3-Methylcholanthrene (3MC) is an aryl hydrocarbon receptor (AhR) agonist, and it has been reported that 3MC induces estrogenic activity through AhR-estrogen receptor A (ERA) interactions. In this study, we used 3MC and 3,3V,4,4V,5-pentachlorobiphenyl (PCB) as prototypical AhR ligands, and both compounds activated estrogen-responsive reporter genes/gene products (cathepsin D) in MCF-7 breast cancer cells. The estrogenic responses induced by these AhR ligands were inhibited by the antiestrogen ICI 182780 and by the transfection of a small inhibitory RNA for ERA but were not affected by the small inhibitory RNA for AhR. These results suggest that 3MC and PCB directly activate ERA, and this was confirmed in a competitive ERA binding assay and in a fluorescence resonance energy transfer experiment in which PCB and 3MC induced CFP-ERA/YFP-ERA interactions. In a chromatin immunoprecipitation assay, PCB and 3MC enhanced ERA (but not AhR) association with the estrogenresponsive region of the pS2 gene promoter. Moreover, in AhR knockout mice, 3MC increased uterine weights and induced expression of cyclin D1 mRNA levels. These results show that PCB and 3MC directly activate ERA-dependent transactivation and extend the number of ligands that activate both AhR and ERA. (Cancer Res 2006; 66(4): 2459-67)

Many antiepileptic drugs (AEDs) have therapeutic applications that extend beyond epilepsy to include neuropathic pain, migraine headaches and psychiatric disorders. The risk of some AEDs has been clearly established, but for newer drugs, small sample sizes and polytherapy exposures preclude a conclusive determination of their teratogenic potential. Most women with epilepsy will require AED therapy throughout their entire pregnancy to control seizures; the vast majority of pregnancies in women with epilepsy have positive outcomes. A conservative estimate suggests that AED monotherapy doubles, and polytherapy triples, the risk for major congenital malformations. Furthermore, while evidence is still accruing, recent investigations suggest that exposure to select AEDs results in altered cognitive function later in development. There is no evidence to suggest that additional folic acid supplementation ameliorates the increased risk of congenital malformations conferred by in utero AED exposure.

No abstract

In an accompanying article (see pp. 183-196), it was reported that administration of very high doses of the chlorotriazine herbicides atrazine, simazine, and diaminochlorotriazine (DACT), a common metabolite, expressed antiestrogenic activity in uteri of female Sprague-Dawley rats without expressing intrinsic estrogenic activity. In the present article, studies of chlorotriazine interaction with rat uterine estrogen receptors (ER) are reported. Under equilibrium conditions, none of the triazine compounds showed an ability to compete against binding of radiolabeled estradiol to ER. A weak competition was evident only if cytosols were preincubated with triazines at 25 degrees C prior to introduction of tracer. Competition was very weak, with kl estimates of 10-100 microM. A limited Scatchard analysis suggested a competitive type of inhibition. Sucrose gradient analysis of cytosol incubations showed that triazine interaction with the 4S isoform of ER may be greater than with the 8S form. When administered to ovariectomized rats for 2 d at 300 mg/kg/d, atrazine, simazine, or DACT all reduced uterine ER binding capacity by approximately 30%. Results from the receptor binding studies indicated that triazine competition against ER binding occurred to a much lesser degree than inhibition of estrogen-mediated responses reported in accompanying articles. This suggests that the complete responses to triazines may include inhibition of events other than or in addition to ER binding of estrogen.