The toxicity profile of HIDROX (Hydrolyzed Aqueous Olive Pulp Extract; OPE) was characterized in a series of toxicology studies. A limit dosage of 2000 mg/kg produced no toxicity in mice (acute oral NOAEL: 2000 mg/kg). In rats, an acute oral NOAEL of 2000 mg/kg was established, based on reductions in weight gains in both sexes at 5000 mg/kg. Reduced gains in female rats at 1500 and 2000 mg/kg were not significantly different from control values. Daily oral dosages of 1000, 1500 and 2000 mg/kg/day for 90 days produced small decreases in body weight gains at 2000 mg/kg/day in the male rats and in all groups of female rats. Feed consumption was comparable to controls. There were no adverse clinical, hematologic, biochemical, organ weight or gross necropsy effects. Focal, minimal or mild hyperplasia of the mucosal squamous epithelium of the limiting ridge of the forestomach occurred in some rats at 2000 mg/kg/day; this change was attributed to local irritation by repeated intubation of large volumes of viscous, granular dosing suspension. A NOAEL of 2000 mg/kg/day was established for the 90-day study, based on the lack of significant adverse effects. Toxicokinetic data indicated that hydroxytyrosol (HT, the major component of OPE) was rapidly absorbed. Mean concentrations were measurable through 1 to 4 hours (t(last)) at 1000 and 1500 mg/kg/day and through 8 hours at 2000 mg/kg/day. Dosages of OPE ranging from 500 to 2000 mg/kg/day did not adversely affect any of the mating, fertility, delivery or litter parameters investigated in an oral rat dosage-range reproduction study. Adverse effects were also absent in a rat developmental toxicity study in which pregnant dams were treated with 1000, 1500 or 2000 mg/kg/day on days 6 through 20 of gestation. Plasma levels for pregnant and lactating rats were comparable to non-pregnant rats; minimal levels crossed the placenta. Quantifiable levels were not identified in maternal milk or plasma from nursing pups. A bacterial reverse mutation and a CHO chromosome aberration assay revealed evidence of mutagenic activity at high dosages with S9 metabolic activation. However, three rat micronucleus evaluations performed after single and repeated (28-day) dosages of up to 2000 mg/kg/day and dosages of 5000 mg/kg/day for 29 days resulted in negative findings; therefore, OPE was not considered to be mutagenic in this in vivo assay.

Skin lightening among Eurasians is thought to have been a convergence occurring independently in Europe and East Asia as an adaptation to high latitude environments. Among Europeans, several genes responsible for such lightening have been found, but the information available for East Asians is much more limited. Here, a genome-wide comparison between dark-skinned Africans and Austro-Asiatic speaking aborigines and light-skinned northern Han Chinese identified the pigmentation gene OCA2, showing unusually deep allelic divergence between these groups. An amino acid substitution (His615Arg) of OCA2 prevalent in most East Asian populations—but absent in Africans and Europeans—was significantly associated with skin lightening among northern Han Chinese. Further transgenic and targeted gene modification analyses of zebrafish and mouse both exhibited the phenotypic effect of the OCA2 variant manifesting decreased melanin production. These results indicate that OCA2 plays an important role in the convergent skin lightening of East Asians during recent human evolution.

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Background Cadmium (Cd) is considered a heavy metal and potential pollutant to the environment. Purpose The purpose of this study was to evaluate the protective potential of piceatannol (PT; 10 mg/kg body weight/day) against cadmium (Cd; 5 mg/kg body weight/day)-induced testicular dysfunction in Wistar rats. Materials and methods Rats were randomly divided into four groups: control, PT, Cd, and Cd + PT. Results Treatment with Cd resulted in a significant decrease in body, testicular, and epididymal weights, sperm quantity and quality, steroidogenic marker–enzyme activities, mRNA- and protein-expression levels of SF1, StAR, and P450 side chain–cleaving enzyme, and serum male sex hormonal levels when compared to controls. Testicular malondialdehyde levels were significantly increased, with a significant reduction in enzymatic and nonenzymatic antioxidants in Cd-treated rats compared to control rats. Testicular histomorphometric results supported the biochemical and molecular alterations observed in the study. In addition, significant downregulation in mRNA- and protein-expression levels of cytosolic Nrf2, HO1, γGCS, GPx, and NQO1, as well as significant upregulation in mRNA- and protein-expression levels of Nrf2 and Keap1 in testicular tissue, were noticed in rats administered Cd. PT treatment inCd-treated rats caused marked alleviation in body and organ weights, sperm analysis, steroidogenesis, serum hormonal levels, histomorphometric changes, and oxidative and antioxidative status in testes when compared to Cd alone–treated rats. Further, treatment of rats with PTl showed a marked improvement in mRNA- and protein-expression levels of Nrf2 and its regulated genes and proteins. Conclusion The present study provides compelling evidence that PT treatment results in significant protection against Cd-induced testicular dysfunctions, such as spermatogenesis, steroidogenesis, and oxidative stress in rats, possibly through modification of the Nrf2–Keap1 signalling pathway.

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