Sex- and age-dependent effects of maternal organophosphate flame-retardant exposure on neonatal hypothalamic and hepatic gene expression

Adams, Sherrill L.; Wiersielis, Kimberly R.; Yasrebi, Ali; Conde, Kristie; Armstrong, Laura E.; Guo, Grace L.; Roepke, Troy A.

doi:10.1016/j.reprotox.2020.04.001

Cited by 32 publications

(24 citation statements)

References 70 publications

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“…In our current study, OPFR exposure reduced AGD in male mice demonstrating a feminization or demasculinization of the genitals from maternal OPFR exposure. A similar observation was reported with PBDE exposure in Long Evans rats (Lilienthal, Hack, Roth‐Härer, Grande, & Talsness, 2006) and in a recent study from our lab examining the influence of maternal OPFR exposure on neonatal and juvenile hypothalamic and hepatic gene expression (Adams et al, 2020). Rodent exposure to bisphenol A (BPA) also reduces AGD in males; however, in multigenerational BPA studies, AGD was increased after both prenatal and postnatal exposure (Gupta, 2000; Honma et al, 2002; Tyl et al, 2002; Tyl et al, 2008).…”

Section: Discussionsupporting

confidence: 82%

“…The OPFR mixture was a combination of TDCPP (Sigma‐Aldrich; CAS#:13674‐87‐8, 95.6% purity), TPP (Sigma‐Aldrich; CAS#:115‐86‐6, 99% purity), and TCP (AccuStandard; CAS#: 1330‐78‐5, 99% purity) at 1 mg/kg each. This dose was previously found to be effective in an adult exposure model in mice (Krumm et al, 2018), in our recent maternal exposure study on neonatal and juvenile gene expression (Adams et al, 2020), and in a developmental exposure model in rats focusing on exploratory behavior and locomotion (Baldwin et al, 2017; Patisaul et al, 2013). To prepare the OPFR stock, each compound was then dissolved into 1 mL of acetone to create a stock solution.…”

Section: Methodsmentioning

confidence: 90%

“…1330-78-5, 99% purity) at 1 mg/kg each. This dose was previously found to be effective in an adult exposure model in mice (Krumm et al, 2018), in our recent maternal exposure study on neonatal and juvenile gene expression (Adams et al, 2020), and in a developmental exposure model in rats focusing on exploratory behavior and locomotion (Baldwin et al, 2017;Patisaul et al, 2013).…”

Section: Chemicalsmentioning

confidence: 96%

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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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Section: Discussionsupporting

confidence: 82%

Section: Methodsmentioning

confidence: 90%

Section: Chemicalsmentioning

confidence: 96%

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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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“…In conclusion, our data suggest that the expression, if not activity, of ERα is a potential mechanism of toxicity for maternal OPFR exposures (La Merrill et al, 2019). This is supported by our recent study demonstrating that maternal OPFR exposure increases ERα and PPARγ expression in the mediobasal hypothalamus and liver of 2-week-old, male and female pups (Adams et al, 2020). As both ERα and PPARγ are involved in energy and glucose homeostasis (Jones et al, 2005;Magliano et al, 2013;Mauvais-Jarvis, Clegg, & Hevener, 2013), future studies will characterize the tissue-specific expression of ERα and PPARγ in the endocrine disruption caused by maternal OPFR exposure.…”

Section: F I G U R Esupporting

confidence: 86%

Maternal organophosphate flame‐retardant exposure alters offspring energy and glucose homeostasis in a sexually dimorphic manner in mice

Walley

Krumm

Yasrebi

et al. 2020

J of Applied Toxicology

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Persistent organic pollutants such as organophosphate flame retardants (OPFRs) can accumulate in the body and interact with nuclear receptors that control energy homeostasis. One sensitive window of exposure is during development, either in utero or neonatal. Therefore, we investigated if maternal exposure to a mixture of OPFRs alters metabolism on a low-fat diet (LFD) or a high-fat diet (HFD) in both male and female offspring. Wild-type C57Bl/6J dams were orally dosed with vehicle (sesame oil) or an OPFR mixture (1 mg/kg 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 LFD or HFD. To assess metabolism, we measured body weight and food intake weekly and determined body composition, metabolism, activity, and glucose homeostasis at 6 months of age. Although maternal OPFR exposure did not alter body weight or adiposity, OPFR exposure altered substrate utilization and energy expenditure depending on diet in both sexes. Systolic and diastolic blood pressure was increased by OPFR in male offspring. OPFR exposure interacted with HFD to increase fasting glucose in females and alter glucose and insulin tolerance in male offspring. Plasma leptin was reduced in male and female offspring when fed HFD, whereas liver expression of Pepck was increased in females and Esr1 (estrogen receptor α) was increased in both sex. The physiological implications indicate maternal exposure to OPFRs programs peripheral organs including the liver and adipose tissue, in a sex-dependent manner, thus changing the response to an obesogenic diet and altering adult offspring energy homeostasis.

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“…Maternal exposure to OPFR mixture including tris(1,3-dichloro-2-propyl) phosphate, tricresyl phosphate, and triphenyl phosphate (TPhP) to mice altered the expression of various genes related to fatty acid synthesis, glucose, and triglycerides metabolism in the liver of mice offspring. It was suggested that the effects were possibly mediated by modulation of NRs, including estrogen receptor (ERα), PPARγ, insulin receptor, ghrelin receptor, and leptin receptor [ 147 ].…”

Section: Biological Actions Of Frs: Role In Inflammatory and Cytokine Signalingmentioning

confidence: 99%

Flame Retardants-Mediated Interferon Signaling in the Pathogenesis of Nonalcoholic Fatty Liver Disease

Negi

Khan

Dirven

et al. 2021

IJMS

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Nonalcoholic fatty liver disease (NAFLD) is a growing concern worldwide, affecting 25% of the global population. NAFLD is a multifactorial disease with a broad spectrum of pathology includes steatosis, which gradually progresses to a more severe condition such as nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and eventually leads to hepatic cancer. Several risk factors, including exposure to environmental toxicants, are involved in the development and progression of NAFLD. Environmental factors may promote the development and progression of NAFLD by various biological alterations, including mitochondrial dysfunction, reactive oxygen species production, nuclear receptors dysregulation, and interference in inflammatory and immune-mediated signaling. Moreover, environmental contaminants can influence immune responses by impairing the immune system’s components and, ultimately, disease susceptibility. Flame retardants (FRs) are anthropogenic chemicals or mixtures that are being used to inhibit or delay the spread of fire. FRs have been employed in several household and outdoor products; therefore, human exposure is unavoidable. In this review, we summarized the potential mechanisms of FRs-associated immune and inflammatory signaling and their possible contribution to the development and progression of NAFLD, with an emphasis on FRs-mediated interferon signaling. Knowledge gaps are identified, and emerging pharmacotherapeutic molecules targeting the immune and inflammatory signaling for NAFLD are also discussed.

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Sex- and age-dependent effects of maternal organophosphate flame-retardant exposure on neonatal hypothalamic and hepatic gene expression

Cited by 32 publications

References 70 publications

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

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

Maternal organophosphate flame‐retardant exposure alters offspring energy and glucose homeostasis in a sexually dimorphic manner in mice

Flame Retardants-Mediated Interferon Signaling in the Pathogenesis of Nonalcoholic Fatty Liver Disease

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