Transient and continued fetal/neonatal hypothyroidism affects epididymis, leydig cell and sertoli cell development

TRANSIENT AND CONTINUED FETAL/NEONATAL HYPOTHYROIDISM AFFECTS EPIDIDYMIS, LEYDIG CELL AND SERTOLI CELL DEVELOPMENT Previously the effects of neonatal hypothyroidism have been investigated using rather unphysiological approaches like propyl-thiouracil (PTU) treatment. These studies showed that PTU induced hypothyroidism delayed the development of epididymis, Sertoli and Leydig cells. In these studies PTU treatment was discontinued before day 28 post partum due to liver and kidney toxicity. Furthermore, it has recently been demonstrated that PTU influences Leydig cell function and possibly development directly, making it difficult to interpret the former hypothyroid data. In the present study a mild form of hypothyroidism was induced already during fetal development. Dams were fed an iodide-poor diet to which 0.5% perchlorate was added to deplete endogenous iodide stores, or received a control diet (iodide content according to the AIN-93 guidelines, 0% perchlorate). The hypothyroid diet was continued up to 0, 7, 14, 28, 35 of age, or continued through life (continuous hypothyroidism). Pups were sacrificed between days 16 and 64 after birth. No significant differences were found if treatment was discontinued at the age of 0 or 7 days. Transient hypothyroidism (14 or 28 days) resulted in a decrease in body and testis weight of the pups, whereas discontinuation of the diet after 35 days resulted in macro-orchidism. In contrast, continuous hypothyroidism did not result in absolute macro-orchidism. Leydig cell proliferation, as identified by BrdU and 3ß-HSD labelling, was slightly decreased by transient (>14d) and absolute hypothyroidism up to day 21 of age, and significantly increased above control levels from day 35 onwards. Plasma testosterone levels were significantly elevated from day 21 post partum onwards. In contrast to the controls, tubular lumen formation was significantly delayed in the testes of both transient and continuous hypothyroid rats. 5¿-reductase type 2 expression was decreased in the epididymis in the continuous hypothyroid group from day 28 onward. Furthermore we will show data on 5¿-reductase type 1 and 2 expression in both epididymis and testis, and thyroid hormone receptor ¿1 and ß1 mRNA and protein levels in testis. The data suggest that (transient) hypothyroidism over an age of 7 days influences both testis and epididymis maturation. Eddy Rijntjes, Department of Animal Sciences, Human and Animal Physiology Group, Marijkeweg 40, 6709 PG Wageningen, the Netherlands, tel: +31(0)317 482876, email eddy.rijntjes@wur.nl