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Markey, CM, EH Luque, M Muñoz de Toro, C Sonnenschein and AM Soto. 2001. In Utero Exposure to Bisphenol A Alters the Development and Tissue Organization of the Mouse Mammary Gland. Biology of Reproduction 65: 1215–1223. |
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Markey et al. raise the stakes in the debate over human health risks of bisphenol A by demonstrating, in laboratory mice, that low level exposure in the womb to the contaminant causes changes in mammary tissue that are associated with carcinogenesis in both rodents and humans. Their findings are consistent with three facts: that the level of intrauterine estrogens is associated with increased risk of breast cancer in daughters (see Ekbom et al. 1997; Weiss et al. 1997; Braun et al. 1995); that bisphenol A is estrogenic (e.g., Brotons et al. 1995); that bisphenol A in the pregnant rat quickly reaches the fetus, where it is more bioavailable than in the mother's serum (Miyakoda et al. 1999, Takahashi and Oishi 2000). Human exposure to bisphenol A is now widespread because of its use in the manufacture of polycarbonate plastics and epoxy resins. Many consumer products are made from these materials, including large drinking water containers, baby bottles, and reusable milk and food containers. The resins are also used to coat the interior of food cans and to create dental sealants. Leaching is known to occur from several of these products but the amount of leaching has not been assessed for many of the current uses of bisphenol A. Hence it is impossible to assess cumulative exposure experienced by people based on current data. Nonetheless, the exposure levels that have been established already are within the range shown by Markey et al. to have adverse effects on mice. Moreover, bisphenol A is but one of a host of environmental estrogens, whose activities at the molecular level most likely will be additive because of their common mechanism of action, binding with the estrogen receptor. What did they do? Markey et al. exposed fetal female mice in utero to bisphenol A via implanted osmotic pumps. Two doses were used, 25 µg/kg body weight of the mother and 250 µg/kg. Bisphenol A was delivered from day 9 of pregnancy onward through delivery (day 20). Different subsets of the treated female offspring were examined at 10 days, 1 month (puberty) and 6 months after birth, using a series of histological, immunochemical and morphometric measurements, comparing treated animals with controls. What did they find? Significant differences emerged by 1 month of age:
While morphological differences between treated and control animals were not noted at this age, biochemical differences were already apparent at 10 days old. Within the epithelium of the mammary gland, DNA synthesis was suppressed. Both treatment groups had lower rates of DNA synthesis compared to controls. In the mammary gland stroma, however, DNA synthesis rates decreased compared to controls at age 10 days but increased compared to controls at 6 months age. Morphological differences accumulated between 1 month and 6 months age. Typically, untreated mice experience significant development of the mammary gland during this period, with growth of a "ductal tree that comprises terminal ducts, terminal endbuds... and very few alveolar buds." Markey et al. discovered that bisphenol A exposure produces a significant increase of the ductal and alveolar structures compared to controls:
Their quantitative analysis of mammary gland structure revealed significant increases in the relative area occupied by ducts (upper left), terminal ducts (upper right), terminal endbuds (lower left) and alveolar buds (lower right).
What does it mean? At this stage of the study of BPA in relation to breast cancer, it is impossible to reach any conclusions. Two aspects of their results raise concerns, however, because they reveal patterns in the impact of BPA that resemble the initiation of breast cancer:
Two practical notes:
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