Hepatotoxicity caused by methylparaben in adult zebrafish

Sterol regulatory element binding proteins (SREBPs) are a family of transcription factors that regulate lipid homeostasis by controlling the expression of a range of enzymes required for endogenous cholesterol, fatty acid (FA), triacylglycerol and phospholipid synthesis. The three SREBP isoforms, SREBP-1a, SREBP-1c and SREBP-2, have different roles in lipid synthesis. In vivo studies using transgenic and knockout mice suggest that SREBP-1c is involved in FA synthesis and insulin induced glucose metabolism (particularly in lipogenesis), whereas SREBP-2 is relatively specific to cholesterol synthesis. The SREBP-1a isoform seems to be implicated in both pathways. SREBP transcription factors are synthetized as inactive precursors bound to the endoplasmic reticulum (ER) membranes. Upon activation, the precursor undergoes a sequential two-step cleavage process to release the NH(2)-terminal active domain in the nucleus (designated nSREBPs). SREBP processing is mainly controlled by cellular sterol content. When sterol levels decrease, the precursor is cleaved to activate cholesterogenic genes and maintain cholesterol homeostasis. This sterol-sensitive process appears to be a major point of regulation for the SREBP-1a and SREBP-2 isoforms but not for SREBP-1c. Moreover, the SREBP-1c isoform seems to be mainly regulated at the transcriptional level by insulin. The unique regulation and activation properties of each SREBP isoform facilitate the co-ordinate regulation of lipid metabolism; however, further studies are needed to understand the detailed regulation pathways that specifically regulate each SREBP isoform.

Parabens are widely used as preservatives in food, cosmetic and pharmaceutical products. Acute, subchronic, and chronic studies in rodents indicate that parabens are practically non-toxic. Parabens are rapidly absorbed, metabolized, and excreted. In individuals with normal skin, parabens are, for the most part, non-irritating and non-sensitizing. However, application of compounds containing parabens to damaged or broken skin has resulted in sensitization. Genotoxicity testing of parabens in a variety of in vitro and in vivo studies primarily gave negative results. The paraben structure is not indicative of carcinogenic potential, and experimental studies support these observations. Some animal studies have reported adverse reproductive effects of parabens. In an uterotrophic assay, methyl and butyl paraben administered orally to immature rats were inactive, while subcutaneous administration of butyl paraben produced a weak positive response. The ability of parabens to transactivate the estrogen receptor in vitro increases with alkyl group size. The detection of parabens in a small number of breast tumor tissue samples and adverse reproductive effects of parabens in animals has provoked controversy over the continued use of these substances. However, the possible estrogenic hazard of parabens on the basis of the available studies is equivocal, and fails to consider the metabolism and elimination rates of parabens, which are dose, route, and species dependent. In light of the recent controversy over the estrogenic potential of parabens, conduct of a reproductive toxicity study may be warranted.