Systematic review and meta-analysis of early life exposure to di(2-ethylhexyl) phthalate and obesity related outcomes in rodents

Wassenaar, Pim N.H.; Legler, Juliette

doi:10.1016/j.chemosphere.2017.08.165

Cited by 56 publications

(21 citation statements)

References 17 publications

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“…With no further changes in body weight nor fat mass, no alteration in physical activity and normal glucose and insulin levels, we did not detect any changes which could be an indication of metabolic disruption through adipogenesis or endocrine pancreas function by developmental exposure to DEHP. Our findings do not support the results of a recent meta-analysis ( 14 ) which showed that early life exposure to DEHP is significantly associated with increased fat weight, but not body weight. It should be noted, however, that the authors judged the quality of evidence for body weight and fat weight to be low due to concerns regarding risk of bias and unexplained inconsistency (i.e., substantial heterogeneity).…”

Section: Discussioncontrasting

confidence: 99%

“…The first line of evidence that developmental exposure to DEHP may promote metabolic disorders was the increases in serum cholesterol (CHOL), triglycerides (TGs) and glucose reported in multiple studies ( 11 – 13 ). Recently, Wassenaar and Legler ( 14 ) conducted a systematic review and meta-analysis of experimental rodent studies with DEHP, and reported a statistically significant positive association between developmental exposure to DEHP and increased fat pad weight. However, further associations with triglycerides, free fatty acids (FFA) and leptin could not be analyzed due to few or no data available.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Lipid Metabolism, Immune Function, and Neurobehavior in Adult C57BL/6JxFVB Mice After Developmental Exposure to di (2-ethylhexyl) Phthalate

et al. 2018

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Background: Developmental exposure to di (2-ethylhexyl) phthalate (DEHP) has been implicated in the onset of metabolic syndrome later in life. Alterations in neurobehavior and immune functions are also affected by phthalate exposure and may be linked to the metabolic changes caused by developmental exposure to DEHP.Objectives: Our goal was to study the effects of developmental exposure to DEHP in the context of metabolic syndrome by integrating different parameters to assess metabolic, neurobehavioral, and immune functions in one model.Methods: Female C57BL/6J mice were exposed to DEHP through the diet during gestation and lactation at doses ranging from 3.3 to 100,000 μg/kg body weight/day (μkd). During a 1-year follow-up period, a wide set of metabolic parameters was assessed in the F1 offspring, including weekly body weight measurements, food consumption, physical activity, glucose homeostasis, serum lipids, and endocrine profile. In addition, neurobehavioral and immune functions were assessed by sweet preference test, object recognition test, acute phase protein, and cytokines production. Animals were challenged with a high fat diet (HFD) in the last 9 weeks of the study.Results: Increased free fatty acids (FFA) and, high density lipoprotein (HDL-C) were observed in serum, together with a decrease in glycated hemoglobin levels in blood of 1-year old male DEHP-exposed offspring after HFD challenge. For the most sensitive endpoint measured (FFA), a lower bound of the 90%-confidence interval for benchmark dose (BMD) at a critical effect size of 5% (BMDL) of 2,160 μkd was calculated. No persistent changes in body weight or fat mass were observed. At 33,000 μkd altered performance was found in the object recognition test in males and changes in interferon (IFN)γ production were observed in females.Conclusions: Developmental exposure to DEHP combined with HFD in adulthood led to changes in lipid metabolism and neurobehavior in male offspring and cytokine production in female offspring. Our findings contribute to the evidence that DEHP is a developmental dyslipidemic chemical, however, more research is needed to further characterize adverse health outcomes and the mechanisms of action associated with the observed sex-specific effects.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Analysis of Lipid Metabolism, Immune Function, and Neurobehavior in Adult C57BL/6JxFVB Mice After Developmental Exposure to di (2-ethylhexyl) Phthalate

et al. 2018

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“…A recent meta-analysis of developmental DEHP exposure in animal studies also indicated that early life phthalate exposures results in increased fat weight. 59 Absolute pancreas weights were increased in mice perinatally exposed to DEHP + DINP + DBP compared with controls, but this difference was mitigated when comparing pancreas weights relative to body weight, and therefore the increased pancreas weights might have been due to the modest increased body weights observed in DEHP + DINP + DBP-exposed females. Decreased relative brain weights were observed in females exposed to a mixture of all three phthalates, and to a lesser degree of significance in males exposed to all three phthalates.…”

Section: Discussionmentioning

confidence: 98%

“…This observation is consistent with the theory that phthalate exposure increases the risk of obesity, and indicates that a mixture of HMW and LMW phthalates have the largest impact on body fat at PND21, with females being more sensitive than males. A recent meta-analysis of developmental DEHP exposure in animal studies also indicated that early life phthalate exposures results in increased fat weight 59 . Absolute pancreas weights were increased in mice perinatally exposed to DEHP+DINP+DBP compared with controls, but this difference was mitigated when comparing pancreas weights relative to body weight, and therefore the increased pancreas weights might have been due to the modest increased body weights observed in DEHP+DINP+DBP-exposed females.…”

