Phthalate esters have been used extensively as plasticizers of synthetic polymers. Recent studies have revealed that these esters induce atrophy of the testis, although its pathogenesis remains unknown. The present study describes the possible involvement of oxidative stress in the pathogenesis of atrophy of the rat testis induced by di(2-ethylhexyl)phthalate (DEHP). Biochemical and immunohistochemical analysis revealed that oral administration of DEHP increased the generation of reactive oxygen species, with concomitant decrease in the concentration of glutathione and ascorbic acid in the testis, and selectively induced apoptosis of spermatocytes, thereby causing atrophy of this organ. Oxidative stress was selectively induced in germ cells, but not in Sertoli cells, treated with mono(2-ethylhexyl)phthalate (MEHP), a hydrolysed metabolite of DEHP. Furthermore, MEHP selectively induced the release of cytochrome c from mitochondria of the testis. These results indicate that oxidative stress elicited by MEHP principally injured mitochondrial function and induced the release of cytochrome c, thereby inducing apoptosis of spermatocytes and causing atrophy of the testis.
Ultraviolet B radiation increases DOPA-positive melanocytes in the skin specifically at the site of exposure. We found unexpectedly that ultraviolet B irradiation of the eye increased the concentration of alpha-melanocyte-stimulating hormone in plasma and systemically stimulated epidermal melanocytes in mice. To test the possible involvement of hypothalamopituitary proopiomelanocortin system in the systemic activation of skin melanocytes, ultraviolet B was also irradiated to the eye after hypophysectomy. Hypophysectomy strongly inhibited the ultraviolet B-induced stimulation of melanocytes. To elucidate the pathway by which ultraviolet B irradiation of the eye activated the hypothalamopituitary system, we examined the effect of bilateral ciliary ganglionectomy and denervation of the optic nerves on the ultraviolet B-induced melanocyte stimulation. Ciliary ganglionectomy, but not optic nerve denervation, strongly inhibited melanocyte stimulation by localized irradiation of the eye. Furthermore, melanocyte stimulation by localized ultraviolet B irradiation of the eye was not observed in mice that lack the inducible type of nitric oxide synthase. These results clearly indicate that a signal evoked by ultraviolet B irradiation of the eye is transmitted in a nitric oxide-dependent manner through the ciliary ganglia involving the first branch of the trigeminal nerve to the hypothalamopituitary proopiomelanocortin system, resulting in upregulation of alpha-melanocyte-stimulating hormone secretion and consequent stimulation of melanocytes in the skin. The novel network involving the trigeminal nerve and nitric oxide-dependent signaling pathway might play important parts in the activation of proopiomelanocortin-dependent biologic reactions, such as alpha-melanocyte-stimulating hormone-induced stimulation of melanocytes in the skin, in ultraviolet B-enriched environments.
Dietary nitrate is reduced to nitrite by some oral bacteria and the resulting nitrite is converted to nitric oxide (NO) in acidic gastric juice. The aim of this study is to elucidate the pathophysiological role of dietary nitrate in the stomach. Intragastric administration of nitrate rapidly increased nitrate and NO in plasma and the gastric headspace, respectively. Water-immersion-restraint stress (WIRS) increased myeloperoxidase (MPO) activity in gastric mucosa and induced hemorrhagic erosions by a nitrate-inhibitable mechanism. In animals that had received either cardiac ligation or oral treatment with povidone-iodine, a potent bactericidal agent, administration of nitrate failed to increase gastric levels of NO and to inhibit WIRS-induced mucosal injury. WIRS decreased gastric mucosal blood flow by a mechanism which was inhibited by administration of nitrate. These data suggested that the enterosalivary cycle of nitrate and related metabolites consisted of gastrointestinal absorption and salivary secretion of nitrate, its conversion to nitrite by oral bacteria and then to NO in the stomach might play important roles in the protection of gastric mucosa from hazardous stress.
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