Because in utero exposure to mercury has been shown to induce phenotypic changes in fetal immune cells that persist in adult offspring, we examined the effects of in utero exposure to mercuric chloride (HgCl2) on the immune response to an antigen, DNP-KLH. Pregnant BALB/c dams received either plain tap water or water containing 10ppm HgCl2 ad libitum throughout gestation, and were switched to plain water after parturition. Adult offspring were immunized with 100?g DNP-KLH, and six weeks later, splenocytes were analyzed for immune phenotype and function. HgCl2 exposure resulted in alterations in splenocyte phenotype in response to DNP-KLH in male and female mice and increased proliferation of splenic lymphocytes to ConA or LPS; in female mice, there was a specific increase in the proliferative response to LPS. HgCl2 exposure did not affect IL-2 production by splenocytes in response to DNP-KLH. There was no effect of HgCl2 exposure on IFN-? or IL-4 production; however, the production of IFN-? or IL-4 in response to DNP-KLH was greater in mercury-exposed male versus female mice. IL-10 production by splenocytes in response to ConA was greater in mercury-exposed male versus female mice. After cells were cultured in media alone, cells from male mice produced greater levels of DNP-KLH-specific IgG as a result of HgCl2 exposure during gestation. HgCl2 exposure did not significantly affect the production of the DNP-KLH-specific immunoglobulins in response to DNP-KLH. Taken together, these data suggest that in utero exposure to HgCl2 may result in long-term gender-specific alterations of immune system responses.