Sex-specific effects of perinatal FireMaster® 550 (FM 550) exposure on socioemotional behavior in prairie voles

Gillera, Sagi Enicole A.; Marinello, William P.; Horman, Brian; Phillips, Allison L.; Ruis, Matthew T.; Stapleton, Heather M.; Reif, David M.; Patisaul, Heather B.

doi:10.1016/j.ntt.2019.106840

Cited by 31 publications

(38 citation statements)

References 119 publications

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“…On the other hand, Doherty and colleagues ( Doherty et al 2019 ) reported slightly stronger associations among girls, for DPHP and BDCIPP exposure, although they were cautious in interpretation due to small sample sizes and imprecise estimates (interaction term p-values not provided). Our findings support the hypothesis that girls are more vulnerable to ADHD from DPHP exposure, which is in line with findings in experimental settings as well: heightened anxiety ( Gillera et al 2020 ) and hyperactivity ( Baldwin et al 2017 ) have been reported in female rats perinatally dosed with Firemaster 550, which contain parent OPEs of DPHP. We, however, did not observe sexually dimorphic relationships for BDCIPP exposure.…”

Section: Discussionsupporting

confidence: 92%

Pregnancy exposure to organophosphate esters and the risk of attention-deficit hyperactivity disorder in the Norwegian mother, father and child cohort study

Choi

Keil

Richardson

et al. 2021

Environment International

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Background: Organophosphate esters (OPEs) are a class of flame retardants in common use. OPEs can easily leach from materials, resulting in human exposure. Increasing concentrations have been reported in human populations over the past decade. Recent studies have linked prenatal OPE exposure to hyperactivity and attention problems in children. Such behaviors are often found among children with attention-deficit hyperactivity disorder (ADHD), however, no study has investigated OPEs in relation to clinically assessed ADHD. Objective: To evaluate prenatal exposure to OPEs as risk factors for clinically assessed ADHD using a case-cohort study nested within the Norwegian Mother, Father, and Child Cohort Study (MoBa). Methods: We included in the case group 295 ADHD cases obtained via linkage with the Norwegian Patient Registry, and the sub-cohort group 555 children sampled at baseline, irrespective of their ADHD case status. Prenatal concentrations of OPE metabolites were measured in maternal urine collected at 17 weeks of gestation, and included diphenyl phosphate (DPHP), di-n-butyl phosphate (DNBP), bis(2-butoxyethyl) hydrogen phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP). We estimated risk ratios and the corresponding 95% confidence intervals [95% CI] using logistic regression, adjusting for season of urine collection, child sex, birth year, and maternal depression, education, and sum of urinary di(2-ethylhexyl) phthalate metabolites ( DEHP) concentration during pregnancy. To assess the overall impact of simultaneously decreasing exposure to all chemical constituents of an OPE-phthalate mixture, quantile based g-computation was implemented. The mixture constituents included OPE and phthalate metabolites commonly detected in our study. In all models, we considered effect measure modification by child sex and polymorphisms in genes encoding paraoxonase 1 (PON1) and cytochrome P450 (P450) enzymes. Mediation analysis was conducted using thyroid function biomarkers estimated from maternal blood collected at 17 weeks of gestation. Results: DPHP was detected in nearly all samples (97.2%), with a higher geometric mean among the case group (0.70 μg/L) as compared to the sub-cohort (0.52 μg/L). DNBP was commonly detected as well (93.8%), while BBOEP (52.9%) and BDCIPP (22.9%) were detected less frequently. A higher risk of ADHD was observed in children with greater than median exposure to DPHP during pregnancy (risk ratio: 1.38 [95% CI: 0.96, 1.99]), which was slightly higher among girls (2.04 [1.03, 4.02]) and children of mothers with PON1 Q192R genotype QR (1.69 [0.89, 3.19]) or PON1 Q192R genotype RR (4.59 [1.38, 15.29]). The relationship between DPHP and ADHD (total risk ratio: 1.34 [0.90, 2.02]) was partially mediated through total triiodothyronine to total thyroxine ratio (natural direct effect: 1.29 [0.87, 1.94]; natural ind...

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Section: Discussionsupporting

confidence: 92%

Pregnancy exposure to organophosphate esters and the risk of attention-deficit hyperactivity disorder in the Norwegian mother, father and child cohort study

Choi

Keil

Richardson

et al. 2021

Environment International

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“…A growing body of literature has detected alterations in behavior from the developmental exposure to OPFRs (Baldwin et al, 2017; Gillera et al, 2019; Patisaul et al, 2013; Wiersielis, Adams, Yasrebi, Conde, & Roepke, 2020). We have previously demonstrated sex‐specific alterations in locomotion and anxiety‐like behavior from maternal exposure to the same OPFR mixture, concentration, and exposure window (Wiersielis et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Maternal organophosphate flame‐retardant exposure alters offspring feeding, locomotor and exploratory behaviors in a sexually‐dimorphic manner in mice

