Durrer Stefan, Ehnes Colin, Fuetsch Michaela, Maerkel Kirsten, Schlumpf Margret, Lichtensteiger Walter
Institute of Pharmacology and Toxicology and GREEN Tox, University of Zurich, Zurich, Switzerland.
Environ Health Perspect. 2007 Dec;115 Suppl 1(Suppl 1):42-50. doi: 10.1289/ehp.9134.
In previous studies, we found that the ultraviolet filter 4-methyl-benzylidene camphor (4-MBC) exhibits estrogenic activity, is a preferential estrogen receptor (ER)-beta ligand, and interferes with development of female reproductive organs and brain of both sexes in rats. Here, we report effects on male development.
4-MBC (0.7, 7, 24, 47 mg/kg/day) was administered in chow to the parent generation before mating, during gestation and lactation, and to offspring until adulthood. mRNA was determined in prostate lobes by real-time reverse transcription-polymerase chain reaction and protein was determined by Western blot analysis.
4-MBC delayed male puberty, decreased adult prostate weight, and slightly increased testis weight. Androgen receptor (AR), insulin-like growth factor-1 (IGF-1), ER-alpha, and ER-beta expression in prostate were altered at mRNA and protein levels, with stronger effects in dorsolateral than ventral prostate. To assess sensitivity of target genes to estrogens, offspring were castrated on postnatal day 70, injected with 17beta-estradiol (E(2); 10 or 50 microg/kg, sc) or vehicle on postnatal day 84, and sacrificed 6 hr later. Acute repression of AR and IGF-1 mRNAs by E(2), studied in ventral prostate, was reduced by 4-MBC exposure. This was accompanied by reduced co-repressor N-CoR (nuclear receptor co-repressor) protein in ventral and dorsolateral prostate, whereas steroid receptor coactivator-1 (SRC-1) protein levels were unaffected.
Our data indicate that 4-MBC affects development of male reproductive functions and organs, with a lowest observed adverse effect level of 0.7 mg/kg. Nuclear receptor coregulators were revealed as targets for endocrine disruptors, as shown for N-CoR in prostate and SRC-1 in uterus. This may have widespread effects on gene regulation.
在先前的研究中，我们发现紫外线过滤剂4-甲基亚苄基樟脑（4-MBC）具有雌激素活性，是一种选择性雌激素受体（ER）-β配体，并且会干扰大鼠两性的雌性生殖器官和大脑发育。在此，我们报告其对雄性发育的影响。
在交配前、妊娠和哺乳期，给亲代喂食含4-MBC（0.7、7、24、47毫克/千克/天）的饲料，并给后代喂食直至成年。通过实时逆转录-聚合酶链反应测定前列腺叶中的mRNA，并通过蛋白质印迹分析测定蛋白质。
4-MBC延迟了雄性青春期，降低了成年前列腺重量，并使睾丸重量略有增加。前列腺中雄激素受体（AR）、胰岛素样生长因子-1（IGF-1）、ER-α和ER-β的表达在mRNA和蛋白质水平上均发生改变，背外侧前列腺的影响强于腹侧前列腺。为了评估靶基因对雌激素的敏感性，在出生后第70天对后代进行去势，在出生后第84天注射17β-雌二醇（E₂；10或50微克/千克，皮下注射）或溶剂，6小时后处死。在腹侧前列腺中研究发现，4-MBC暴露可降低E₂对AR和IGF-1 mRNA的急性抑制作用。这伴随着腹侧和背外侧前列腺中共同抑制因子N-CoR（核受体共同抑制因子）蛋白的减少，而类固醇受体共激活因子-1（SRC-1）蛋白水平未受影响。
我们的数据表明，4-MBC会影响雄性生殖功能和器官的发育，最低观察到的有害作用水平为0.7毫克/千克。核受体共调节因子被揭示为内分泌干扰物的作用靶点，如前列腺中的N-CoR和子宫中的SRC-1所示。这可能对基因调控产生广泛影响。
