Many toxic environmental and food agents have been suspected to be potential risk factors in inducing memory disabilities under normal and pathological conditions. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (known as dioxin or TCDD) is a common and prototypical member of a class of noxious environmental and food contaminants called the halogenated aromatic hydrocarbons. Since the role of dioxin in memory processes has not been studied in detail, the present report aims at elucidating the role of this pollutant in the maintenance of cognitive function. We found that TCDD (50miccrog/kg) induced spatial memory deficits in the Morris water maze (MWM) task in female but not male mice. This sex-dependant effect of dioxin seems to be related to the alteration of estrogen pathways, as treatment with 17beta-estradiol-3-benzoate (E; 5microg/day) reversed memory deficits induced by TCDD. We also observed that cognitive impairments produced by dioxin, which is known to interfere with retinoid turnover and metabolism, were abolished by retinoic acid (RA) treatment (150microg/kg). The cognitive effects of E and RA treatments seem to derive from common rather than additive mechanisms since memory deficits produced by TCDD were fully reversed by these compounds when used separately or in combination. Attenuation of dioxin-induced memory deficits in mice lacking transthyretin (TTR) suggests that TCDD may be acting by affecting the major route of retinol transport involving TTR. Taken together, these results suggest that the environmental and food pollutant TCDD can induce memory deficits by altering the estrogen pathways and a main route of TTR-mediated retinol transport.