Liver X receptors LXR alpha (NR1H3) and LXR beta (NR1H2) are transcription factors belonging to the nuclear receptor superfamily, activated by specific oxysterols, oxidized derivatives of cholesterol. These receptors are involved in the regulation of testis physiology. Lxr-deficient mice pointed to the physiological roles of these nuclear receptors in steroid synthesis, lipid homeostasis and germ cell apoptosis and proliferation. Diethylstilbestrol (DES) is a synthetic estrogen considered as an endocrine disruptor that affects the functions of the testis. Various lines of evidences have made a clear link between estrogens, their nuclear receptors ER alpha (NR3A1) and ER beta (NR3A2), and Lxr alpha/beta. As LXR activity could also be regulated by the nuclear receptor small heterodimer partner (SHP, NROA2) and DES could act through SHP, we wondered whether LXR could be targeted by estrogen-like endocrine disruptors such as DES. For that purpose, wildtype and Lxr-deficient mice were daily treated with 0.75 mu g DES from days 1 to 5 after birth. The effects of DES were investigated at 10 or 45 days of age. We demonstrated that DES induced a decrease of the body mass at 10 days only in the Lxr-deficient mice suggesting a protective effect of Lxr. We defined three categories of DES-target genes in testis: those whose accumulation is independent of Lxr; those whose accumulation is enhanced by the lack of both Lxr alpha/beta; those whose accumulation is repressed by the absence of Lxr alpha/beta. Lipid accumulation is also modified by neonatal DES injection. Lxr-deficient mice present different lipid profiles, demonstrating that DES could have its effects in part due to Lxr alpha/beta. Altogether, our study shows that both nuclear receptors Lxr alpha. and Lxr beta are not only basally important for testicular physiology but could also have a preventive effect against estrogen-like endocrine disruptors. (C) 2013 Elsevier Inc. All rights reserved.