the regulation of cell proliferation. Acta Biochim. Pol. 53, 641–650. [PubMed] [Google Scholar]
  78. Quevedo C., Behl M., Ryan K., Paules R. S., Alday A., Muriana A., Alzualde A. (2019). Detection and prioritization of developmentally neurotoxic and/or neurotoxic compounds using zebrafish. Toxicol. Sci. 168, 225–240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. R Foundation for Statistical Computing. (2015). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria: Available at: http://www.R-project.org/. [Google Scholar]
  80. Richter C. A., Birnbaum L. S., Farabollini F., Newbold R. R., Rubin B. S., Talsness C. E., Vandenbergh J. G., Walser-Kuntz D. R., vom Saal F. S. (2007). In vivo effects of bisphenol A in laboratory rodent studies. Reprod. Toxicol. 24, 199–224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Rock K. D., Horman B., Phillips A. L., McRitchie S. L., Watson S., Deese-Spruill J., Jima D., Sumner S., Stapleton H. M., Patisaul H. B. (2018). EDC IMPACT: Molecular effects of developmental FM 550 exposure in Wistar rat placenta and fetal forebrain. Endocr. Connect. 7, 305–324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Roland L., Beauchemin D., Acteau G., Fradette C., St-Pierre I., Bilodeau J. F. (2010). Effects of labor on placental expression of superoxide dismutases in preeclampsia. Placenta 31, 392–400. [DOI] [PubMed] [Google Scholar]
  83. Ruis M. T., Rock K. D., Hall S. M., Horman B., Patisaul H. B., Stapleton H. M. (2019). PBDEs concentrate in the fetal portion of the placenta: Implications for thyroid hormone dysregulation. Endocrinology 160, 2748–2758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Sarma S. N., Saleem A., Lee J. Y., Tokumoto M., Hwang G. W., Man Chan H., Satoh M. (2018). Effects of long-term cadmium exposure on urinary metabolite profiles in mice. J. Toxicol. Sci. 43, 89–100. [DOI] [PubMed] [Google Scholar]
  85. Shemer A. V., Azmitia E. C., Whitaker-Azmitia P. M. (1991). Dose-related effects of prenatal 5-methoxytryptamine (5-MT) on development of serotonin terminal density and behavior. Brain Res. Dev. Brain Res. 59, 59–63. [DOI] [PubMed] [Google Scholar]
  86. Shemer A., Whitaker-Azmitia P. M., Azmitia E. C. (1988). Effects of prenatal 5-methoxytryptamine and parachlorophenylalanine on serotonergic uptake and behavior in the neonatal rat. Pharmacol. Biochem. Behav. 30, 847–851. [DOI] [PubMed] [Google Scholar]
  87. Shi Q., Wang M., Shi F., Yang L., Guo Y., Feng C., Liu J., Zhou B. (2018). Developmental neurotoxicity of triphenyl phosphate in zebrafish larvae. Aquat. Toxicol. 203, 80–87. [DOI] [PubMed] [Google Scholar]
  88. Slotkin T. A., Seidler F. J. (2005). The alterations in CNS serotonergic mechanisms caused by neonatal chlorpyrifos exposure are permanent. Brain Res. Dev. Brain Res. 158, 115–119. [DOI] [PubMed] [Google Scholar]
  89. Slotkin T. A., Seidler F. J. (2007). Prenatal chlorpyrifos exposure elicits presynaptic serotonergic and dopaminergic hyperactivity at adolescence: Critical periods for regional and sex-selective effects. Reprod. Toxicol. 23, 421–427. [DOI] [PubMed] [Google Scholar]
  90. Slotkin T. A., Seidler F. J. (2008). Developmental neurotoxicants target neurodifferentiation into the serotonin phenotype: Chlorpyrifos, diazinon, dieldrin and divalent nickel. Toxicol. Appl. Pharmacol. 233, 211–219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Souza M. S., Magnarelli G. G., Rovedatti M. G., Cruz S. S., De D. A. (2005). Prenatal exposure to pesticides: Analysis of human placental acetylcholinesterase, glutathione S-transferase and catalase as biomarkers of effect. Biomarkers 10, 376–389. [DOI] [PubMed] [Google Scholar]
