Di-(2-ethylhexyl) phthalate induces production of inflammatory molecules in human macrophages

Nishioka, Junko; Iwahara, Chihiro; Kawasaki, Mikiko; Yoshizaki, Fumiko; Nakayama, Hitoshi; Takamori, Kenji; Ogawa, Hideoki; Iwabuchi, Kazuhisa

doi:10.1007/s00011-011-0390-x

Cited by 98 publications

(59 citation statements)

References 43 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition, KC/GRO has been hypothesized to be involved in germ cell proliferation, due to its role as a growth stimulator in certain cells such as human umbilical vein endothelial cells and melanocytes (Aubry et al 2000). Consistent with the current study, short term DEHP exposure (3 hours) has been shown to upregulate gene expression of KC in human macrophage-like THP-1 cells in vitro (Nishioka et al 2012). Similarly, 3 hours after DBP exposure (500mg/kg), Johnson, et al observed increased KC gene expression in rat testis in vivo (Johnson et al 2007).…”

Section: Discussionsupporting

confidence: 90%

The presence of macrophages and inflammatory responses in an in vitro testicular co-culture model of male reproductive development enhance relevance to in vivo conditions

Harris

Shubin

Wegner

et al. 2016

Toxicology in Vitro

View full text Add to dashboard Cite

Our 3-dimensional testis co-culture system (3D-TCS) represents a promising model of male reproductive toxicity which captures sensitive processes of male reproductive development and contains the main testes cell types (germ, Leydig and Sertoli cells). Macrophages are another cell type important for testicular function and help to modulate immuno-endocrine processes during testes development. Chemicals such as phthalate esters (PE’s) affect macrophage function and testosterone production in the testes in vivo. The aim of this study was to determine whether macrophages were present in the 3D-TCS and investigate responses in our model that may be related to immuno-endocrine functions. We observed consistent expression of the resident macrophage marker ED2 as well as increases in inflammatory cytokines produced by macrophages and testes cells (IL-6, TNF-α and KC/GRO) after exposure to toxic PE’s. Pathway analysis of gene expression changes after exposure to PE’s showed that IL-6 and TNF-α signaling pathways were enriched after treatment with reproductively toxic, but not non-reproductively toxic phthalates. These results indicate that macrophages and inflammatory processes are captured in the 3D-TCS and that these processes are impacted by exposure to reproductive toxicants. These processes represent a major mode of action for in vivo testis toxicity for a variety of compounds and our novel in vitro model is able to capture toxicant perturbation of immune function.

show abstract

Section: Discussionsupporting

confidence: 90%

The presence of macrophages and inflammatory responses in an in vitro testicular co-culture model of male reproductive development enhance relevance to in vivo conditions

Harris

Shubin

Wegner

et al. 2016

Toxicology in Vitro

View full text Add to dashboard Cite

show abstract

“…These markers are associated with antigen processing and presentation and cytokine–cytokine receptor interaction in immune cells. Similar increases in inflammatory marker expression have been reported after DEHP and MEHP treatment in different monocyte/macrophage models, such as the macrophage RAW264.7 cell line, 37 human acute monocytic leukemia THP-1 cell line 38 and rat alveolar macrophages. 39 Moreover, MEHP increases IL-5 and IL-10 levels in cultures of local lymph node cells, suggesting that phthalates activate the adaptive immune system.…”

Section: Discussionsupporting

confidence: 77%

In utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate promotes local adipose and systemic inflammation in adult male offspring

