The effects of ethyl and butyl paraben on steroidogenesis were evaluated in rats exposed in utero. Pregnant Wistar rats were dosed from gestational day (GD) 7 to GD 21, followed by examination of the dams, and the fetuses. Additionally, both parabens were tested in vitro in the H295R steroidogenesis assay and in the T-screen assay, the later to test for their ability to act as thyroid hormone receptor agonist or antagonist. In the in utero exposure toxicity study, neither ethyl nor butyl paraben showed any treatment-related effects on testosterone production, anogenital distance, or testicular histopathology. However, butyl paraben caused a significant decrease in the mRNA expression level of estradiol receptor-beta in fetal ovaries, and also significantly decreased the mRNA expression of steroidogenic acute regulatory protein and peripheral benzodiazepine receptor in the adrenal glands. In vitro butyl paraben increased the proliferation of the GH3 cells in the T-Screen assay, thereby acting as a weak thyroid hormone receptor agonist. In the adrenal H295R steroidogenesis assay both ethyl and butyl paraben caused a significant increase in the progesterone formation. Overall, the results indicate that butyl paraben might have the ability to act as endocrine disruptor by interfering with the transport of cholesterol to the mitochondrion, thereby interfering with steroidogenesis, but also that the two tested parabens do not show clear endocrine disrupting capabilities in our short-term in vivo experiment.

The sensitivity of juvenile brown trout towards estrogenic chemicals (17beta-estradiol [E2], estrone [E1], 17alpha-ethinylestradiol [EE2], 4-tert-octylphenol [OP], and n-butylparaben [BP]) was tested in laboratory experiments with plasma and liver vitellogenin concentrations as endpoints. Vitellogenin concentrations were also assessed in juvenile brown trout collected in streams affected by agricultural runoff and discharges from scattered houses in the open land. In the laboratory, juvenile brown trout were exposed to the chemicals in flow-through tanks for 7 to 12 d and concentration-response relationships for the induction of vitellogenin synthesis were obtained. The actual exposure concentrations were determined by liquid chromatography-mass spectrometry. The median plasma vitellogenin concentration in first year control brown trout reared in recirculated groundwater was 165 ng/ml with 783 ng/ml as the highest value. The median effective concentration (EC50) values for vitellogenin induction (based on plasma concentrations) were 3.7 ng EE2/L, 15 ng E2/L, 88 ng E1/L, 68 microg BP/L, and 7 microg OP/L. Median effective concentrations derived from liver vitellogenin concentrations were similar. The 166 brown trout caught in the field were mainly first and second year fish and a few third year fish. Plasma vitellogenin concentrations were below 1000 ng/L in 146 of the fish, between 1000 ng/L and 4234 ng/L in 19 fish and 5.3 x 10(6) ng/L in one male fish. Vitellogenin concentrations did not differ between first and second year fish, but were elevated in third year fish. The data may indicate that juvenile (<2 years) trout with plasma vitellogenin concentrations above 1000 ng/ml have had their vitellogenin synthesis induced by exposure to estrogens in the environment. Plasma and liver vitellogenin concentrations were closely correlated in brown trout with elevated vitellogenin concentrations. It is noteworthy, however, that exposure to synthetic estrogens (EE2, BP, and OP) resulted in higher liver concentrations (for the same plasma concentration) than exposure to the natural estrogens E1 and E2.

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Animal studies have shown that nitrate acts as an endocrine disrupter affecting the androgen production in adult males. This raises a concern for more severe endocrine disrupting effects after exposure during the sensitive period of prenatal male sexual development. As there are no existing studies of effects of nitrate on male sexual development, the aim of the study was to examine how in utero exposure to nitrate would affect male rat fetuses. Pregnant dams were dosed with nitrate in the drinking water from gestational day (GD) 7 to GD21 at the following dose levels 17.5, 50, 150, 450, and 900 mg/l. At GD21, fetuses were examined for anogenital distance, plasma thyroxine levels, testicular and plasma levels of testosterone and progesterone, and testicular testosterone production and histopathology. In addition, endocrine disrupting activity of nitrate and nitrite were studied in two in vitro assays, the H295R assay and T-screen. There were no consistent indications that nitrate induces anti-androgenic effects in male fetuses or that prenatal nitrate exposure affected the thyroid axis. However, a more comprehensive study with long-term exposure before and during pre- and postnatal development would be relevant to sufficiently address the concerns based on the indications for endocrine disrupting effects in adult animals.

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