Neurobehavioral toxicity study of dibutyl phthalate on rats following <i>in utero </i>and lactational exposure

Li, Yuanfeng; Zhuang, Meizhu; Li, Tao; Shi, Ning

doi:10.1002/jat.1447

Cited by 60 publications

(35 citation statements)

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“…Experimental animal studies have shown that prenatal DEHP and di-n-butyl phthalate can lead to impaired spatial learning and memory, and decreased grooming behavior (Hoshi and Ohtsuka, 2009; Tanaka, 2002; Li et al, 2009). Epidemiological studies report that urinary concentrations of low molecular weight phthalate metabolites, such as mono-n-butyl phthalate (MnBP) and monoisobutyl phthalate (MiBP), measured during the 2nd and 3rd trimesters of pregnancy were associated with neonatal behavior and reflexes (Yolton et al, 2011; Engel et al, 2009), aggression, rule breaking, and conduct problems (Engel et al, 2010; Whyatt et al, 2012; Kobrosly et al, 2014; Lien et al, 2015), autistic traits (Miodovnik et al, 2011), lower mental and psychomotor development (Whyatt et al, 2012; Balogh et al, 2011), emotional problems (Whyatt et al, 2012) and reduced IQ (Factor-Litvak et al, 2014); whereas others have not (Braun et al, 2014; Huang et al, 2015; Gascon et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Paternal and maternal preconception urinary phthalate metabolite concentrations and child behavior

Messerlian

Bellinger

Mínguez-Alarcón

et al. 2017

Environmental Research

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Background Prenatal phthalate exposure has been associated with behavioral problems and lower performance on measures of cognitive ability in children. However, the potential effect of phthalate exposure during the sensitive preconception period is unknown. Objectives To estimate the association of maternal and paternal preconception urinary phthalate metabolite concentrations with child behavior and evaluate potential modification by child sex. Methods We used data from 166 children (111 singletons, 26 pairs of twins, and 1 set of triplets) born to 134 mothers and 100 fathers participating in a prospective preconception cohort study of subfertile couples from the Massachusetts General Hospital Fertility Center. We estimated mean maternal and paternal preconception exposures by averaging individual phthalate metabolite concentrations in multiple urine samples collected before pregnancy. We assessed children's behavior at 2–9 years of age by parent report using the Behavior Assessment System for Children-2 (BASC-2). We estimated the covariate-adjusted association between individual phthalate metabolite concentrations and the sum of di(2-ethylhexyl) phthalate metabolites (Σ DEHP) and behavior scores, and evaluated differences in associations by child sex using linear regression with Generalized Estimating Equations. Models were further adjusted for prenatal phthalate concentrations in sensitivity analyses. Results Each loge-unit increase in maternal and paternal preconception concentrations of ΣDEHP was associated with a 2.0 (95% CI: − 3.2, − 0.7) and 1.8 (95% CI: − 3.1, − 0.4) point decrease in BASC-2 internalizing behavior scores among all children, respectively. We observed sex-specific associations for some phthalate biomarkers: among boys, maternal monoisobutyl phthalate (MiBP) was positively associated with externalizing behaviors, and paternal MiBP and mono-n-butyl phthalate were positively associated with internalizing behaviors. Conclusions In this cohort, paternal and maternal preconception concentrations of some phthalate biomarkers were associated with specific aspects of child behavior, even after adjustment for prenatal concentrations. While additional research is warranted to confirm these results, our findings suggest that the preconception period of exposure may be a critical window for offspring neurodevelopment.

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Section: Introductionmentioning

confidence: 99%

Paternal and maternal preconception urinary phthalate metabolite concentrations and child behavior

Messerlian

Bellinger

Mínguez-Alarcón

et al. 2017

Environmental Research

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“…This compound inhibited acetylcholinesterase activity in zebrafish ( Danio rerio ) embryos and up-regulated transcripts of growth-associated protein 43, embryonic lethal abnormal vision-like 3, glial fibrillary acidic protein, myelin basic protein, α1-tubulin and neurogenin1 (Xu et al 2013). DBP also had adverse effects on the behavior and cognitive abilities of rats that were prenatally exposed to the phthalate (Li et al 2009). Recently, exposures to DBP have been correlated with behavioral disorders in eight-year-old children (Lien et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Dibutyl Phthalate (DBP)-Induced Apoptosis and Neurotoxicity are Mediated via the Aryl Hydrocarbon Receptor (AhR) but not by Estrogen Receptor Alpha (ERα), Estrogen Receptor Beta (ERβ), or Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Mouse Cortical Neurons

