Gestational and Chronic Low-Dose PFOA Exposures and Mammary Gland Growth and Differentiation in Three Generations of CD-1 Mice

Background: Prenatal exposure to perfluorooctanoic acid (PFOA), a ubiquitous industrial surfactant, has been reported to delay mammary gland development in female mouse offspring (F1) and the treated lactating dam (P0) after gestational treatments at 3 and 5 mg PFOA/kg/day

Mammary Gland Development as a Sensitive End Point after Acute Prenatal Exposure to an Atrazine Metabolite Mixture in Female Long-Evans Rats

BACKGROUND: Atrazine (ATR), a widely used chlorotriazine herbicide, inhibits a number of endocrine-dependent processes, including gonadotrophin surges and mammary gland development in rats. Chlorotriazine herbicides are rapidly metabolized in plants and animals to form a group of metabolites that are detected both in the environment and in exposed animals. The extent to which these metabolites are responsible directly for the observed health effects is not understood. OBJECTIVES: Our goal was to determine if a mixture of ATR metabolites, in proportions found in the environment, might produce developmental effects in Long-Evans rats following exposure late in pregnancy. METHODS: We administered an ATR metabolite mixture (AMM) containing ATR, hydroxyatrazine, diaminochlorotriazine, deethylatrazine, and deisopropylatrazine orally to pregnant Long-Evans rats at 0.09, 0.87, or 8.73 mg/kg body weight (bw)/day, on gestation days 15–19, using 0 and 100 mg ATR/kg bw/day as negative and positive controls, respectively. RESULTS: We observed no significant effect of acute AMM exposure on body weight gain in dams during the dosing period, weight loss in pups on postnatal day (PND)4, or pubertal timing, as is seen with ATR alone. However, as with ATR, we detected delayed mammary gland development, evaluated by whole mount analysis, as early as PND4 in all treatment groups. CONCLUSIONS: Our data suggest that acute exposure to AMM at levels as low as 0.09 mg/kg bw during late pregnancy causes persistent alterations in mammary gland development of female offspring, and that these effects do not appear to be related to bw or associated with pubertal timing

Effects of prenatal exposure to a low dose atrazine metabolite mixture on pubertal timing and prostate development of male Long-Evans rats

The present study examines the postnatal reproductive development of male rats following prenatal exposure to an atrazine metabolite mixture (AMM) consisting of the herbicide atrazine and its environmental metabolites diaminochlorotriazine, hydroxyatrazine, deethylatrazine, and deisopropylatrazine. Pregnant Long Evans rats were treated by gavage with 0.09, 0.87, or 8.73 mg AMM/kg body weight (BW), vehicle, or 100 mg ATR/kg BW positive control, on gestation days 15-19. Preputial separation was significantly delayed in 0.87 mg and 8.73 mg AMM-exposed males. AMM-exposed males demonstrated a significant treatment-related increase in incidence and severity of inflammation in the prostate on postnatal day (PND) 120. A dose-dependent increase in epididymal fat masses and prostate foci were grossly visible in AMM-exposed offspring. These results indicate that a short, late prenatal exposure to mixture of chlorotriazine metabolites can cause chronic prostatitis in male LE rats. The mode of action for these effects is presently unclear

Effects of perfluorooctanoic acid on mouse mammary gland development and differentiation resulting from cross-foster and restricted gestational exposures

The adverse consequences of developmental exposures to perfluorooctanoic acid (PFOA) are established in mice, and include impaired development of the mammary gland (MG). However, the relationships between timing or route of exposure, and consequences in the MG have not been characterized. To address the effects of these variables on the onset and persistence of MG effects in female offspring, timed pregnant CD-1 dams received PFOA by oral gavage over various gestational durations. Cross-fostering studies identified the 5 mg/kg dose, under either lactational- or intrauterine-only exposures, to delay MG development as early as postnatal day (PND) 1, persisting beyond PND 63. Intrauterine exposure during the final days of pregnancy caused adverse MG developmental effects similar to that of extended gestational exposures. These studies confirm a window of MG sensitivity in late fetal and early neonatal life, and demonstrate developmental PFOA exposure results in early and persistent MG effects, suggesting permanent consequences

Analysis of PFOA in dosed CD-1 mice. Part 2: Disposition of PFOA in tissues and fluids from pregnant and lactating mice and their pups

