Region-specific growth effects in the developing rat prostate following fetal exposure to estrogenic ultraviolet filters.

Exposure to environmental endocrine disruptors is a potential risk factor for humans. With the increasing use of ultraviolet (UV) filters in sunscreens and cosmetics and as additives in plastics and household products, their possible environmental impact deserves consideration. UV filters may be directly introduced into surface waters during swimming or they may enter wastewater from households or industry. There is good evidence that pharmaceuticals and ingredients of personal care products can spread into the biosphere and reach the food chain: UV filters are present in water downstream of sewage treatment plants (Kupper et al. 2006; Plagellat et al. 2006) in surface waters (Buser et al. 2005, 2006), and they bioaccumulate in fish (Balmer et al. 2005, Buser et al. 2006; Nagtegaal et al. 1997). In a recent monitoring study, UV filters were found in 75% of human milk samples (Schlumpf et al. 2008), indicating potential exposure of newborns. Certain UV filters have been shown to exhibit estrogenic activity in both in vitro and in vivo assays (Schlumpf et al. 2001, 2004a), and they have also shown developmental toxicity (Durrer et al. 2005, 2007; Maerkel et al. 2007). In vitro studies showed that 4-methyl-benzylidene camphor (4-MBC) and 3-benzylidene camphor (3-BC), are estrogen receptor (ER)-β ligands (Schlumpf et al. 2004a), but they are also active in ER-α–typical in vivo tests such as the uterotrophic assay (Schlumpf et al. 2001, 2004a). Many endocrine-active xenobiotics affect normal cellular and developmental processes in animal models, with the prostate being one sensitive target (Timms et al. 2005; vom Saal et al. 1997). These effects can be seen in both the juvenile and adult stages of growth in the prostate. Developmental exposure to 4-MBC and 3-BC affects prostate weight and estrogen target gene expression, in addition to effects on other targets such as brain, uterus, and thyroid (Durrer et al. 2005, 2007; Maerkel et al. 2007; Schlumpf et al. 2004b). Although fetal prostate development is primarily regulated by androgens (Siiteri and Wilson 1974), addition of exogenous estrogens during critical periods of growth has the potential to alter the development of the prostate (Richter et al. 2007; Timms et al. 2005; vom Saal et al. 1997). Growth responses to estrogen and estrogen mimics are variable and depend on dose and timing of treatment. Low-level exposure to estrogenic compounds administered during fetal development results in a region-specific proliferative growth response (Timms et al. 2005; vom Saal et al. 1997). Conversely, postnatal treatment with higher doses of estrogen has an inhibitory effect on growth (Huang et al. 2005; Prins and Korach 2007; Timms et al. 2005). In the present study we investigated the effects of 4-MBC and 3-BC on the developing prostate in the fetal rat. This experiment was designed, as previously described (Durrer et al. 2005, 2007; Maerkel et al. 2007), to examine the effects caused by systemic, low-dose exposure throughout in utero development. We administered 4-MBC and 3-BC at two dose levels, corresponding to previously published classical lowest observed adverse effect level (LOAEL) and classical no observed adverse effect level (NOAEL)/molecular LOAEL, respectively (Durrer et al. 2005, 2007; Maerkel et al. 2007; Schlumpf et al. 2008). Our data support the hypothesis that exposure to low doses of environmentally relevant endocrine disruptors during early prostate development alters normal growth patterns and extends the range of active chemicals to UV filters used in cosmetics.