Howdeshell, K.L.*; Ruhlen, R.L.; Welshons, W.V.; vom Saal, F.S.: Serum regulation of estrogenic endocrine-disrupting chemicals during mouse neonatal development

Certain chemicals used in plastics and other products are capable of disrupting development by mimicking the action of the sex hormone estradiol, and thus are referred to as estrogenic endocrine disrupting chemicals (EEDCs). While traditional risk assessment for EEDCs has focused on high dose effects, low-dose in utero exposure to EEDCs can alter postnatal reproductive function and physiology. In adult human serum, EEDCs exhibit lower affinity than endogenous estradiol (E2) for serum binding proteins, which are responsible for maintaining the free (bioactive) level of E2 in blood; this reduced affinity translates into increased availability of EEDCs to bind to the estrogen receptor. We hypothesized that EEDCs will also exhibit low affinity for serum regulatory proteins during development, thus resulting in a higher bioactive fraction of EEDCs and result in different levels of estrogen-responsiveness dependent on dose. Neonatal mice were exposed to a range of doses of E2 and the EEDC diethylstilbestrol (DES) by capsule implant on postnatal day 1-5. The actual dose released from the capsules was characterized using tritium-labeled labeled E2 and DES. Neonatal response varied as a function of dose; uterine weight was significantly heavier (P<0.001) than controls with low dose DES exposure (0.32 ng/24 hr), while a higher dose of DES (239.17 ng/24 hr) depressed the response relative to the low DES dose. Similar results were found with 10-fold higher E2 exposure; uterine weight was increased (P<0.001) above controls at low dose of 4.68 ng/24 hr. Ongoing research will be presented regarding the bioactive versus total dose of DES and E2 delivered to serum and their affinity for serum binding proteins as well as data from similar investigations with the EEDC, bisphenol A.