Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene

The formation of estrogens from C19 steroids is catalyzed by aromatase cytochrome P450 (P450arom), the product of the cyp19 gene. The actions of estrogen include dimorphic anatomical, functional, and behavioral effects on the development of both males and females, considerations that prompted us to examine the consequences of deficiency of aromatase activity in mice. Mice lacking a functional aromatase enzyme (ArKO) were generated by targeted disruption of the cyp19 gene. Male and female ArKO mice were born with the expected Mendelian frequency from F1 parents and grew to adulthood. Female ArKO mice at 9 weeks of age displayed underdeveloped external genitalia and uteri. Ovaries contained numerous follicles with abundant granulosa cells and evidence of antrum formation that appeared arrested before ovulation. No corpora lutea were present. Additionally the stroma were hyperplastic with structures that appeared to be atretic follicles. Development of the mammary glands approximated that of a prepubertal female. Examination of male ArKO mice of the same age revealed essentially normal internal anatomy but with enlargement of the male accessory sex glands because of increased content of secreted material. The testes appeared normal. Male ArKO mice are capable of breeding and produce litters of approximately average size. Whereas serum estradiol levels were at the limit of detection, testosterone levels were elevated, as were the levels of follicle-stimulating hormone and luteinizing hormone. The phenotype of these animals differs markedly from that of the previously reported ERKO mice, in which the estrogen receptor α is deleted by targeted disruption.

Targeted ablation of the 25-hydroxyvitamin D 1α-hydroxylase enzyme: Evidence for skeletal, reproductive, and immune dysfunction

The active form of vitamin D, 1α,25-dihydroxyvitamin D [1α,25(OH)2D], is synthesized from its precursor 25 hydroxyvitamin D [25(OH)D] via the catalytic action of the 25(OH)D-1α-hydroxylase [1α(OH)ase] enzyme. Many roles in cell growth and differentiation have been attributed to 1,25(OH)2D, including a central role in calcium homeostasis and skeletal metabolism. To investigate the in vivo functions of 1,25(OH)2D and the molecular basis of its actions, we developed a mouse model deficient in 1α(OH)ase by targeted ablation of the hormone-binding and heme-binding domains of the 1α(OH)ase gene. After weaning, mice developed hypocalcemia, secondary hyperparathyroidism, retarded growth, and the skeletal abnormalities characteristic of rickets. These abnormalities are similar to those described in humans with the genetic disorder vitamin D dependent rickets type I [VDDR-I; also known as pseudovitamin D-deficiency rickets (PDDR)]. Altered non-collagenous matrix protein expression and reduced numbers of osteoclasts were also observed in bone. Female mutant mice were infertile and exhibited uterine hypoplasia and absent corpora lutea. Furthermore, histologically enlarged lymph nodes in the vicinity of the thyroid gland and a reduction in CD4- and CD8-positive peripheral T lymphocytes were observed. Alopecia, reported in vitamin D receptor (VDR)-deficient mice and in humans with VDDR-II, was not seen. The findings establish a critical role for the 1α(OH)ase enzyme in mineral and skeletal homeostasis as well as in female reproduction and also point to an important role in regulating immune function.

Vanuatu fossil coral SST reconstruction for 4200 yr BP

We present a 47-year-long record of sea surface temperature (SST) derived from Sr/Ca and U/Ca analysis of a massive Porites coral which grew at ~4150 calendar years before present (B.P.) in Vanuatu (southwest tropical Pacific Ocean). Mean SST is similar in both the modern instrumental record and paleorecord, and both exhibit El Niño-Southern Oscillation (ENSO) frequency SST oscillations. However, several strong decadal-frequency cooling events and a marked modulation of the seasonal SST cycle, with power at both ENSO and decadal frequencies, are observed in the paleorecord, which are unprecedented in the modern record.

(Table A1) Uranium and Thorium determination from IODP Site 310-M0007B

The Integrated Ocean Drilling Program (IODP) Expedition 310 recovered drill cores from the drowned reefs around the island of Tahiti (17°40'S, 149°30'W), many of which contained samples of massive corals from the genus Porites. Herein we report on one well-preserved fossil coral sample: a 13.6 cm long Porites sp. dated by uranium series techniques at 9523 ± 33 years. Monthly delta18O and Sr/Ca determinations reveal nine clear and robust annual cycles. Coral delta18O and Sr/Ca determinations estimate a mean temperature of ca. 24.3°C (ca. 3.2°C colder than modern) for Tahiti at 9.5 ka; however, this estimate is viewed with caution since potential sources of cold bias in coral geochemistry remain to be resolved. The interannual variability in coral delta18O is similar between the 9.5 ka coral record and a modern record from nearby Moorea. The seasonal cycle in coral Sr/Ca is approximately the same or greater in the 9.5 ka coral record than in modern coral records from Tahiti. Paired analysis of coral delta18O and Sr/Ca indicates cold/wet (warm/dry) interannual anomalies, opposite from those observed in the modern instrumental record.