2014

View full text Add to dashboard Cite

Background:Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer used to increase the flexibility of polyvinyl chloride. DEHP and its active metabolite mono-(2-ethylhexyl) phthalate are detected in many biological fluids during fetal and postnatal life. In rodent models, in utero DEHP exposure has been shown to alter sexual organ development, decrease testosterone and aldosterone production, increase body and epididymal adipose tissue weight, and raise serum lipids and glucose levels in male offspring.Objectives:The objective of this study is to characterize the effects of in utero DEHP exposure on adipose tissue development and function in male offspring.Methods:Sprague–Dawley pregnant dams were gavaged 1, 20, 50 or 300 mg DEHP per kg per day from gestational day 14 until birth.Results:Global gene expression analyses of postnatal day 60 male offspring that were exposed in utero to 300 mg DEHP per kg per day revealed increased expression of immune response and inflammation markers, and increased expression of differentiation pathway genes in the epididymal whole-adipose tissue and isolated stromal vascular fraction. C-reactive protein and tumor necrosis factor (TNF) serum levels were increased in the 300 mg DEHP in utero-exposed offspring. TNF levels in adipose tissue homogenates were increased in the 50 and 300 mg DEHP in utero-exposed offspring. Immunofluorescence studies revealed focal macrophage infiltration in whole-adipose tissue confirmed by increased CD163 tissue content.Conclusions:In utero DEHP exposure promotes local adipose tissue inflammation and chronic low-grade systemic inflammation. Moreover, evidence is presented, suggesting that DEHP increases the differentiation capacity of the pre-adipocytes of male offspring without affecting total body weight.

show abstract

“…Some phthalates have also been shown to induce proinflammatory cytokine release in cell lines (Jepsen et al 2004; Nishioka et al 2012) and have been linked to increased systemic levels of inflammatory markers such as C-reactive protein in humans (Ferguson et al 2011). Our data support this mechanism, as for spontaneous preterm births we saw the strongest associations with phthalate metabolites measured in third trimester urine samples.…”

Section: Discussionmentioning

confidence: 99%

Variability in urinary phthalate metabolite levels across pregnancy and sensitive windows of exposure for the risk of preterm birth

Ferguson

McElrath

et al. 2014

Environment International

200

167

View full text Add to dashboard Cite

Background Preterm birth is a significant public health problem, affecting over 1 in 10 live births and contributing largely to infant mortality and morbidity. Everyday exposure to environmental chemicals such as phthalates could contribute, and may be modifiable. In the present study we examine variability in phthalate exposure across gestation and identify windows of susceptibility for the relationship with preterm birth. Methods Women were recruited early in pregnancy as part of a prospective, longitudinal birth cohort at the Brigham and Women’s Hospital in Boston, Massachusetts. Urine samples were collected at up to 4 time points during gestation for phthalate measurement, and birth outcomes were recorded at delivery. From this population we selected all 130 cases of preterm birth, defined as delivery before 37 weeks completed gestation, as well as 352 random controls. Results Urinary phthalate metabolite levels were moderately variable over pregnancy, but levels measured at multiple time points were associated with increased odds of preterm birth. Adjusted odds ratios (aOR) for spontaneous preterm birth were strongest in association with phthalate metabolite concentrations measured at the beginning of the third trimester (aOR for summed di-2-ethylhexyl phthalate metabolites [∑DEHP]=1.33, 95% confidence interval [CI]=1.02, 1.73). Odds ratios for placental preterm birth, defined as delivery with presentation of preeclampsia or intrauterine growth restriction, were slightly elevated in the first trimester for DEHP metabolites (aOR for ∑DEHP=1.33, 95% CI=0.99, 1.78). Conclusions Pregnant women with exposure to phthalates both early and late in pregnancy are at increased risk of delivering preterm, but mechanisms may differ based on etiology.

show abstract

Di-(2-ethylhexyl) phthalate induces production of inflammatory molecules in human macrophages

Abstract: DEHP enhances the production of inflammatory cytokines and chemokines by macrophages, and exacerbates their inflammatory response.

Cited by 98 publications

References 43 publications

The presence of macrophages and inflammatory responses in an in vitro testicular co-culture model of male reproductive development enhance relevance to in vivo conditions

The presence of macrophages and inflammatory responses in an in vitro testicular co-culture model of male reproductive development enhance relevance to in vivo conditions

In utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate promotes local adipose and systemic inflammation in adult male offspring

Variability in urinary phthalate metabolite levels across pregnancy and sensitive windows of exposure for the risk of preterm birth

Contact Info

Product

Resources

About