Maternal behavior in F0 and F2 dams.

<p>Maternal behavior in F0 and F2 dams.</p

Effects of DEHP on juvenile pairs social behaviors tests in F1 mice.

<p>Mean ± SEM proportion of time spent A) sitting side-by-side, B) sniffing partner, C) sitting alone, and D) exploring the cage alone during a 30-min. test. White bars represent data from control mice, light grey bars show data from the lowest dose (5 μg/kg), dark grey bars show data from the medium dose (40 μg/kg), and black bars represent data from the highest dose (400 μg/kg). * Dose(s) significantly different from control and 5 μg/kg groups, p<0.05. && Significantly different from same-sex control and 5 μg/kg groups, p<0.05. #Significantly different from males, p<0.05. ##Significantly different from females of the same dose group, p<0.05. Numbers of F1 mice per group: Control male N = 18, Control female N = 14, 5 μg/kg Male N = 14, 5 μg/kg Female N = 14, 40 μg/kg Male N = 6, 40 μg/kg Female N = 12, 400 μg/kg Male N = 8, 400 μg/kg Female N = 6.</p

Elevated Plus Maze Behavior.

<p>Mean ± SEM for each group A) Time (sec) spent in the closed arm of the elevated plus maze (EPM) in F1 mice. B) Total number of crosses through the center of the EPM in F1 mice. C) Time (in seconds) spent in the closed arm of the EPM in F3 mice. D) Total number of crosses into the center of the EPM in F3 mice. White bars represent data from control mice, light grey bars show data from the lowest dose (5 μg/kg), dark grey bars show data from the medium dose (40 μg/kg), and black bars represent data from the highest dose (400 μg/kg). **Doses significantly different from controls, p<0.05. #Significantly different from other sex, p<0.05. Numbers of F1 mice per group: Control male N = 8, Control female N = 9, 5 μg/kg Male N = 8, 5 μg/kg Female N = 11, 40 μg/kg Male N = 5, 40 μg/kg Female N = 9, 400 μg/kg Male N = 5, 400 μg/kg Female N = 4. Numbers of F3 mice per group: Control male N = 7, Control female N = 7, 5 μg/kg Lineage Male N = 13, 5 μg/kg Lineage Female N = 9, 400 μg/kg Lineage Male N = 8, 400 μg/kg Lineage Female N = 12.</p

Direct and transgenerational effects of low doses of perinatal di-(2-ethylhexyl) phthalate (DEHP) on social behaviors in mice

<div><p>Di-(2-ethylhexyl) phthalate (DEHP) is an endocrine disrupting chemical commonly used as a plasticizer in medical equipment, food packaging, flooring, and children’s toys. DEHP exposure during early development has been associated with adverse neurobehavioral outcomes in children. In animal models, early exposure to DEHP results in abnormal development of the reproductive system as well as altered behavior and neurodevelopment. Based on these data, we hypothesized that developmental exposure to DEHP would decrease social interactions and increase anxiety-like behaviors in mice in a dose-dependent manner, and that the effects would persist over generations. C57BL/6J mice consumed one of three DEHP doses (0, 5, 40, and 400 μg/kg body weight) throughout pregnancy and during the first ten days of lactation. The two higher doses yielded detectable levels of DEHP metabolites in serum. Pairs of mice from control, low, and high DEHP doses were bred to create three dose lineages in the third generation (F3). Average anogenital index (AGI: anogenital distance/body weight) was decreased in F1 males exposed to the low dose of DEHP and in F1 females exposed to the highest dose. In F1 mice, juvenile pairs from the two highest DEHP dose groups displayed fewer socially investigative behaviors and more exploratory behaviors as compared with control mice. The effect of DEHP on these behaviors was reversed in F3 mice as compared with F1 mice. F1 mice exposed to low and medium DEHP doses spent more time in the closed arms of the elevated plus maze than controls, indicating increased anxiety-like behavior. The generation-dependent effects on behavior and AGI suggest complex mechanisms by which DEHP directly impacts reproductive and neurobehavioral development and influences germline-inherited traits.</p></div

Maternal behavior in F0 and F2 dams.

<p>Maternal behavior in F0 and F2 dams.</p

Effects of DEHP on juvenile pairs social behaviors tests in F3 mice.

<p>Mean ± SEM proportion of time spent A) sitting side-by-side, B) sniffing partner, C) sitting alone, and D) exploring the cage alone during a 30-min. test. White bars represent data from control mice; light grey bars show data from the lowest dose (5 μg/kg), and black bars represent data from the highest dose (400 μg/kg). *Significantly different from other groups, p<0.05. **Significantly different from same-sex controls, p<0.05. & Significantly different from all other groups except low DEHP dose females, p<0.05. Numbers of F3 mice per group: Control lineage male N = 10, Control lineage female N = 6, 5 μg/kg Lineage Male N = 8, 5 μg/kg Lineage Female N = 12, 400 μg/kg Lineage Male N = 4, 400 μg/kg Lineage Female N = 6.</p

Effects on AGI and body weights in F1 and F3 generations.

