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Exposure to tert-Butylphenyl Diphenyl Phosphate, an Organophosphate Ester Flame Retardant and Plasticizer, Alters Hedgehog Signaling in Murine Limb Bud Cultures.

ABSTRACT: Organophosphate esters have become widely used as flame retardants since the phase out of polybrominated diphenyl ethers. Previously, we demonstrated that some organophosphate esters, such as tert-butylphenyl diphenyl phosphate (BPDP), were more detrimental to endochondral ossification in murine limb bud cultures than one of the major polybrominated diphenyl ethers that they replaced, 2,2',4,4'-tetrabromodiphenyl ether. Here, we used a transcriptomic approach to elucidate the mechanism of action of BPDP in the developing limb. Limb buds collected from gestation day 13 CD1 mouse embryos were cultured for 3 or 24 h in the presence of vehicle, 1 μM, or 10 μM BPDP. RNA sequencing analyses revealed that exposure to 1 µM BPDP for 24 h increased the expression of 5 transcripts, including Ihh, and decreased 14 others, including Gli1, Ptch1, Ptch2, and other targets of Hedgehog (Hh) signaling. Pathway analysis predicted the inhibition of Hh signaling. Attenuation of Hh signaling activity began earlier and reached a greater magnitude after exposure to 10 µM BPDP. Because this pathway is part of the regulatory network governing endochondral ossification, we used a known Hh agonist, purmorphamine, to determine the contribution of Hh signaling inhibition to the negative impact of BPDP on endochondral ossification. Cotreatment of limbs with purmorphamine rescued the detrimental morphological changes in the cartilage template induced by BPDP exposure though it did not restore the expression of key transcription factors, Runx2 and Sp7, to control levels. These data highlight Hh signaling as a developmentally important pathway vulnerable to environmental chemical exposures.

SUBMITTER: Yan H

PROVIDER: S-EPMC7706402 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo evaluate whether urinary concentrations of organophosphate flame retardant (PFR) metabolites are associated with pregnancy loss among women conceiving with assisted reproductive technology (ART).DesignProspective preconception cohort of subfertile women.SettingAcademic hospital fertility center in Boston, Massachusetts.Patient(s)A total of 155 women conceiving 179 pregnancies with ART.Intervention(s)None. Mean exposure to each of five PFR metabolites was estimated by averaging the specific-gravity adjusted natural log concentrations from two urine samples collected during the ART cycle of conception.Main outcome measure(s)Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for biochemical and total pregnancy loss (all losses <20 weeks' gestation) by quartiles of PFR metabolite concentrations were estimated using a repeated measures log-binomial model, accounting for multiple pregnancies per woman.Result(s)Of the 179 pregnancies, 31% ended in pregnancy loss (12% in biochemical loss). Among the three metabolites with high detection frequency [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), and isopropylphenyl phenyl phosphate (ip-PPP)], an increased risk of biochemical loss was observed for women with DPHP concentrations in the fourth vs. first quartile (RR 1.64; 95% CI 0.61-4.39). Also found was an elevated risk of biochemical pregnancy loss among women in the highest quartile of the molar sum of urinary PFR metabolites compared with the lowest (RR 1.89; 95% CI 0.64-5.58). Urinary concentrations of ip-PPP and BDCIPP were not associated with either outcome.Conclusion(s)Among subfertile women, urinary DPHP metabolite concentrations measured during the ART cycle of conception may be associated with early pregnancy loss. Although this study is uniquely designed to investigate early markers of pregnancy success and maintenance, the small sample size likely contributed to imprecision. Given their increasing use as replacement chemicals for traditional flame retardants, exposure to PFRs may increase, and more studies will be needed to investigate their potential to impact pregnancy and reproduction.

Project description:BackgroundOrganophosphate esters (OPEs), used as flame retardants and plasticizers, are chemicals of concern for maternal and infant health. Prior studies examining temporal trends and predictors of OPE exposure are primarily limited by small sample sizes.ObjectivesCharacterize temporal trends and predictors of OPE exposure biomarkers.MethodsWe determined urinary concentrations of eight biomarkers of OPE exposure at three timepoints during pregnancy for participants in the LIFECODES Fetal Growth Study (n = 900), a nested case-cohort recruited between 2007 and 2018. We examined biomarker concentrations, their variability during pregnancy, and temporal trends over the study period. In addition, we identified sociodemographic and pregnancy characteristics associated with biomarker concentrations. Analyses were conducted using both the within-subject pregnancy geometric means and biomarker concentrations measured at individual study visits.ResultsFive OPE biomarkers were detected in at least 60% of the study participants. Biomarkers were not strongly correlated with one another and intraclass correlation coefficients, measuring within-subject variability during pregnancy, ranged from 0.27 to 0.51. Biomarkers exhibited varying temporal trends across study years. For example, bis(1-chloro-2-propyl) phosphate (BCIPP) increased monotonically, whereas bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP), displayed non-monotonic trends with concentrations that peaked between 2011 and 2014. We observed associations between sociodemographic characteristics and OPE biomarkers. In general, concentrations of most OPE biomarkers were higher among participants from racial and ethnic minority populations, participants who were younger, had higher pre-pregnancy body mass index (BMI), and less than a college degree. We observed consistent results using either averaged or visit-specific biomarker concentrations.SignificanceWe observed widespread exposure to several OPEs and OPE biomarkers displayed varying temporal trends in pregnant people from 2007 to 2018. Concentrations of most OPE biomarkers varied according to sociodemographic factors, suggesting higher burdens of exposure among participants with higher pre-pregnancy BMI, those belonging to racial and ethnic minority populations, and lower educational attainment.

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Exposure to tert-Butylphenyl Diphenyl Phosphate, an Organophosphate Ester Flame Retardant and Plasticizer, Alters Hedgehog Signaling in Murine Limb Bud Cultures.

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