Breaching the Placenta Fast Fetal Absorption of a Common Compound
Environmental Health Perspectives Volume 108, Number 10, Oct00
Most maternally administered chemicals have the potential to cross the placental barrier, and the question is not whether a chemical crosses the placenta, but the rate at which it does so. In this issue, Osamu Takahashi and Shinshi Oishi of the Tokyo Metropolitan Research Laboratory of Public Health present their findings that the placenta fails to act as a barrier to a potentially toxic compound, 2,2-bis(4-hydroxyphenyl)propane, also known as bisphenol A or BPA [EHP 108:931-935]. The researchers found that BPA can be transferred across the placental barriers of female Fischer 344 rats to their fetuses. They also discovered that BPA is absorbed and distributed in maternal internal organs and fetuses extremely rapidly.
Rapid dam-fetus transfer. It took only 20 minutes for maternally ingested BPA to reach maximum concentration in fetal Fischer 344 rats. Photo credit: Greenwell/EHP
BPA has been widely used in plastics manufacture and as a fungicide, antioxidant, flame retardant, rubber chemical, and polyvinyl chloride stabilizer. The estimated production of BPA in Japan in 1995 was about 260,000 tons. Release and migration of BPA from various resins and plastic products into the environment have been recognized; small amounts of the compound are detectable in river and tap water.
BPA has not been found to be carcinogenic or teratogenic. At doses of 5.0-6.3 grams per kilogram per day (g/kg/day), it is nephrotoxic in mice. Doses of 400-1,000 milligrams (mg)/kg/day of BPA have produced estrogenic activity in immature rats or female mice whose ovaries have been surgically removed, and doses at 437-1,750 mg/kg/day have adversely affected the reproductive system and sperm production in male mice. However, although lower doses (2-400 micrograms [µg]/kg/day) of BPA administered into the uterus through the mother's circulation have been reported to affect reproductive organs in male offspring of mice and rats, scientists have to date been unable to reproduce these results, so such toxicity remains controversial.
What impressed Takahashi and Oishi was the speed with which BPA was transferred from the pregnant rat dam to her fetuses. On day 18 of gestation, they administered 1 g/kg BPA dissolved in propylene glycol at 25% weight per volume. This dose is about one-fourth the median lethal dose for rats. It took only 20 minutes for the BPA to attain its maximum concentrations in maternal blood, liver, and kidneys (these concentrations were 14.7, 171.0, and 36.2 µg/g, respectively). Likewise, in 20 minutes, BPA concentration in the fetuses reached its maximum at 9.22 µg/g. Six hours after administration of BPA, its concentrations in the maternal blood and organs and in the fetuses were reduced to 2-5% of maximum. In the view of the authors, the attainment of maximum concentrations of BPA in the mother rat and her fetuses suggests that BPA's absorption and distribution are extremely rapid and that the placenta does not act as a barrier to BPA.
One factor that determines whether a compound is absorbed by the fetus are its lipophilic or hydrophilic properties--that is, whether it dissolves better in a lipid or in water. Compounds with a high octanol/water partition coefficient (Pow)--compounds that are more lipophilic--cross slowly; examples are pentachlorophenol and DDT, whose log Pow is 5.0-6.0 (such compounds, nevertheless, can be accumulated). By contrast, chemicals with a lower log Pow, such as diethylstilbestrol and salicylic acid, are more hydrophilic and they more easily cross the placenta; their log Pow may vary between -0.9 and 5.0. (The log Pow of BPA, which crosses the placenta so rapidly, is 3.3.) Takahashi and Oishi suggest that the speed and degree of transplacental absorption may be mediated by the lipophilic or hydrophilic properties of a chemical.
In the case of BPA, because the placenta essentially presents no barrier, the compound was rapidly passed through and could show toxicologic effects; yet in this study it largely cleared after several hours. However, the BPA dose of 1 g/kg was quite high. When a dose of 0.1 g/kg BPA was administered, its concentrations in the mother and fetuses could be determined accurately only near peak levels. -Julian Josephson
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