  92. Stapleton H. M., Allen J. G., Kelly S. M., Konstantinov A., Klosterhaus S., Watkins D., McClean M. D., Webster T. F. (2008). Alternate and new brominated flame retardants detected in U.S. house dust. Environ. Sci. Technol. 42, 6910–6916. [DOI] [PubMed] [Google Scholar]
  93. Stapleton H. M., Klosterhaus S., Eagle S., Fuh J., Meeker J. D., Blum A., Webster T. F. (2009). Detection of organophosphate flame retardants in furniture foam and U.S. house dust. Environ. Sci. Technol. 43, 7490–7495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Stapleton H. M., Klosterhaus S., Keller A., Ferguson P. L., van Bergen S., Cooper E., Webster T. F., Blum A. (2011). Identification of flame retardants in polyurethane foam collected from baby products. Environ. Sci. Technol. 45, 5323–5331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Stapleton H. M., Sharma S., Getzinger G., Ferguson P. L., Gabriel M., Webster T. F., Blum A. (2012). Novel and high volume use flame retardants in US couches reflective of the 2005 pentabde phase out. Environ. Sci. Technol. 46, 13432–13439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Tajima S., Araki A., Kawai T., Tsuboi T., Ait Bamai Y., Yoshioka E., Kanazawa A., Cong S., Kishi R. (2014). Detection and intake assessment of organophosphate flame retardants in house dust in Japanese dwellings. Sci. Total Environ. 478, 190–199. [DOI] [PubMed] [Google Scholar]
  97. Tanaka M., Sato A., Kasai S., Hagino Y., Kotajima-Murakami H., Kashii H., Takamatsu Y., Nishito Y., Inagaki M., Mizuguchi M., et al. (2018). Brain hyperserotonemia causes autism-relevant social deficits in mice. Mol. Autism 9, 60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Timofeeva O. A., Roegge C. S., Seidler F. J., Slotkin T. A., Levin E. D. (2008. a). Persistent cognitive alterations in rats after early postnatal exposure to low doses of the organophosphate pesticide, diazinon. Neurotoxicol. Teratol. 30, 38–45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Timofeeva O. A., Sanders D., Seemann K., Yang L., Hermanson D., Regenbogen S., Agoos S., Kallepalli A., Rastogi A., Braddy D., et al. (2008. b). Persistent behavioral alterations in rats neonatally exposed to low doses of the organophosphate pesticide, parathion. Brain Res. Bull. 77, 404–411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Van den Eede N., Heffernan A. L., Aylward L. L., Hobson P., Neels H., Mueller J. F., Covaci A. (2015). Age as a determinant of phosphate flame retardant exposure of the Australian population and identification of novel urinary PFR metabolites. Environ. Int. 74, 1–8. [DOI] [PubMed] [Google Scholar]
  101. Van den Eede N., Maho W., Erratico C., Neels H., Covaci A. (2013. a). First insights in the metabolism of phosphate flame retardants and plasticizers using human liver fractions. Toxicol. Lett. 223, 9–15. [DOI] [PubMed] [Google Scholar]
  102. Van den Eede N., Neels H., Jorens P. G., Covaci A. (2013. b). Analysis of organophosphate flame retardant diester metabolites in human urine by liquid chromatography electrospray ionisation tandem mass spectrometry. J. Chromatogr. A 1303, 48–53. [DOI] [PubMed] [Google Scholar]
  103. van der Veen I., de Boer J. (2012). Phosphorus flame retardants: Properties, production, environmental occurrence, toxicity and analysis. Chemosphere 88, 1119–1153. [DOI] [PubMed] [Google Scholar]
  104. Viau M., Lafond J., Vaillancourt C. (2009). Expression of placental serotonin transporter and 5-HT 2A receptor in normal and gestational diabetes mellitus pregnancies. Reprod. Biomed. Online 19, 207–215. [DOI] [PubMed] [Google Scholar]
