Elemental mercury (Hg(0)) is a ubiquitous toxic pollutant. Exposure to Hg(0) vapor typically is by inhalation, and the kidney is the primary target organ. Glutathione (GSH) and metallothionein (MT) appear to mitigate mercury toxicity. However, little is known about GSH or MT regulation after Hg(0) vapor exposure, particularly during pregnancy, a time of high sensitivity to most metals. Thus, this study sought to determine renal mercury accumulation and MT- and GSH-related gene expression following Hg(0) vapor exposure in nonpregnant, pregnant, and neonatal rats exposed in utero. Groups (n = 5) of pregnant rats (Long-Evans) were exposed to Hg(0) vapor (4 mg/m(3)) or air (control) for 2 h/d from gestational day (GD) 6 to 15, and kidneys from dams and pups were removed at various times during and after the onset of exposure. For comparative purposes, nonpregnant female rats were exposed to Hg(0) for 10 d under the same conditions. Renal mercury, MT protein, and GST activity were assayed by standard analytical techniques. Western blot analysis was also performed using antibodies against MT and GST-pi. GSH-related gene expression was studied by cDNA microarray. Hg(0) vapor exposure produced renal accumulation of mercury in nonpregnant, pregnant, and neonatal rats. However, the transplacentally exposed neonates accumulated approximately 1000-fold less mercury than adults. Hg(0) vapor exposure produced a time-dependent increase in renal MT protein in nonpregnant and pregnant rats, but not in neonatal rats. Maximum MT increases were observed on d 10 (fivefold) in nonpregnant and GD 15 (threefold) in pregnant rats. Activation of the MT gene by Hg(0) was confirmed at the translational level by Western blot analysis and at the transcriptional level by Northern blot analysis. Microarray analysis revealed a significant upregulation in the renal expression of the GST-pi, GST-Ya, and microsomal GST and GST5-5 genes in nonpregnant and pregnant rats. Western blot and enzyme assay confirmed the upregulation of GST genes after Hg(0) exposure. Thus, in response to Hg(0) vapor exposure, the expression of the MT gene and various GST genes is activated in nonpregnant and pregnant rats. Activation of these genes could be part of a defensive response directed at decreasing renal mercury toxicity, and may help divert the metal away from the fetus.