Adjuvant Effect of di‐n‐Butyl‐, di‐n‐Octyl‐, di‐iso‐Nonyl‐ and di‐iso‐Decyl Phthalate in a Subcutaneous Injection Model Using BALB/c Mice

Abstract

During the last decades, the prevalence of the allergic airway diseases, asthma and rhinitis, has increased worldwide. Introduction of environmental chemicals with adjuvant effect may play a role in this increase. In the present study, the adjuvant effects of di-n-butyl-, di-n-octyl-, di-iso-nonyl-and di-iso-decyl phthalate are studied in a screening model. Ovalbumin, used as the model antigen, was injected subcutaneously in the neck region of BALB/cJ mice with the selected phthalate in concentrations from 2-2000 mg/ml. Additionally, the mice were boosted once or twice with ovalbumin alone. Immunization with ovalbumin alone, the ovalbumin control group, served as the baseline for antibody production, whereas aluminium hydroxide served as the positive control. The levels of ovalbumin-specific IgE, IgG1 and IgG2a antibodies in sera were determined. Adjuvant effect was accepted to be present if a statistical increase in antibody production occurred in a test group as compared to an ovalbumin control group together with the fulfillment of dose-response relationships. Adjuvant effect varied strongly between the phthalates investigated. Phthalates with 8 or 9 carbon atoms in the alkyl side chains were the stronger adjuvants whereas phthalates with shorter or longer alkyl side chains possessed less adjuvant activity. Adjuvant effects were apparent either from the IgE or the IgG1 response or both, whereas no effect was seen on the IgG2a response. Additional studies with airborne exposure are required to establish whether the hazards also result in a significant risk for the development of allergy in man.

Low-dose exposure to di-(2-ethylhexyl) phthalate (DEHP) increases susceptibility to testicular autoimmunity in mice

“…In addition, exposure to MEHP decreases the inhibition of metalloproteinase-2 expression in testes tissue, which allows for matrix metalloproteinase 2 activation, leading to the remodeling of tight junctions between adjacent Sertoli cells [34]. On the other hand, many reports have also shown that while DEHP itself is not an immunogenic antigen, it can act as an adjuvant [4][5][6][7][8]. Here, we demonstrated that exposure to the low level of DEHP did not affect spermatogenesis, but caused functional damage to the BTB and induced the production of serum autoantibodies against TGC.…”

“…Di-(2-ethylhexyl) phthalate (DEHP) is widely used as a plastic plasticizer for synthetic polymers, and derived compounds constitute a group of xenobiotics that promote the development of an immune response [3]. While DEHP itself is not an immunogenic antigen, it can enhance immunogenic activity in mice, therefore, DEHP can also act as an adjuvant [4][5][6][7][8]. It was reported that exposure to DEHP causes testicular atrophy with spermatogenic disturbance (SD) in mice and rats [9][10][11][12][13][14].…”

Airway inflammation and adjuvant effect after repeated airborne exposures to di-(2-ethylhexyl)phthalate and ovalbumin in BALB/c mice

“…With respect to human exposures, the phthalate di-(2-ethylhexyl) phthalate (DEHP) is interesting, as DEHP accounts for approximately 50% of the total global phthalate consumption of about 3.5 million metric tonnes (Cadogan and Howick, 1996). Phthalates are not antigenic in themselves (Butala et al, 2004) but animal studies have shown that certain phthalate plasticizers are immuno-modulatory by increasing the immunogenicity of a co-administered antigen (Larsen et al, 2001(Larsen et al, , 2002. Among the phthalates studied, DEHP has proved to be one of the most potent enhancers of immune responses to simultaneously administered ovalbumin (OVA) (Larsen et al, 2002).…”

Enhancement of Interleukin-4 Production in Activated CD4+ T Cells by Diphthalate Plasticizers via Increased NF-AT Binding Activity

“…Phthalates are animal carcinogens and can cause fetal death, malformations, and reproductive toxicology in laboratory animals [4, 5]. Recently, it has become known that phthalates have an adjuvant effect, defined as an increase in IgE or IgG1 antibody level when injecting ovalbumin with phthalate into BALB/c mice [6, 7]. Toxicity profiles and potency, however, vary according to specific phthalates.…”