<p>Effects on AGI and body weights in F1 and F3 generations.</p

Disposition of bisphenol AF, a bisphenol A analogue, in hepatocytes <i>in vitro</i> and in male and female Harlan Sprague-Dawley rats and B6C3F1/N mice following oral and intravenous administration

<div><p></p><p>1. Bisphenol AF (BPAF) is used as a crosslinking agent for polymers and is being considered as a replacement for bisphenol A (BPA).</p><p>2. In this study, comparative clearance and metabolism of BPAF and BPA in hepatocytes and the disposition and metabolism of BPAF in rodents following oral administration of 3.4, 34 or 340 mg/kg [¹⁴C]BPAF were investigated.</p><p>3. BPAF was cleared more slowly than BPA in hepatocytes with the rate: rat > mouse > human.</p><p>4. [¹⁴C]BPAF was excreted primarily in feces by 72 h after oral administration to rats (65–80%) and mice (63–72%). Females excreted more in urine (rat, 15%; mouse, 24%) than males (rat, 1–4%; mouse, 10%). Residual tissue radioactivity was <2% of the dose at 72 h. Similar results were observed following intravenous administration.</p><p>5. In male rats, 52% of a 340 mg/kg oral dose was excreted in 24 h bile and was mostly comprised of BPAF glucuronide. However, >94% of fecal radioactivity was present as BPAF, suggesting extensive deconjugation in the intestine.</p><p>6. Metabolites identified in bile were BPAF-glucuronide, -diglucuronide, -glucuronide sulfate and -sulfate.</p><p>7. In conclusion, BPAF was well absorbed following gavage administration and highly metabolized and excreted mostly in the feces as BPAF.</p></div

Pharmacodynamic Relationships between Duration of Action of JDTic-like Kappa-Opioid Receptor Antagonists and Their Brain and Plasma Pharmacokinetics in Rats

JDTic is a potent and selective κ-opioid receptor (KOR) antagonist that reverses U50,488-induced diuresis in rats. It partitions into brain with a duration of action lasting for weeks. In a search for KOR antagonists that do not accumulate in the brain, we compared single doses of five methylated JDTic analogs (RTI-97, -194, -212, -240, and -241) for reversal of U50,488 diuresis and pharmacokinetic (PK) properties. All six compounds showed potent and selective KOR antagonism in a [³⁵S]­GTPγS binding assay. Plasma half-lives ranged from 24 to 41 h and brain half-lives from 24 to 76 h. JDTic and RTI-194 showed increasing brain to plasma ratios over time, indicating increasing partitioning into brain and a longer duration of action for reversal of diuresis than did RTI-97. RTI-240 did not show significant brain accumulation. RTI-212 showed no substantive difference between brain and plasma levels and was inactive against diuresis. RTI-241, with a lower brain to plasma ratio than JDTic and RTI-194, formed JDTic as a metabolite, which still reduced diuresis after 9 weeks. The fact that the duration of action was correlated with the brain to blood plasma ratios and area under the concentration–time curves suggests that PK properties could help to predict safety and acceptable duration of action for KOR antagonists

Disposition of [¹⁴C]hydroquinone in Harlan Sprague-Dawley rats and B6C3F1/N mice: species and route comparison

<p>1.Hydroquinone (HQ) is present in some foods and has varied industrial, medical and consumer uses. These studies were undertaken to investigate the disposition of HQ in rats and mice following gavage, intravenous (IV) and dermal exposure.</p> <p>2.[¹⁴C]HQ administered (0.5, 5 or 50 mg/kg) by gavage or IV routes to male and female Harlan Sprague-Dawley (HSD) rats and B6C3F1/N mice was well absorbed and rapidly excreted primarily in urine. Radioactivity remaining in tissues at 72 h was <1% for both species at all dose levels and routes. No sex, species or route related differences in disposition were found.</p> <p>3.With dermal application of 2, 10 or 20% [¹⁴C]HQ, mice absorbed higher percentages of the dose than rats (37, 12, 12% versus 18.6, 4.43 and 1.79%, respectively). The HQ mass absorbed by mice increased with dose, while in rats it was more constant over the dose range. Absorbed HQ was rapidly excreted in urine of both species and urinary excretion indicated continued absorption over the exposure period. No sex differences in disposition were found.</p> <p>4.The oral bioavailability of HQ at 5 mg/kg was low in both rats (1.6%) and mice (3.9%) demonstrating significant first pass metabolism. Dermal bioavailability in mice was 9.4% following application of 2% formulation.</p> <p>5.Urinary metabolites for both species and all routes included the glucuronide and sulfate conjugates; no parent was found in urine.</p