Nonylphenol (NP) treatment of neonatal male rat pups decreased the size of their testes, epididymis, seminal vesicle, and ventral prostate, and increased the frequency of cryptorchidism (60.7%, n = 56 vs 0% in vehicle-treated control, n = 58) when examined at 31 d of age. NP effects are dose-dependent. These effects were only seen when NP was given at > or =20.8 mg/kg daily for 15 d. There is a critical period of vulnerability to NP during male reproductive development in the neonatal stage. Changes were found when NPs were given to male pups before 13 d of age, but not when given at > or =13 d of age. NP acts on the male reproductive tissues through the estrogen receptor (ER), since concomitant treatment with ICI 182,780, a specific ER antagonist, blocked NP's effects on the testis and male accessory organs. NP-treated males in the neonatal period had greatly reduced their subsequent capacity to impregnate young fertile females. Our results suggest that exposure of neonatal male rats to NP is potentially deleterious to their reproductive development and affects their reproductive performance.

Neonatal hypoxia is a common condition resulting from pulmonary and/or cardiac dysfunction. Dexamethasone therapy is a common treatment for many causes of neonatal distress, including hypoxia. The present study examined the effects of dexamethasone treatment on both normoxic and hypoxic neonatal rats. We performed comprehensive hepatic fatty acid/lipid profiling and evaluated changes in pertinent plasma hormones and lipids and a functional hepatic correlate, i.e. hepatic lipase activity. Rats were exposed to hypoxia from birth to 7 d of age. A 4-d tapering dose regimen of dexamethasone was administered on: postnatal day (PD)3 (0.5 mg/kg), PD4 (0.25 mg/kg), PD5 (0.125 mg/kg), and PD6 (0.05 mg/kg). The most significant finding was that dexamethasone attenuated nearly all hypoxia-induced changes in hepatic lipid profiles. Hypoxia increased the concentration of hepatic triacylglyceride and free fatty acids and, more specifically, increased a number of fatty acid metabolites within these lipid classes. Administration of dexamethasone blocked these increases. Hypoxia alone increased the plasma concentration of cholesterol and triacylglyceride, had no effect on plasma glucose, and only tended to increase plasma insulin. Dexamethasone administration to hypoxic pups resulted in an additional increase in plasma lipid concentrations, an increase in insulin, and a decrease in plasma glucose. Hypoxia and dexamethasone treatment each decreased total hepatic lipase activity. Normoxic pups treated with dexamethasone displayed increased plasma lipids and insulin. The effects of dexamethasone on hepatic function in the hypoxic neonate are dramatic and have significant implications in the assessment and treatment of metabolic dysfunction in the newborn.

Lactational exposure of male rat pups to nonylphenols (NPs) decreased the size of their testes and male accessory glands. At 31 d of age, NP-treatment of male rats resulted in less cellular differentiation of the seminiferous tubules (STs) and increased intertubular space compared to controls. At maturity, NP-treated males showed varying degrees of abnormalities in the affected testes. In the moderately affected ones, about 20-30% of their STs had poorly differentiated germinal elements. Cell lineage was less organized. In extreme cases, all STs of the affected testis failed to differentiate into germinal elements. These abnormalities in germinal element differentiation might be the primary cause for a number of the NP-treated males having a lower epididymal sperm count and a lower percentage of motile sperm compared to age-matched control males. Zymogram analysis of testis homogenates by sodium dodecyl sulfate gelatin gels revealed two major forms (64-66 kDa and 50-52 kDa) of gelatinases. Only the 50-52-kDa form was greatly reduced or absent in the affected testis. Lactational exposure of male pups to NPs thus leads to various testicular abnormalities including lack of differentiation of STs, lowering of sperm count, and reduction in the percentage of motile sperm and modulation of a specific form of testicular proteinases.

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Increases in plasma lipids occur during hypoxia in suckling but not in weaned rats and may result from altered hepatic enzyme activity. We exposed rats to 7 days of hypoxia from birth to 7 days of age (suckling) or from 28 to 35 days of age (weaned at day 21). Hypoxia led to an increase in hepatic lipid content in the suckling rat only. Hepatic lipase was decreased to approximately 45% of control in 7-day-old rats exposed to hypoxia but not in hypoxic 35-day-old rats. Hypoxic suckling rats also had a 50% reduction in lactate dehydrogenase activity, whereas transaminase activity and CYP1A and CYP3A protein content were not different between hypoxic and normoxic groups. Additional rats were studied 7 and 14 days after recovery from hypoxic exposure from birth to 7 days of age; hepatic lipase activity had recovered to 85% by 7 days and to 100% by 14 days in the rats previously exposed to hypoxia. Administration of dexamethasone to neonatal rats to simulate the hyperglucocorticoid state found in hypoxic 7-day-old rats led to a moderate decrease ( approximately 75% of control) in hepatic lipases. Developmentally, in the normoxic state, hepatic lipases increased rapidly after birth and reached levels more than twofold that of the newborn by 7 days of age. Hypoxia delays the maturation of hepatic lipases. We suggest that the decrease in hepatic lipase activity contributes to hyperlipemia in the hypoxic newborn rats.