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Dichloroacetic acid (DCA) is carcinogenic to the B6C3[F.sub.1] mouse and the F344 rat. Given the carcinogenic potential of DCA in rodent liver and the known concentrations of this compound in [...]

Introduction Disinfection of drinking water is important in controlling microbial contamination in tap water and has proven to be a major advancement in public health. However, oxidizing disinfectants react with [...], BACKGROUND: Trihalomethanes (THMs) and haloacetic acids (HAAs) are regulated disinfection by-products (DBPs); their joint reproductive toxicity in drinking water is unknown. OBJECTIVE: We aimed to evaluate a drinking water mixture of the four regulated THMs and five regulated HAAs in a multigenerational reproductive toxicity bioassay. METHODS: Sprague-Dawley rats were exposed (parental, [F.sub.1], and [F.sub.2] generations) from gestation day 0 of the parental generation to postnatal day (PND) 6 of the [F.sub.2] generation to a realistically proportioned mixture of THMs and HAAs at 0, 500x, 1,000x, or 2,000x of the U.S. Environmental Protection Agency's maximum contaminant levels (MCLs). RESULTS: Maternal water consumption was reduced at [greater than or equal to] 1,000x; body weights were reduced at 2,000x. Prenatal and postnatal survival were unaffected. [F.sub.1] pup weights were unaffected at birth but reduced at 2,000x on PND6 and at ≥ 1,000x on PND21. Postweaning [F.sub.1] body weights were reduced at 2,000x, and water consumption was reduced at [greater than or equal to] 500x. Males at 2,000x had a small but significantly increased incidence of retained nipples and compromised sperm motility. Onset of puberty was delayed at 1,000x and 2,000x. [F.sub.1] estrous cycles and fertility were unaffected, and [F.sub.2] litters showed no effects on pup weight or survival. Histologically, [P.sub.0] (parental) dams had nephropathy and adrenal cortical pathology at 2,000x. CONCLUSIONS: A mixture of regulated DBPs at up to 2,000x the MCLs had no adverse effects on fertility, pregnancy maintenance, prenatal survival, postnatal survival, or birth weights. Delayed puberty at [greater than or equal to] 1,000x may have been secondary to reduced water consumption. Male nipple retention and compromised sperm motility at 2,000x may have been secondary to reduced body weights. http://dx.doi.org/10.1289/ehp.1408579

Abstract Background Simian Virus 40 (SV40) immortalization followed by treatment of cells with 3-methylcholanthrene (3-MC) has been used to elicit tumors in athymic mice. 3-MC carcinogenesis has been thoroughly studied, however gene-level interactions between 3-MC and SV40 that could have produced the observed tumors have not been explored. The commercially-available human uroepithelial cell lines were either SV40-immortalized (HUC) or SV40-immortalized and then 3-MC-transformed (HUC-TC). Results To characterize the SV40 - 3MC interaction, we compared human gene expression in these cell lines using a human cancer array and confirmed selected changes by RT-PCR. Many viral Large T Antigen (Tag) expression-related changes occurred in HUC-TC, and it is concluded that SV40 and 3-MC may act synergistically to transform cells. Changes noted in IFP 9-27, 2'-5' OAS, IF 56, MxA and MxAB were typical of those that occur in response to viral exposure and are part of the innate immune response. Because interferon is crucial to innate immune host defenses and many gene changes were interferon-related, we explored cellular growth responses to exogenous IFN-γ and found that treatment impeded growth in tumor, but not immortalized HUC on days 4 - 7. Cellular metabolism however, was inhibited in both cell types. We conclude that IFN-γ metabolic responses were functional in both cell lines, but IFN-γ anti-proliferative responses functioned only in tumor cells. Conclusions Synergism of SV40 with 3-MC or other environmental carcinogens may be of concern as SV40 is now endemic in 2-5.9% of the U.S. population. In addition, SV40-immortalization is a generally-accepted method used in many research materials, but the possibility of off-target effects in studies carried out using these cells has not been considered. We hope that our work will stimulate further study of this important phenomenon.