An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita.

X-linked adrenal hypoplasia congenita is a developmental disorder of the human adrenal gland that results in profound hormonal deficiencies and is lethal if untreated. We have isolated the gene responsible for the disease, DAX-1, which is deleted or mutated in X-linked adrenal hypoplasia patients. DAX-1 encodes a new member of the nuclear hormone receptor superfamily displaying a novel DNA-binding domain. The DAX-1 product acts as a dominant negative regulator of transcription mediated by the retinoic acid receptor.

The hypothalamus and photoperiodic control of FSH secretion by melatonin in the male Syrian hamster.

In the photoinhibited castrated male Syrian hamster, removal of the pineal gland or transfer to long photoperiods was followed by a rapid increase in the serum concentration of FSH. Levels were significantly above those of controls within 10 days. Central passive immunization of pineal-intact photoinhibited castrated animals against melatonin had a stimulatory effect on serum FSH levels, comparable with that observed following pinealectomy or transfer to short days. The effects of pinealectomy were blocked by programmed s.c. infusions of melatonin in a time-dependent manner. Serum FSH levels remained low in animals receiving 100 ng melatonin delivered over 10 h but the same mass of melatonin delivered over 4 h had no effect on the response to pinealectomy. Lesions of the anterior hypothalamus had no effect on the pinealectomy-induced increase of serum FSH in animals receiving saline infusions. However, in lesioned animals, programmed infusions of melatonin were no longer able to suppress the rise in FSH following pinealectomy. These results demonstrated that pineal melatonin is the mediator of central photoperiodic control of FSH secretion. The duration of the melatonin signal determines its effectiveness and an intact anterior hypothalamus is necessary for the signal to be read and/or the appropriate neuroendocrine response expressed.

A more realistic animal technique for predicting human eye response.

The FHSA test (CPSC, 1981) for eye irritation in rabbits overpredicts the likely response of the human eye. Nineteen different chemicals, mixtures or solutions that had different degrees of recognized irritancy potential to the human eye were tested in albino rabbit eyes at dose volumes of 0.003, 0.01, 0.03 and 0.1 ml. The material was administered directly onto the rabbit cornea, without forced closing of the eyelid and without rinsing. A dose volume of 0.01 ml most often gave results that were consistent with information on effects of human eye exposures. The report of this work (Griffith et al. Toxic. appl. Pharmac. 1980, 55, 501) recommended that this more realistic 'low-volume' technique (0.01 ml of test material) should replace the FHSA test (0.1 ml of test material). The recovery times of human eyes after accidental exposure to consumer products in the USA, either during manufacture or in incidents involving consumers, were compared with the number of days-to-clear of rabbit eyes (tested in either the FHSA or the low-volume test) or monkey eyes exposed to the same products. Over 500 incidents involving human eyes (over several years) are included in the review. All three animal techniques are shown to overestimate the severity of the human eye response, the FHSA method being the worst in this respect. Only the results of the low-volume rabbit test show a statistically significant correlation (P less than 0.05 r greater than 0.5) with human experience. It is recommended that this low-volume test in rabbits should replace the FHSA test as the internationally agreed test for eye-irritancy potential because it correlates best with the response of the human eye.