The alkylphenol breakdown products of alkylphenol ethoxylates have been shown in in vitro studies to be weakly estrogenic, but few in vivo data address this issue in mammals. Because estrogens have been found to be most potent during developmental/perinatal exposures, this study maximized developmental exposure to nonylphenol (NP) by treating 3.5 generations of Sprague-Dawley rats to NP in diet at 200, 650, and 2000 ppm to determine the range and severity of any toxicity. Dose rate was higher for younger rats; calculated dose ranges were 9-35, 30-100, and 100-350 mg/kg/d for the low (200NP), middle (650NP), and high (2000NP) dose groups, respectively. There were adult (F0, F1, F2) and postnatal day (pnd) 21 (F1, F2, F3) necropsies; the oldest F3 rats were killed on pnd 55-58. Body weight gain was reduced by 8-10% in the 650NP and 2000NP groups. Vaginal opening was accelerated by approximately 2 days (650NP) and approximately 6 days (2000NP) in F1, F2, and F3 generations. Uterine weights at pnd 21 were increased in 650NP (14%) and 2000NP (50%) F1 females, but not in other generations. Testis descent, anogenital distance, and preputial separation were not consistently changed. No consistent changes were seen in pup number, weight or viability, litter indices, or other functional reproductive measures. Relative ovary weight in F2 adults was decreased at 650NP and 2000NP by 12%; relative ovary was unchanged in other generations. Follicle counts were unchanged in F2 adults. Sperm indices, including CASA measures, were unchanged in F0 and F1 males. In F2 rats, epididymal sperm density was reduced by 8% and 13% at 650NP and 2000NP, respectively. Testicular spermatid count was reduced by 13% in 2000NP F2 males; testis and epididymis weights were unchanged. Erosion of gastric and duodenal mucosa was monitored grossly and microscopically, and never found. Kidney weights were increased in 650NP and 2000NP males, and renal medullary tubular dilatation and cyst formation were noted in all generations of males, and often at the lowest dose tested. These data show that NP had limited effects on the reproductive system in the presence of measurable nephrotoxicity. The F2 sperm effects are either statistical/biological "noise," or imply heretofore unknown pharmacokinetics or toxicodynamics. These sperm data should be interpreted cautiously until the findings are repeated.

Deriving No Observed Adverse Effect Level (NOAEL) or benchmark dose is important for risk assessment and can be influenced by study design considerations. In order to define the di-(2-ethylhexyl) phthalate (DEHP) dose-response curve for reproductive malformations, we retained more offspring to adulthood to improve detection of these malformations in the reproductive assessment by continuous breeding study design. Sprague-Dawley rats were given a dietary administration of 1.5 (control), 10, 30, 100, 300, 1000, 7500, and 10,000 ppm DEHP. Male pups were evaluated for gross reproductive tract malformations (RTMs) associated with the "phthalate syndrome." DEHP treatment had minimal effects on P0 males. There was a statistically significant increase in F1 and F2 total RTMs (testis, epididymides, seminal vesicle, and prostate) in the 7500-ppm dose group and F1 10,000-ppm dose group. The 10,000-ppm exposed F1 males did not produce an F2 generation. The NOAEL for F1 and F2 RTM combined data, because in utero exposures were similar, were 100 ppm (4.8 mg/kg/day), which was close to the 5% response benchmark dose lower confidence limit of 142 ppm. The utility of evaluating more pups per litter was examined by generating power curves from a Monte Carlo simulation. These curves indicate a substantial increase in detection rate when three males are evaluated per litter rather than one. A 10% effect across male pups would be detected 5% of the time if one pup per litter was evaluated, but these effects would be detected 66% of the time if three pups per litter were evaluated. Taken together, this study provides a well-defined dose response of DEHP-induced RTMs and demonstrates that retention of more adult F1 and F2 males per litter, animals that were already produced, increases the ability to detect RTMs and presumably other low-incidence phenomena.

Human immunodeficiency virus (HIV)-infected pregnant women are administered nucleoside-analogue antiretrovirals to reduce maternal-infant viral transmission. The current protocol recommends treating newborns for 6 additional weeks postpartum. The treatment is effective, but the risk of drug-induced chromosomal damage in neonates remains undefined. We used a mouse model to investigate this concern. In a multigeneration reproductive toxicity study, female CD-1 mice received 3'-azido-3'-deoxythymidine (AZT) and dideoxyinosine (ddI) (50/250, 75/375, 150/750 mg/kg/day AZT/ddI) by gavage twice daily in equal fractions beginning prior to mating and continuing throughout gestation and lactation. Direct pup dosing (same regimen) began on postnatal day (PND) 4. Peripheral blood erythrocytes of male pups were screened for micronuclei, markers of chromosomal damage, on PNDs 1, 4, 8, and 21. Extraordinary increases in micronucleated cells were noted in pups for each treatment group at each sampling time; treated dams exhibited smaller yet significant increases in micronucleated erythrocytes. The frequencies of micronucleated cells in untreated pups were higher than in the untreated dams, and all pups had markedly elevated levels of circulating reticulocytes compared to dams. These observations suggest that fetal and neonatal mouse hematopoietic precursor cells have heightened sensitivity to genotoxic agents, perhaps due to rapid cell proliferation during the perinatal period of development. The amount of genetic damage observed in treated pups raises concern for the potential of similar damage in humans. Investigations of chromosomal integrity in exposed newborns and children are recommended.

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Iminosugars are capable of targeting the life cycles of multiple viruses by blocking host endoplasmic reticulum α-glucosidase enzymes that are required for competent replication of a variety of enveloped, glycosylated viruses. Iminosugars as a class are approved for use in humans with diseases such as diabetes and Gaucher’s disease, providing evidence for safety of this class of compounds. The in vitro antiviral activity of iminosugars has been described in several publications with a subset of these demonstrating in vivo activity against flaviviruses, herpesviruses, retroviruses and filoviruses. Although there is compelling non-clinical in vivo evidence of antiviral efficacy, the efficacy of iminosugars as antivirals has yet to be demonstrated in humans. In the current study, we report a novel iminosugar, UV-12, which has efficacy against dengue and influenza in mouse models. UV-12 exhibits drug-like properties including oral bioavailability and good safety profile in mice and guinea pigs. UV-12 is an example of an iminosugar with activity against multiple virus families that should be investigated in further safety and efficacy studies and demonstrates potential value of this drug class as antiviral therapeutics.