leptin and 2-2--4-4--tetrahydroxybenzophenone

The tetrahydroxylated biphenyl-ketone 2,2',4,4'-tetrahydroxybenzophenone (BP2), one of twelve benzophenone-derived UV-filters, is used in cosmetic products and in packaging materials to protect these products from light induced damage. Recently published studies showed that BP2 exerts estrogenic activity; thus, it is an endocrine active chemical. We present data from a pharmacodynamic dose-response experiment with five dosages of BP2 applied per gavage to adult ovariectomized (ovx) rats for 5 days. Estradiol-valerate (E2) served as a control compound. The uterotrophic assay, proposed by the OECD, was modified to have a broader view on endocrine activity outside the urogenital tract to prevent that undesirable actions in other organs regulated by estrogens are missed. The gene expression levels of marker genes of estrogenic action were measured by semi-quantitative RT-PCR. Metabolic parameters were assessed by determination of the serum concentrations of leptin, cholesterol, high- and low-density lipoproteins, and triglycerides in the serum. Administration of BP2 at dosages of 10-1,000 mg/kg bodyweight led to changes of these parameters comparable to the changes in the E2 group with 0.6 mg/kg bodyweight. For the observed estrogenic activities of BP2, the "no observed adverse effect levels" were determined. Additionally, the data were further analyzed using the benchmark approach. If BP2 is transcutaneously absorbed in the human, the obtained threshold values would suggest refraining from the further use of BP2 as UV-filter in cosmetic products although additional toxicological studies should be conducted to clarify possible adverse effects.

Topics: Animals; Benzophenones; Complement C3; Dose-Response Relationship, Drug; Estrogen Receptor beta; Estrogens; Female; Gene Expression Regulation; Glycoprotein Hormones, alpha Subunit; Humans; Insulin-Like Growth Factor I; Leptin; Lipids; Liver; Luteinizing Hormone, beta Subunit; No-Observed-Adverse-Effect Level; Organ Size; Ovariectomy; Pituitary Gland; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Risk Assessment; RNA, Messenger; Sunscreening Agents; Uterus

The endocrine active substances BPA, DBP and BP2 have estrogenic effects in the uterus. Proc and Lin were shown to be antiandrogenic. Whether other estrogen-regulated parameters like lipids, fat metabolism and hormones are also affected by these substances is unknown. We compared the effects of a 3 months lasting administration of these substances with those of E2 on an estrogen-regulated fat depot and on serum TSH, T3, T4, LH, and lipid concentrations. BP2 shared many of the effects of E2 by suppressing LH, cholesterol, LDL, HDL and the size of a small estrogen-regulated fat depot in the lower hindleg. BP2 suppressed T4 but not T3 and TSH. The effects of DBP and BPA were mostly negligible whereas Lin and Proc also reduced the fat depot and serum leptin but increased triglycerides and serum lipids. Serum T3 and T4 concentrations were reduced by Lin and Proc. These data indicate that BP2 has similar, though slightly weaker effects as E2 whereas the effects of Proc and Lin differ from those of E2 on serum lipids and hormones. BP2 can be regarded as an estrogenic endocrine active substance whereas the effects of Lin and Proc appear not to involve estrogen receptors.

Topics: Adipose Tissue; Animals; Benzhydryl Compounds; Benzophenones; Bridged Bicyclo Compounds; Dibutyl Phthalate; Estradiol; Estrogens, Non-Steroidal; Female; Hormone Antagonists; Hormones; Leptin; Linuron; Lipids; Luteinizing Hormone; Ovariectomy; Phenols; Rats; Rats, Sprague-Dawley; Thyrotropin; Thyroxine; Triiodothyronine