Wójtowicz¹,

et al. 2016

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Dibutyl phthalate (di-n-butyl phthalate, DBP) is one of the most commonly used phthalate esters. DBP is widely used as a plasticizer in a variety of household industries and consumer products. Because phthalates are not chemically bound to products, they can easily leak out to enter the environment. DBP can pass through the placental and blood–brain barriers due to its chemical structure, but little is known about its mechanism of action in neuronal cells. This study demonstrated the toxic and apoptotic effects of DBP in mouse neocortical neurons in primary cultures. DBP stimulated caspase-3 and LDH activities as well as ROS formation in a concentration (10 nM–100 µM) and time-dependent (3–48 h) manner. DBP induced ROS formation at nanomolar concentrations, while it activated caspase-3 and LDH activities at micromolar concentrations. The biochemical effects of DBP were accompanied by decreased cell viability and induction of apoptotic bodies. Exposure to DBP reduced Erα and Pparγ mRNA expression levels, which were inversely correlated with protein expression of the receptors. Treatment with DBP enhanced Ahr mRNA expression, which was reflected by the increased AhR protein level observed at 3 h after exposure. ERα, ERβ, and PPARγ antagonists stimulated DBP-induced caspase-3 and LDH activities. AhR silencing demonstrated that DBP-induced apoptosis and neurotoxicity are mediated by AhR, which is consistent with the results from DBP-induced enhancement of AhR mRNA and protein expression. Our study showed that AhR is involved in DBP-induced apoptosis and neurotoxicity, while the ERs and PPARγ signaling pathways are impaired by the phthalate.

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“…In animal studies, neurobehavioral deficits include impaired righting ability (Li et al, 2009;Tanaka, 2002), weakened grasp strength and grip time (Li et al, 2009;Tanaka, 2005), and impaired spatial learning and reference memory (Li et al, 2009;Tanaka, 2005). Decreased grooming behavior following DBP exposure was also reported (Hoshi and Ohtsuka, 2009).…”

Section: Introductionmentioning

confidence: 99%

Classification of phthalates based on an <i>in vitro</i> neurosphere assay using rat mesencephalic neural stem cells

Ishido

Suzuki

2014

J. Toxicol. Sci.

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-Exposure to environmental neurotoxic chemicals both in utero and during the early postnatal period can cause neurodevelopmental disorders. To evaluate the disruption of neurodevelopmental programming, we previously established an in vitro neurosphere assay system using rat mesencephalic neural stem cells that can be used to evaluate. Here, we extended the assay system to examine the neurodevelopmental toxicity of the endocrine disruptors butyl benzyl phthalate, di-n-butyl phthalate, dicyclohexyl phthalate, diethyl phthalate, di(2-ethyl hexyl) phthalate, di-n-pentyl phthalate, and dihexyl phthalate at a range of concentrations (0-100 μM). All phthalates tested inhibited cell migration with a linear or non-linear range of concentrations when comparing migration distance to the logarithm of the phthalate concentrations. On the other hand, some, but not all, phthalates decreased the number of proliferating cells. Apoptotic cells were not observed upon phthalate exposure under any of the conditions tested, whereas the dopaminergic toxin rotenone induced significant apoptosis. Thus, we were able to classify phthalate toxicity based on cell migration and cell proliferation using the in vitro neurosphere assay.

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Neurobehavioral toxicity study of dibutyl phthalate on rats following in utero and lactational exposure

Cited by 60 publications

References 44 publications

Paternal and maternal preconception urinary phthalate metabolite concentrations and child behavior

Paternal and maternal preconception urinary phthalate metabolite concentrations and child behavior

Dibutyl Phthalate (DBP)-Induced Apoptosis and Neurotoxicity are Mediated via the Aryl Hydrocarbon Receptor (AhR) but not by Estrogen Receptor Alpha (ERα), Estrogen Receptor Beta (ERβ), or Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Mouse Cortical Neurons

Classification of phthalates based on an <i>in vitro</i> neurosphere assay using rat mesencephalic neural stem cells

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