Effect of Gestational and Lactational Exposure to DEHP, DINP, and DEP on Intestinal Morphology, Disaccharidases, and Alkaline Phosphatase in Rats during Postnatal Development

Ahmed, Khaled S.; Kharoubi, Omar; Aoues, Abdelkader; Bouchekara, Mohamed; Khaladi, B.; Taleb, Mohammed

doi:10.1055/s-0038-1642027

Cited by 11 publications

(11 citation statements)

References 44 publications

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“…In a gestational exposure study in Sprague-Dawley rats, Howdeshell et al (2008) reported a statistically significant increase in resorptions and fetal mortality at 600 mg/kg-day DEP, but this effect was not observed in any other higher or lower DEP dose groups and thus did not appear to be treatment-related. Otherwise, in the rat two-generation study and in the remaining gestational exposure studies in rats, mice, and rabbits, there were no effects on the number of implantations or resorptions ( Fujii et al 2005 ; NTP 1988 ; Procter & Gamble 1994 ), viability of fetuses ( Furr et al 2014 ; NTP 1988 ; Procter & Gamble 1994 ), or viability of pups at birth ( Fujii et al 2005 ; Gray et al 2000 ; Hardin et al 1987 ; Setti Ahmed et al 2018 ). There was no effect on offspring sex ratio in any of the studies that assessed this endpoint, which included studies in rats, mice, and rabbits ( Fujii et al 2005 ; NTP 1988 ; Procter & Gamble 1994 ; RTI International 1984 ).…”

Section: Resultsmentioning

confidence: 88%

“…NTP (1988) and Procter & Gamble (1994) evaluated fetal survival, growth, and structural alterations in rats and rabbits following exposure from GD 6–15 and 6–18, respectively. Setti Ahmed et al (2018) evaluated intestinal morphology and organ weight changes in rats exposed from GD 8 – PND 30. Most of these developmental exposure studies also provided relevant data on maternal reproductive endpoints (e.g.…”

Section: Resultsmentioning

confidence: 99%

“…Four studies evaluated fetal survival following gestational exposure to DEP ( Furr et al 2014 ; Howdeshell et al 2008 ; NTP 1988 ; Procter & Gamble 1994 ), and five studies evaluated the number of live pups at birth following gestational ( Gray et al. 2000 ; Hardin et al 1987 ; Setti Ahmed et al 2018 ) or multigenerational ( Fujii et al 2005 ; RTI International 1984 ) exposure to DEP. Of these, only the continuous breeding study in CD-1 mice ( RTI International 1984 ) observed a dose-related effect.…”

Section: Resultsmentioning

confidence: 99%

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Hazards of diethyl phthalate (DEP) exposure: A systematic review of animal toxicology studies

Weaver

Beverly

Keshava

et al. 2020

Environment International

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Background: Diethyl phthalate (DEP) is widely used in many commercially available products including plastics and personal care products. DEP has generally not been found to share the antiandrogenic mode of action that is common among other types of phthalates, but there is emerging evidence that DEP may be associated with other types of health effects. Objective: To inform chemical risk assessment, we performed a systematic review to identify and characterize outcomes within six broad hazard categories (male reproductive, female reproductive, developmental, liver, kidney, and cancer) following exposure of nonhuman mammalian animals to DEP or its primary metabolite, monoethyl phthalate (MEP). Methods: A literature search was conducted in online scientific databases (PubMed, Web of Science, Toxline, Toxcenter) and Toxic Substances Control Act Submissions, augmented by review of online regulatory sources as well as forward and backward searches. Studies were selected for inclusion using PECO (Population, Exposure, Comparator, Outcome) criteria. Studies were evaluated using criteria defined a priori for reporting quality, risk of bias, and sensitivity using a domain-based approach. Evidence was synthesized by outcome and life stage of exposure, and strength of evidence was summarized into categories of robust , moderate , slight , indeterminate , or compelling evidence of no effect , using a structured framework. Results: Thirty-four experimental studies in animals were included in this analysis. Although no effects on androgen-dependent male reproductive development were observed following gestational exposure to DEP, there was evidence including effects on sperm following peripubertal and adult exposures, and the overall evidence for male reproductive effects was considered moderate . There was moderate evidence that DEP exposure can lead to developmental effects, with the major effect being reduced postnatal growth following gestational or early postnatal exposure; this generally occurred at doses associated with maternal effects, consistent with the observation that DEP is not a potent developmental toxicant. The evidence for liver effects was considered moderate based on consistent changes in relative liver weight at higher dose levels; histopathological and biochemical changes indicative of hepatic effects were also observed, but primarily in studies that had significant concerns for risk of bias and sensitivity. The evidence for female reproductive effects was considered slight based on few reports of statistically significant effects on maternal body weight gain, organ weight changes, and pregnancy outcomes. Evidence for cancer and effects on kidney were judged to be...

