Junpei Mutoh

Maternal Exposure to Dioxin Disrupts Gonadotropin Production in Fetal Rats and Imprints Defects in Sexual Behavior

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related substances are a class of environmental pollutants with suspected toxic effects on reproductive and developmental processes. This study investigated a hypothesis that maternal exposure to TCDD damages gonadotropin-regulated steroidogenesis in fetal gonads to imprint defects in sexual behavior as well as the maturation of gonadal tissues. Oral administration of 1 μg/kg TCDD to pregnant Wistar rats at gestational day (GD) 15 attenuated the expression of luteinizing hormone (LH), a regulator of gonadal steroidogenesis, in the pituitaries of male and female fetuses at GD20. TCDD treatment also reduced the fetal expression of testicular and ovarian steroidogenic proteins, including steroidogenic acute-regulatory protein. These changes in pituitary and gonadal proteins were fetus-specific, and this seems not to be because of the greater delivery of TCDD to the brain of fetuses than adults. This is because a reduction in LH production was not reproduced even although TCDD was administered intraventricularly to adult rats. Direct supplementation of equine chorionic gonadotropin (eCG), an LH-mimicking hormone, to TCDD-exposed fetuses at GD17 restored the reduced expression of gonadal steroidogenic proteins. Maternal exposure to TCDD delayed the development of gonadal tissues in male and female pups and impaired their sexual behavior. However, eCG treatment at the fetal stage again restored not only tissue maturation but also many of the behavioral defects that occurred at adulthood. These results demonstrate that TCDD disrupts steroidogenesis in fetuses by targeting pituitary gonadotropin production and imprints demasculinization in males and defeminization in females in terms of their copulatory behavior.

Proteasome affects the expression of aryl hydrocarbon receptor-regulated proteins

The effect of proteasome inhibition with N-acetyl-leucyl-leucyl-norleucinal (ALLN) on the protein expression regulated by aryl hydrocarbon receptor (AhR) was studied in T47D breast tumor cells. The luciferase reporter gene assay using a construct which has the xenobiotic responsive element showed that the inducible expression of the reporter with AhR ligands was significantly reduced by co-treatment with ALLN. The same suppressive effect by ALLN was observed for ethoxyresorufin O-deethylase (EROD) activity induced by an AhR ligand, 3-methylcholanthrene (3MC). Despite the above effects, the induced expression of CYP1A1 and CYP1B1 mRNAs was unaffected by ALLN. While lactacystin, another proteasome inhibitor, exhibited the same effect as ALLN on EROD activity induced by 3MC, leupeptin, which is one of the cysteine protease inhibitors, had no such effect. Based on the evidence obtained, it appears that proteasome inhibition results in a reduction in the expression of AhR-regulated proteins.