  105. Wang R., Tang J., Xie Z., Mi W., Chen Y., Wolschke H., Tian C., Pan X., Luo Y., Ebinghaus R. (2015. a). Occurrence and spatial distribution of organophosphate ester flame retardants and plasticizers in 40 rivers draining into the Bohai Sea, north China. Environ. Pollut. 198, 172–178. [DOI] [PubMed] [Google Scholar]
  106. Wang X., Mu X., Zhang J., Huang Q., Alamdar A., Tian M., Liu L., Shen H. (2015. b). Serum metabolomics reveals that arsenic exposure disrupted lipid and amino acid metabolism in rats: A step forward in understanding chronic arsenic toxicity. Metallomics 7, 544–552. [DOI] [PubMed] [Google Scholar]
  107. Wei G. L., Li D. Q., Zhuo M. N., Liao Y. S., Xie Z. Y., Guo T. L., Li J. J., Zhang S. Y., Liang Z. Q. (2015). Organophosphorus flame retardants and plasticizers: Sources, occurrence, toxicity and human exposure. Environ. Pollut. 196, 29–46. [DOI] [PubMed] [Google Scholar]
  108. Wise L. M., Sadowski R. N., Kim T., Willing J., Juraska J. M. (2016). Long-term effects of adolescent exposure to bisphenol A on neuron and glia number in the rat prefrontal cortex: Differences between the sexes and cell type. Neurotoxicology 53, 186–192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Yida Z., Imam M. U., Ismail M., Ismail N., Ideris A., Abdullah M. A. (2015). High fat diet-induced inflammation and oxidative stress are attenuated by N-acetylneuraminic acid in rats. J. Biomed. Sci. 22, 96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Yu X., Yin H., Peng H., Lu G., Liu Z., Dang Z. (2019). OPFRs and BFRs induced A549 cell apoptosis by caspase-dependent mitochondrial pathway. Chemosphere 221, 693–702. [DOI] [PubMed] [Google Scholar]
  111. Yue S., Yu J., Kong Y., Chen H., Mao M., Ji C., Shao S., Zhu J., Gu J., Zhao M. (2019). Metabolomic modulations of HepG2 cells exposed to bisphenol analogues. Environ. Int. 129, 59–67. [DOI] [PubMed] [Google Scholar]

Cited by

Sorted by citations

Authors
Rock, K. D., St Armour, G., Horman, B., Phillips, A., Ruis, M., Stewart, A. K., Jima, D., Muddiman, D. C., Stapleton, H. M., & Patisaul, H. B.
Affiliations
  • North Carolina State University (US)
  • Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina 27619
  • Duke University (US)
Corresponding author
Patisaul, Heather B
ORCID
Venue
Toxicological Sciences
Publisher
Oxford University Press (OUP)
Published
2020-04-03
Volume
176
Issue
1
Pages
203-223
ISSN
  • 1096-0929 (ISSN-L)
  • 1096-6080
DOI
10.1093/toxsci/kfaa046
PMC
PMC7357193
OpenAlex
W3014358433
Cited by
69
References
3
Citations by year
2026: 8 · 2025: 14 · 2024: 12 · 2023: 14 · 2022: 11 · 2021: 8 · 2020: 2
FWCI
3.50
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Toxicological Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute of Environmental Health Sciences (F31ES02900-01, R56ES022957, T32ES007046, P30ES025128)
  • NCSU (R01ES028110, R01ES016099)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Pesticide Exposure and Toxicity
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
Keywords
organophosphate flame retardants, prenatal exposure, placenta, serotonin, tryptophan metabolism, kynurenine pathway, serotoninergic innervation, triphenyl phosphate, developmental neurotoxicity, placental gene expression, sex differences
MeSH terms
Animals, Brain, Female, Fetus, Flame Retardants, Humans, Male, Organophosphorus Compounds, Organophosphates, Placenta, Plasticizers, Polybrominated Biphenyls, Pregnancy, Prenatal Exposure Delayed Effects, Serotonin, Gene Expression, Rats, Wistar, Fetal Development, Rats

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