Section: Discussionmentioning

confidence: 99%

Perinatal exposures to phthalates and phthalate mixtures result in sex-specific effects on body weight, organ weights and intracisternal A-particle (IAP) DNA methylation in weanling mice

Neier

Cheatham

Bedrosian

et al. 2018

J Dev Orig Health Dis

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Developmental exposure to phthalates has been implicated as a risk for obesity; however, epidemiological studies have yielded conflicting results and mechanisms are poorly understood. An additional layer of complexity in epidemiological studies is that humans are exposed to mixtures of many different phthalates. Here, we utilize an established mouse model of perinatal exposure to investigate the effects of three phthalates, diethylhexyl phthalate (DEHP), diisononyl phthalate (DINP) and dibutyl phthalate (DBP), on body weight and organ weights in weanling mice. In addition to individual phthalate exposures, we employed two mixture exposures: DEHP+DINP and DEHP+DINP+DBP. Phthalates were administered through phytoestrogen-free chow at the following exposure levels: 25 mg DEHP/kg chow, 25 mg DBP/kg chow and 75 mg DINP/kg chow. The viable yellow agouti (A vy ) mouse strain, along with measurement of tail DNA methylation, was used as a biosensor to examine effects of phthalates and phthalate mixtures on the DNA methylome. We found that female and male mice perinatally exposed to DINP alone had increased body weights at postnatal day 21 (PND21), and that exposure to mixtures did not exaggerate these effects. Females exposed to DINP and DEHP+DINP had increased relative liver weights at PND21, and females exposed to a mixture of DEHP+DINP+DBP had increased relative gonadal fat weight. Phthalate-exposed A vy /a offspring exhibited altered coat color distributions and altered DNA methylation at intracisternal A-particles (IAPs), repetitive elements in the mouse genome. These findings provide evidence that developmental exposures to phthalates influence body weight and organ weight changes in early life, and are associated with altered DNA methylation at IAPs.

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“…Moreover, chronic exposure to DEHP induced significant genotoxicity via kinds of pathways to reverse effects including the potential carcinogenic mechanism and potential adverse health outcomes [32,33]. However, researches proved that long-term exposure to DEHP in early life related to obesity and neuro-behavior and reproductive outcomes [34,35]. Previous researches proved that the toxicity of DEHP in parents can be transferred to offspring and thus affect the development and growth of animals [36].…”

Section: Introductionmentioning

confidence: 99%

DEHP chronic exposure disturbs the gut microbial community and metabolic homeostasis: Gender-based differences in zebrafish

Pei

Jia

Xin

et al. 2020

Preprint

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Background: Di-(2-ethylhexyl) phthalate (DEHP), a predominant phthalate ester (PAE), exhibits various toxic potentials with environmental and human health risks. However, the chronic effects of DEHP exposure on gut microbiota and associated host’s health are still largely unexplored. Here, zebrafish were exposed to relative environmental levels (0-100 μg/L) of DEHP from embryos to adult (3.5 months), then the developmental indexes and microbiota as well as the related energy metabolites in gut tissues were checked to unveil the effects during the growth progress. Results: The results indicated that the composition of gut microbiota was different among male and female adult zebrafish, and DEHP disrupted the diversity and richness of the bacterial community. The histopathological analysis of intestinal tissues revealed the decrease of villus length and tunica muscularis thickness, especially the goblet cells per villi in male fish. Moreover, energy metabolites in gut tissues were actively increased at lower levels groups, which probably contribute to the condition factor of host. For immune-related genes, the expression levels of il-8 was increased both in female and male fish in the lowest concentration (10 μg/L), but the tlr-5 and il-1β genes were in the different response with significantly decreased in female fish. Conclusion: Taken all together, those results indicated that chronic exposure to DEHP led to zebrafish obesity with the disturbed bacterial community in the gut and related metabolism pathways. Those findings provided deep insights on the perturbation of gut microbiota, metabolic homeostasis, and gender-based differences by DEHP exposure.

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Systematic review and meta-analysis of early life exposure to di(2-ethylhexyl) phthalate and obesity related outcomes in rodents

Abstract: The results of this systematic review indicate that early life exposure to DEHP is potentially associated with increased adiposity in rodents. More data is needed to strengthen the evidence base.

Cited by 56 publications

References 17 publications

Analysis of Lipid Metabolism, Immune Function, and Neurobehavior in Adult C57BL/6JxFVB Mice After Developmental Exposure to di (2-ethylhexyl) Phthalate

Analysis of Lipid Metabolism, Immune Function, and Neurobehavior in Adult C57BL/6JxFVB Mice After Developmental Exposure to di (2-ethylhexyl) Phthalate

Perinatal exposures to phthalates and phthalate mixtures result in sex-specific effects on body weight, organ weights and intracisternal A-particle (IAP) DNA methylation in weanling mice

DEHP chronic exposure disturbs the gut microbial community and metabolic homeostasis: Gender-based differences in zebrafish

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