Walley

Krumm

Yasrebi

et al. 2020

J of Applied Toxicology

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Increased usage of organophosphate flame retardants (OPFRs) has led to detectable levels in pregnant women and neonates, which is associated with negative neurological outcomes. Therefore, we investigated if maternal OPFR exposure altered adult offspring feeding, locomotor, and anxiety‐like behaviors on a low‐fat (LFD) or high‐fat diet (HFD). Wild‐type C57Bl/6J dams were orally dosed with vehicle (sesame oil) or an OPFR mixture (1 mg/kg combination each of tris(1,3‐dichloro‐2‐propyl)phosphate, triphenyl phosphate and tricresyl phosphate) from gestation day 7 to postnatal day 14. After weaning, pups were fed either a LFD or HFD until 19 weeks of age. Locomotor and anxiety‐like behaviors were evaluated with the open field test, elevated plus maze, and metabolic cages. Feeding behaviors and meal patterns were analyzed by a Biological Data Acquisition System. Anogenital distance was reduced in OPFR‐exposed male pups, but no effect was detected on adult body weight. We observed interactions of OPFR exposure and HFD consumption on locomotor and anxiety‐like behavior in males, suggesting an anxiogenic effect while reducing overall nighttime activity. We also observed an interaction of OPFR exposure and HFD on weekly food intake and feeding behaviors. OPFR‐exposed males consumed more total HFD than oil‐exposed males during the 72‐hour trial. However, when arcuate gene expression was analyzed, OPFR exposure induced Agrp expression in females, which would suggest greater orexigenic tone. Collectively, the implications of our study are that the behavioral effects of OPFR exposure are modulated by adult HFD consumption, which may influence the metabolic and neurological consequences of maternal OPFR exposure.

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“…Thus, they may be more appropriate models of human social attachment than rats or mice. Exposure of prairie voles to FM 550 during gestation and weaning led to dose–responsive effects that were more pronounced in female than male offspring ( Gillera et al. 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, they may be more appropriate models of human social attachment than rats or mice. Exposure of prairie voles to FM 550 during gestation and weaning led to dose-responsive effects that were more pronounced in female than male offspring (Gillera et al 2020). Exposure-related outcomes in females included elevated anxiety, decreased social interaction, decreased exploratory motivation, and aversion to novelty.…”

Section: Mammalian Studiesmentioning

confidence: 97%

Beyond Cholinesterase Inhibition: Developmental Neurotoxicity of Organophosphate Ester Flame Retardants and Plasticizers

Patisaul

Behl

Birnbaum

et al. 2021

Environ Health Perspect

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Background: To date, the toxicity of organophosphate esters has primarily been studied regarding their use as pesticides and their effects on the neurotransmitter acetylcholinesterase (AChE). Currently, flame retardants and plasticizers are the two largest market segments for organophosphate esters and they are found in a wide variety of products, including electronics, building materials, vehicles, furniture, car seats, plastics, and textiles. As a result, organophosphate esters and their metabolites are routinely found in human urine, blood, placental tissue, and breast milk across the globe. It has been asserted that their neurological effects are minimal given that they do not act on AChE in precisely the same way as organophosphate ester pesticides. Objectives: This commentary describes research on the non-AChE neurodevelopmental toxicity of organophosphate esters used as flame retardants and plasticizers (OPEs). Studies in humans, mammalian, nonmammalian, and in vitro models are presented, and relevant neurodevelopmental pathways, including adverse outcome pathways, are described. By highlighting this scientific evidence, we hope to elevate the level of concern for widespread human exposure to these OPEs and to provide recommendations for how to better protect public health. Discussion: Collectively, the findings presented demonstrate that OPEs can alter neurodevelopmental processes by interfering with noncholinergic pathways at environmentally relevant doses. Application of a pathways framework indicates several specific mechanisms of action, including perturbation of glutamate and gamma-aminobutyric acid and disruption of the endocrine system. The effects may have implications for the development of cognitive and social skills in children. Our conclusion is that concern is warranted for the developmental neurotoxicity of OPE exposure. We thus describe important considerations for reducing harm and to provide recommendations for government and industry decision makers. https://doi.org/10.1289/EHP9285

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Sex-specific effects of perinatal FireMaster® 550 (FM 550) exposure on socioemotional behavior in prairie voles

Cited by 31 publications

References 119 publications

Pregnancy exposure to organophosphate esters and the risk of attention-deficit hyperactivity disorder in the Norwegian mother, father and child cohort study

Pregnancy exposure to organophosphate esters and the risk of attention-deficit hyperactivity disorder in the Norwegian mother, father and child cohort study

Maternal organophosphate flame‐retardant exposure alters offspring feeding, locomotor and exploratory behaviors in a sexually‐dimorphic manner in mice

Beyond Cholinesterase Inhibition: Developmental Neurotoxicity of Organophosphate Ester Flame Retardants and Plasticizers

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