Previous studies in mice with multiple gestational exposures to perfluorooctanoic acid (PFOA) demonstrate numerous dose dependent growth and developmental effects which appeared to worsen if offspring exposed in utero nursed from PFOA-exposed dams. To evaluate the disposition of PFOA in the pregnant and lactating dam and her offspring, time-pregnant CD-1 mice received a single 0, 0.1, 1, or 5 mg PFOA/kg BW dose (n = 25/dose group) by gavage on gestation day 17. Maternal and pup fluids and tissues were collected over time. Pups exhibited significantly higher serum PFOA concentrations than their respective dams, and their body burden increased after birth until at least postnatal day 8, regardless of dose. The distribution of milk:serum PFOA varied by dose and time, but was typically in excess of 0.20. These data suggest that milk is a substantial PFOA exposure route in mice and should be considered in risk assessment modeling designs for this compound

Histopathologic changes in the uterus, cervix and vagina of immature CD-1 mice exposed to low doses of perfluorooctanoic acid (PFOA) in a uterotrophic assay

The estrogenic and antiestrogenic potential of perfluorooctanoic acid (PFOA) was assessed using an immature mouse uterotrophic assay and by histologic evaluation of the uterus, cervix and vagina following treatment. Female offspring of CD-1 dams were weaned at 18 days old and assigned to groups of equal weight, and received 0, 0.01, 0.1, or 1 mg PFOA/kg BW/d by gavage with or without 17-β estradiol (E2, 500 μg/kg/d) from PND18-20 (n=8/treatment/block). At 24 hr after the third dose (PND 21), uteri were removed and weighed. Absolute and relative uterine weights were significantly increased in the 0.01 mg/kg PFOA only group. Characteristic estrogenic changes were present in all E2-treated mice; however, they were minimally visible in the 0.01 PFOA only mice. These data suggest that at a low dose PFOA produces minimal histopathologic changes in the reproductive tract of immature female mice, and does not antagonize the cellular effects of E2

Effects of prenatal exposure to a low dose atrazine metabolite mixture on pubertal timing and prostate development of male Long-Evans rats

The present study examines the postnatal reproductive development of male rats following prenatal exposure to an atrazine metabolite mixture (AMM) consisting of the herbicide atrazine and its environmental metabolites diaminochlorotriazine, hydroxyatrazine, deethylatrazine, and deisopropylatrazine. Pregnant Long Evans rats were treated by gavage with 0.09, 0.87, or 8.73 mg AMM/kg body weight (BW), vehicle, or 100 mg ATR/kg BW positive control, on gestation days 15-19. Preputial separation was significantly delayed in 0.87 mg and 8.73 mg AMM-exposed males. AMM-exposed males demonstrated a significant treatment-related increase in incidence and severity of inflammation in the prostate on postnatal day (PND) 120. A dose-dependent increase in epididymal fat masses and prostate foci were grossly visible in AMM-exposed offspring. These results indicate that a short, late prenatal exposure to mixture of chlorotriazine metabolites can cause chronic prostatitis in male LE rats. The mode of action for these effects is presently unclear

Anti-Pneumocystis Activities of Aromatic Diamidoxime Prodrugs

Aromatic dicationic compounds, such as pentamidine, have potent antimicrobial activities. Clinical use of these compounds has been restricted, however, by their toxicity and limited oral activity. A novel approach, using amidoxime derivatives as prodrugs, has recently been proposed to overcome these limitations. Although results were presented for amidoxime derivatives of only one diamidine, pentamidine, the authors in the original proposal claimed that amidoxime derivatives would work as effective prodrugs for all pharmacologically active diamidines. Nine novel amidoxime derivatives were synthesized and tested in the present study for activity against Pneumocystis carinii in corticosteroid-suppressed rats. Only three of the nine compounds had significant oral anti-Pneumocystis activity. The bisbenzamidoxime derivatives of three direct pentamidine analogs had excellent oral and intravenous activities and reduced acute host toxicity. These compounds are not likely candidates for future drug development, however, because they have chronic toxic effects and the active amidine compounds have multiple sites susceptible to oxidative metabolism, which complicates their pharmacology and toxicology. Novel diamidoximes from three other structural classes, containing different groups linking the cationic moieties, lacked significant oral or intravenous anti-Pneumocystis activity, even though the corresponding diamidines were very active intravenously. Both active and inactive amidoximes were readily metabolized to the corresponding amidines by cell-free liver homogenates. Thus, the amidoxime prodrug approach may provide a strategy to exploit the potent antimicrobial and other pharmacological activities of selected, but certainly not all, aromatic diamidines