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Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Hazards of diethyl phthalate (DEP) exposure: A systematic review of animal toxicology studies

Weaver

Beverly

Keshava

et al. 2020

Environment International

View full text Add to dashboard Cite

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“…Few studies have examined the impact of any phthalates on the gut, and even fewer studies have investigated the impact of DiNP on the gut. So far, only one other study has investigated the impact of DiNP on the gut, and this study reported that DiNP exposure at 380 mg/kg/day for 30 days resulted in villous atrophy in the small intestine during gestation and lactation of female rats 34 . Overall, data on how DiNP affects the gut are still scarce.…”

Section: Introductionmentioning

confidence: 99%

Subacute exposure to di-isononyl phthalate alters the morphology, endocrine function, and immune system in the colon of adult female mice

Bashir

Nowak

Mei

et al. 2020

Sci Rep

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Di-isononyl phthalate (DiNP), a common plasticizer used in polyvinyl chloride products, exhibits endocrine-disrupting capabilities. It is also toxic to the brain, reproductive system, liver, and kidney. However, little is known about how DiNP impacts the gastrointestinal tract (GIT). It is crucial to understand how DiNP exposure affects the GIT because humans are primarily exposed to DiNP through the GIT. Thus, this study tested the hypothesis that subacute exposure to DiNP dysregulates cellular, endocrine, and immunological aspects in the colon of adult female mice. To test this hypothesis, adult female mice were dosed with vehicle control or DiNP doses ranging from 0.02 to 200 mg/kg for 10–14 days. After the treatment period, mice were euthanized during diestrus, and colon tissue samples were subjected to morphological, biochemical, and hormone assays. DiNP exposure significantly increased histological damage in the colon compared to control. Exposure to DiNP also significantly decreased sICAM-1 levels, increased Tnf expression, decreased a cell cycle regulator (Ccnb1), and increased apoptotic factors (Aifm1 and Bcl2l10) in the colon compared to control. Colon-extracted lipids revealed that DiNP exposure significantly decreased estradiol levels compared to control. Collectively, these data indicate that subacute exposure to DiNP alters colon morphology and physiology in adult female mice.

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“…The toxicity assessment of PAEs showed their ability to affect immune and allergic responses, body weight, and intestinal development in experimental animals and in vitro (Kimber and Dearman, 2010;Ahmed et al, 2018). Previous reports highlighted that the utility and intestinal biology to functionally validate candidate genes identified through genome-wide association studies are significant to the zebrafish model (Zhao and Pack, 2017).…”

Section: Introductionmentioning

confidence: 99%

Disruption of Intestinal Homeostasis Through Altered Responses of the Microbial Community, Energy Metabolites, and Immune System in Zebrafish After Chronic Exposure to DEHP

et al. 2021

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Di-(2-ethylhexyl) phthalate (DEHP) is ubiquitously reported in global water bodies and exhibits various environmental and human health risks. However, the effects of DEHP chronic exposure on the intestinal microbiota and associated host health concerns in aquatic species are still largely unexplored. In this study, chronic exposure to DEHP at environmental levels significantly increased the body weight, length, and body mass index (BMI), especially in male fish. The microbial community was disrupted with the relative abundance of phylum Firmicutes and genera diversity for Prevotella-7, Deefgea, PeM15, Halomonas, Akkermansia, Chitinibacter, and Roseomonas, which are significantly activated in zebrafish after exposure to DEHP. The height of the gut villus, the thickness of muscularis layer, and the number of goblet cells per villus were significantly decreased, as well as showed differences between female and male zebrafish. Further, the levels of energy-related metabolites in gut tissues were increased, compared to the control group. The expression levels of immune-related genes (interleukin 8, il-8, also referred to as cxcl8a), microbial defense-related genes (lysozyme, lyz, interleukin 10, and il-10), and obesity-related genes (aquaporin 8a, aqp8, mucin 2.1, muc2.1, fibroblast growth factor 2, fgf2, and proopiomelanocortin a, pomca) were significantly up-regulated in zebrafish, except the down-regulated expressions of toll-like receptor-5 (tlr-5) and interleukin 1β (il-1β) in the females and pomca in the males, respectively. Importantly, Spearman’s correlation analyses revealed that the levels of metabolites and gene expressions in the gut were closely related to the dominant microbial genera, such as Aeromonas, Deefgea, Akkermansia, PeM15, Mycobacterium, and Rhodobacter. Taken together, chronic exposure to DEHP at environmental levels disturbed bacterial composition accompanied by the altered expressions of intestinal metabolites and the critical immune and intestinal function-related genes, which provided novel insights into DEHP effects on perturbation of gut microbiota and metabolic homeostasis in zebrafish.

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Effect of Gestational and Lactational Exposure to DEHP, DINP, and DEP on Intestinal Morphology, Disaccharidases, and Alkaline Phosphatase in Rats during Postnatal Development

Abstract: Our results suggest that exposure to phthalates during gestational and lactational phases negatively impacts the development of the small intestine.

Cited by 11 publications

References 44 publications

Hazards of diethyl phthalate (DEP) exposure: A systematic review of animal toxicology studies

Hazards of diethyl phthalate (DEP) exposure: A systematic review of animal toxicology studies

Subacute exposure to di-isononyl phthalate alters the morphology, endocrine function, and immune system in the colon of adult female mice

Disruption of Intestinal Homeostasis Through Altered Responses of the Microbial Community, Energy Metabolites, and Immune System in Zebrafish After Chronic Exposure to DEHP

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