Lichtensteiger, W; Ceccatelli, R; Conscience, M; Cotton, B; Durrer, S; Faass, O; Fleischmann, I; Ma, R; Maerkel, K; Schlumpf, M
Introduction: Both, UV screens, used for UV absorbance in sunscreen products and many other cosmetic articles, and the flame retardants, polybrominated diphenyl ethers (PBDE), have recently been noticed for their increasing presence in environmental compartments and biosphere. It thus seemed important to analyze their potential biological activities more closely. Identification of endocrine activity: In an in vitro study on MCF7 cells, five out of six frequently used UV screens, i.e. benzophenone-3 (Bp-3), homosalate (HMS), 4-methylben- zylidene camphor (4-MBC), octyl-dimethyl-p-aminobenzoic acid (OD-PABA), and octylmethoxy cinnamate (OMC), displayed estrogenic activity. 4-MBC, OMC and Bp-3 were also orally active in vivo in the uterotrophic assay (M. Schlumpf et al., EHP 109, 239, 2001). The effects of 4-MBC in uterotrophic assay and MCF7 cells have been confirmed by H. Tinwell et al. (EHP 110 (2002) 533). In a further analysis of these UV screens on MDA-MB-453-KB2 cells expressing androgen receptor and luciferase reporter gene, we detected antiandrogenic activity for Bp-3 and HMS with IC50s at around 10 uM. Preliminary results from a pubertal rat model point to in vivo antiandrogenic activity of Bp-3, the compound studied so far. PBDE have been shown by I.A.T.M. Meerts et al. (EHP 109 (2001) 399) to possess estrogenic activity in vitro, with considerable differences between individual congeners. Developmental toxicity of 4-MBC: 4-MBC, the most active compound in the uterotrophic assay, was administered orally to male and female F0 Long Evans rats for at least 10 weeks prior to mating, during pregnancy and lactation and to F1 offspring until adulthood, in the chow at doses of 7, 24, 47 and 70 mg/kg/day. Even after prolonged exposure (12 months), adult F0 animals did not exhibit signs of adverse effects. In contrast, F1 offspring showed a dose-dependent reduction of survival rate (significant at greater than or equal to 24 mg/kg/day) during the first two postnatal weeks, and reductions of thymus weight and body weight on the day of birth (PN1). Male puberty (preputial separation) was delayed, testis weight was reduced at PN14, but increased in adult offspring (greater than or equal to 7 mg/kg/day). Additional organ weight changes were noted for epididymis, seminal vesicles and ventral prostate. Estrogen target gene expression patterns are being investigated by real time PCR in reproductive organs and brain regions. Preliminary data indicate changes in adult uterine progesterone receptor mRNA and ventral prostate IGF-I mRNA levels. Dynamics of gene regulation are presently studied in gonadectomized male and female F1 offspring following acute estrogen challenge. PBDE: Inspite of the absence of estrogenic (Meerts et al., 2001) or (anti)androgenic activity (tested onMDA-MB-453-KB2 cells), the first congener studied, PBDE99 (2,2',4,4',5-pentaBDE), affected sexual development, delaying female puberty (vaginal opening) when injected s.c. to time-pregnant Long Evans rats from gestational day 10 to 18 at 10 mg/kg/day, without affecting body weight. Ventral prostate weight of adult F1 offspring was increased and epididymis weight decreased at 1 mg/kg/day. The effect pattern differed from that of the PCB mixture Aroclor 1254 (10 or 30 mg/kg/day) used as positive control. Gene expression patterns are under investigation. Our data indicate that the two chemicals selected out of the groups of UV screens and PBDE, have the potential to interfere with the ontogeny of neuroendocrine systems, specifically the development of reproductive organs. Hence, these groups of chemicals should be studied thoroughly for their endocrine disruptor potential upon long term exposure.
