Altered Cord Blood Lipid Concentrations Correlate with Birth Weight and Doppler Velocimetry of Fetal Vessels in Human Fetal Growth Restriction Pregnancies.

Fetal growth restriction (FGR) is associated with short- and long-term morbidity, often with fetal compromise in utero, evidenced by abnormal Doppler velocimetry of fetal vessels. Lipids are vital for growth and development, but metabolism in FGR pregnancy, where fetuses do not grow to full genetic potential, is poorly understood. We hypothesize that triglyceride concentrations are increased in placentas and that important complex lipids are reduced in cord plasma from pregnancies producing the smallest babies (birth weight < 5%) and correlate with ultrasound Dopplers. Dopplers (umbilical artery, UA; middle cerebral artery, MCA) were assessed longitudinally in pregnancies diagnosed with estimated fetal weight (EFW) < 10% at ≥29 weeks gestation. For a subset of enrolled women, placentas and cord blood were collected at delivery, fatty acids were extracted and targeted lipid class analysis (triglyceride, TG; phosphatidylcholine, PC; lysophosphatidylcholine, LPC; eicosanoid) performed by LCMS. For this sub-analysis, participants were categorized as FGR (Fenton birth weight, BW ≤ 5%) or SGA "controls" (Fenton BW > 5%). FGRs (n = 8) delivered 1 week earlier (p = 0.04), were 29% smaller (p = 0.002), and had 133% higher UA pulsatility index (PI, p = 0.02) than SGAs (n = 12). FGR plasma TG, free arachidonic acid (AA), and several eicosanoids were increased (p < 0.05); docosahexaenoic acid (DHA)-LPC was decreased (p < 0.01). Plasma TG correlated inversely with BW (p < 0.05). Plasma EET, non-esterified AA, and DHA correlated inversely with BW and directly with UA PI (p < 0.05). Placental DHA-PC and AA-PC correlated directly with MCA PI (p < 0.05). In fetuses initially referred for inadequate fetal growth (EFW < 10%), those with BW ≤ 5% demonstrated distinctly different cord plasma lipid profiles than those with BW > 5%, which correlated with Doppler PIs. This provides new insights into fetal lipidomic response to the FGR in utero environment. The impact of these changes on specific processes of growth and development (particularly fetal brain) have not been elucidated, but the relationship with Doppler PI may provide additional context for FGR surveillance, and a more targeted approach to nutritional management of these infants.

COMPROMISED FERTILITY IN FREE FEEDING OF WILD-CAUGHT NORWAY RATS (RATTUS NORVEGICUS) WITH A LIQUID BAIT CONTAINING 4-VINYLCYCLOHEXENE DIEPOXIDE AND TRIPTOLIDE.

Wild rat pests in the environment cause crop and property damage and carry disease. Traditional methods of reducing populations of these pests involve poisons that can cause accidental exposures in other animals and humans. Fertility management with nonlethal chemicals would be an improved method of rat pest population control. Two chemicals known to target ovarian function in female rats are 4-vinylcyclohexene diepoxide (VCD) and triptolide. Additionally, triptolide impairs spermatogenesis in males. A liquid bait containing no active ingredients (control), or containing triptolide (0.001%) and VCD (0.109%; active) was prepared to investigate the potential use of these agents for wild rat pest population control. Liquid bait was made available to male (n = 8 control; n = 8 active) and female (n = 8 control; n = 8 active) Sprague Dawley rats ( Rattus norvegicus ) for oral consumption prior to breeding. Whereas, control bait-treated females produced normal-sized litters (10.0 ± 1.7 pups/litter), treated females delivered no pups. Wild Norway male (n = 20) and female (n = 20) rats ( Rattus norvegicus ) were trapped, individually housed, and one group given free access to control bait, one group to active bait. Following three cycles of treatment-matched mating pairs, females consuming control bait (control) produced normal litter sizes (9.73 ± 0.73 pups/litter). Females who had consumed active bait (treated) produced no litters on breeding cycles one and two; however, 2 of 10 females produced small litters on the third mating cycle. In a fourth breeding cycle, control females were crossmated with treated males, and treated females were crossmated with control males. In both groups, some dams produced litters, while others did not. The differences in response reflect a heterogeneity in return to cyclicity between females. These results suggest a potential approach to integrated pest management by compromising fertility, and could provide a novel alternative to traditional poisons for reducing populations of wild rat pests.

Accelerated follicle depletion in vitro and in vivo in Sprague-Dawley rats using the combination of 4-vinylcyclohexene diepoxide and triptolide.

Rodent pests cause major damage to the world's agricultural crops and food stores. Rodenticides used since World War II did not lead to sustained reduction of rodent populations, and so fertility control is becoming attractive because rats reproduce with great efficiency. Chemical acceleration of ovarian failure via oral dosing also would improve management of rat pest populations. The chemical 4-vinylcyclohexene diepoxide (VCD) is orally efficacious, causing depletion of nonregenerating primordial ovarian follicles of Sprague-Dawley rats. However, to cause rapid reduction in pups in the first breeding cycle after dosing, all stages of ovarian follicle development must be targeted. To achieve this goal, the Chinese herb triptolide was tested because it can precipitate apoptosis and deplete growing follicles. The impact of triptolide was tested in cultured postnatal day 4 Sprague-Dawley rat pup ovaries. Triptolide at 5 nM caused 100% primordial, primary, and secondary follicle depletion after 8 days of culture, compared to 38% follicle depletion caused by VCD at 30 microM. Next, a palatable rat bait was developed, containing 1% VCD with increasing concentrations of triptolide at 25, 50, and 100 microg/kg body weight. Rats ate an average 3-6% of their body weight/day over 15 feeding days. Two days after the end of baiting, rats were euthanized to conduct necropsies and collect ovaries to count all follicular stages and corpora lutea. At 50 microg triptolide/kg body weight, there was significant reduction of all follicular stages; primordial follicles were 50% lower, secondary follicles were 64% lower, antral follicles were 80% lower, and there were no corpora lutea. These results suggest that combining VCD and triptolide in an oral bait leads to significantly compromised rat ovarian function and reduced ovulations, and is likely to reduce pup production.

Drinking water with uranium below the U.S. EPA water standard causes estrogen receptor-dependent responses in female mice.

BACKGROUND: The deleterious impact of uranium on human health has been linked to its radioactive and heavy metal-chemical properties. Decades of research has defined the causal relationship between uranium mining/milling and onset of kidney and respiratory diseases 25 years later. OBJECTIVE: We investigated the hypothesis that uranium, similar to other heavy metals such as cadmium, acts like estrogen. METHODS: In several experiments, we exposed intact, ovariectomized, or pregnant mice to depleted uranium in drinking water [ranging from 0.5 microg/L (0.001 microM) to 28 mg/L (120 microM). RESULTS: Mice that drank uranium-containing water exhibited estrogenic responses including selective reduction of primary follicles, increased uterine weight, greater uterine luminal epithelial cell height, accelerated vaginal opening, and persistent presence of cornified vaginal cells. Coincident treatment with the antiestrogen ICI 182,780 blocked these responses to uranium or the synthetic estrogen diethylstilbestrol. In addition, mouse dams that drank uranium-containing water delivered grossly normal pups, but they had significantly fewer primordial follicles than pups whose dams drank control tap water. CONCLUSIONS: Because of the decades of uranium mining/milling in the Colorado plateau in the Four Corners region of the American Southwest, the uranium concentration and the route of exposure used in these studies are environmentally relevant. Our data support the conclusion that uranium is an endocrine-disrupting chemical and populations exposed to environmental uranium should be followed for increased risk of fertility problems and reproductive cancers.