Structure-activity relationship of a series of 17 parabens and related compounds for histamine release in rat peritoneal mast cells and skin allergic reaction in guinea pigs

Abstract

-Parabens, which are a homologous series of esters of p-hydroxybenzoic acid, have been used as preservatives in cosmetics, medicines and foods because of their antimicrobial activity. However, parabens in cosmetics have been suspected to cause allergic contact dermatitis. In this study, we examined paraben-induced histamine release from rat peritoneal mast cells and skin reaction in guinea pigs using a series of 17 parabens with different alcohol side chains, ranging from methylparaben to dodecylparaben. Octylparaben showed the greatest histamine release-inducing activity from mast cells, and the activity was decreased in shorter-and longer-side-chain parabens. Octyl benzoate, octyl o-hydroxybenzoate and phenyloctane caused no significant degranulation of mast cells, whereas octyl m-hydroxybenzoate, octyl p-hydroxybenzoate and octyl phenol induced concentration-related degranulation. Metabolites of these parabens (p-hydroxybenzoic acid and alcohols) did not show histamine release-inducing activity. In the guinea pig skin reaction test, heptylparaben induced a typical strong skin reaction, while butylparaben induced a typical weak skin reaction, and methylparaben and dodecylparaben were inactive. Metabolites of parabens (p-hydroxybenzoic acid and alcohols) were also inactive. These results indicate that interaction of parabens with rat mast cells requires a minimum length and adequate lipophilicity of the alkyl side chain. Since metabolites of parabens were inactive, parabens appear to be direct-acting allergens.

Immune Cells in the Uterine Remodeling: Are They the Target of Endocrine Disrupting Chemicals?

“…This was not ER-mediated (174). In contrast, the structure of the specific paraben, used as preservatives in cosmetic, medicines and food, determines if the EDC enhance, inhibit, or do not have any influence on the histamine release of rat peritoneal MCs (175). During the embryo stage of zebrafish, the EDCs 17β-estradiol, 17-αethynyestradiol (EE2), permethrin, atrazine, and nonylphenol significantly change innate immune-related gene transcription.…”

Mast cells partially contribute to mucosal adjuvanticity of surfactin in mice

“…One major difference between SF and PMB chemical structures is the length of alkyl chain: 11 and 6–7 carbon atoms, respectively . Indeed, when the release of histamine from mast cells was induced by parabens with different alkyl chains, ranging from methylparaben to dodecylparaben, a complex relationship was observed between the extent of mast cell activation and the length of alkyl chain . Structural differences between SF and PMB likely explain higher adjuvanticity of SF mediated by mast cell activation.…”

Interplay Between Endocrine Disruptors and Immunity: Implications for Diseases of Autoreactive Etiology

“…Notably, dose ranges often fall within or surpass the doses at which activation of ERs has been described. For example, straight-chain parabens spanning from heptyl-to-decyl (low dose HP-DP, 2,360-2,780 μg/L) or pentyl-tododecyl (high dose PP-DDP, 20,800-30,600 μg/L) cause a significant release of histamine from degranulating mast cells (Uramaru et al, 2014). This is also sustained by exposure to the branched isopentyl paraben (IPP, 20,800 μg/L).…”

“…Nevertheless, clinical case reports identify anomalous serology characterized by both anti-paraben antibodies and paraben-associated auto anti-Jk a antibodies (Judd et al, 1982;Judd et al, 2001;Gniadek et al, 2018). Although characterization of paraben-specific IgE antibodies is limited by their half-life, sensitization with BP and HP followed by challenge produces a significant allergic reaction (Uramaru et al, 2014). This suggests that prior paraben priming is sufficient to generate recall upon antigen re-presentation and is a hallmark feature of adaptive immunity.…”