Phthalate Exposure During the Prenatal and Lactational Period Increases the Susceptibility to Rheumatoid Arthritis in Mice.

Elena Elter,Marita Wagner,Mario Bauer,Lisa Buchenauer,Tobias Polte

doi:10.3389/fimmu.2020.00550

Elena Elter, Marita Wagner + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2020.00550

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Abstract

The prenatal and early postnatal period is highly sensitive to environmental exposures that may interfere with the developmental programming of the immune system leading to an altered disease risk in later life. To clarify the role of early influences in activation or exacerbation of autoimmune diseases like rheumatoid arthritis (RA) we investigated the effect of maternal exposure during the prenatal and lactational period of DBA/1 mice to the plasticizer benzyl butyl phthalate (BBP) on the development of RA in the offspring. Using a mild collagen-induced arthritis (CIA) model, maternal BBP-exposure increased both the prevalence and the severity of RA in the progeny compared to un-exposed dams. Additionally, maternal BBP exposure led to elevated serum IgG1 and IgG2a level in the offspring and increased the IFN-γ and IL-17 release from collagen-re-stimulated spleen cells. Transcriptome analysis of splenocytes isolated from 3-week-old pups before RA-induction revealed considerable changes in gene expression in the offspring from BBP-exposed dams. Among them were regulator of G-protein signaling 1 (rgs1), interleukin-7 receptor (il-7r) and CXC chemokine 4 (cxcr4), all genes that have previously been described as associated with RA pathology. In summary, our results demonstrate that perinatal exposure to BBP increases the susceptibility of the offspring to RA, probably via a phthalate-induced disturbed regulation of RA-relevant genes or signaling pathways.

Highlights

Environmental influences have been shown to play a crucial role in the development of various diseases like allergic asthma, cancer, or metabolic diseases [1, 2]
In recent years phthalates have been associated with an increased prevalence of diseases like obesity and allergies or shown to affect the cardiovascular and reproductive system [10, 11, 32]
We show that perinatal exposure to benzyl butyl phthalate (BBP) increased both the rheumatoid arthritis (RA) prevalence and the clinical severity in the offspring

Summary

Introduction

Environmental influences have been shown to play a crucial role in the development of various diseases like allergic asthma, cancer, or metabolic diseases [1, 2]. External factors such as chemicals, pathogens or stress may act as drivers of the individual’s risk to develop disease and as triggers of underlying genetic predispositions [3]. In the present study we focused on phthalates, namely n-benzyl butyl phthalate, a representative of a group of chemicals commonly used as plasticizers in large quantities worldwide This chemical is present in a wide range of consumer products like food packaging and plastics [6, 7].

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