The oxidation handicap hypothesis and the carotenoid allocation trade-off

The oxidation handicap hypothesis proposes that testosterone mediates the trade-off between the expression of secondary sexual traits and the fight against free radicals. Coloured traits controlled by testosterone can be produced by carotenoid pigments (yellow-orange-red traits), but carotenoids also help to quench free radicals. Recently, it has been shown that testosterone increases the amount of circulating carotenoids in birds. Here, a testosterone-mediated trade-off in the carotenoid allocation between colour expression and the fight against oxidative stress is proposed. Male red-legged partridges were treated with testosterone, anti-androgens or manipulated as controls. Testosterone-treated males maintained the highest circulating carotenoid levels, but showed the palest red traits and no evidence of oxidative damage. Increased levels of a key intracellular antioxidant (i.e. glutathione) indicated that an oxidative challenge was in fact induced but controlled. The trade-off was apparently solved by reducing redness, allowing increased carotenoid availability, which could have contributed to buffer oxidative stress.     

Prenatal exposure to testosterone impairs oxidative damage repair efficiency in the domestic chicken (Gallus gallus)

Elevated levels of maternal androgens in avian eggs affect numerous traits, including oxidative stress. However, current studies disagree as to whether prenatal androgen exposure enhances or ameliorates oxidative stress. Here, we tested how prenatal testosterone exposure affects oxidative stress in female domestic chickens (Gallus gallus) during the known oxidative challenge of an acute stressor. Prior to incubation, eggs were either injected with an oil vehicle or 5 ng testosterone. At either 17 or 18 days post-hatch, several oxidative stress markers were assessed from blood taken before and after a 20 min acute stressor, as well as following a 25 min recovery from the stressor. We found that, regardless of yolk treatment, during both stress and recovery all individuals were in a state of oxidative stress, with elevated levels of oxidative damage markers accompanied by a reduced total antioxidant capacity. In addition, testosterone-exposed individuals exhibited poorer DNA damage repair efficiencies in comparison with control individuals. Our work suggests that while yolk androgens do not alter oxidative stress directly, they may impair mechanisms of oxidative damage repair.     

Maternal dietary carotenoids mitigate detrimental effects of maternal GnRH on offspring immune function in Japanese quail Coturnix japonica

Maternal resources deposited in eggs can affect the development of several offspring phenotypic traits and result in trade‐offs among them. For example, maternal androgens in eggs may be beneficial to offspring growth and competitive ability, but detrimental to immunocompetence and oxidative stress. In contrast, maternal antioxidants in eggs may be beneficial if they mitigate oxidative stress and immunosuppressive effects of androgens. We investigated possible interactive effects of maternal steroids and carotenoids on aspects of offspring physiology and phenotype, by simultaneously manipulating levels of androgens (via gonadotropin‐releasing hormone, GnRH‐challenges) and carotenoids (via diet supplementation) in captive female Japanese quail Coturnix japonica during egg laying. Carotenoid supplementation of hens, which elevates yolk concentrations of carotenoid and vitamins A and E, enhanced egg hatching success, offspring survival to age 15 d, and size of the bursa of Fabricius in offspring. In contrast, repeated maternal GnRH challenges, which elevated yolk testosterone concentrations, enhanced offspring neonatal size, but negatively affected bursa size. However, interaction among the treatments suggests that the positive effect of maternal carotenoid supplementation on plasma bactericidal capacity was mediated by maternal GnRH challenges. Chicks originating from carotenoid‐supplemented hens were less immunosuppressed than those originating from carotenoid‐supplemented + GnRH‐challenged hens, which were less immunosuppressed than chicks from GnRH‐challenged females not supplemented with carotenoids. Females availability of carotenoid enriched diets allows them to enhance the development of offspring immune system via carotenoids and vitamins deposited in egg yolks and offset detrimental effects of androgens deposited by GnRH‐challenged females.     

An experimental test of the immunocompetence handicap hypothesis in a teleost fish: 11-ketotestosterone suppresses innate immunity in three-spined sticklebacks

The immunocompetence handicap hypothesis (ICHH) provides a functional explanation for how sexual ornaments can provide honest signals of male quality. A key aspect of this hypothesis is that testosterone (T) has a bimodal effect: a higher T level enhances the expression of ornaments (increasing mating success and, ultimately, fitness); however, at the same time, it suppresses immune function. Tests of the latter assumption, which have focused mainly on aspects of adaptive immunity in birds, led to equivocal results. We performed a hormone-implant experiment in male three-spined sticklebacks (Gasterosteus aculeatus) to test the key assumptions of the ICHH in a fish, where the dominant circulating androgen is 11-ketotestosterone (11kT) rather than T. Males were implanted with 11-ketoandrostenedione, which is a natural precursor of 11kT. Each individual's circulating 11kT level, ornamentation, and immunocompetence were measured 2 weeks later. In addition, we quantified oxidative tissue damage because the ICHH has been hypothesized to work via oxidative stress. We found that the males' 11kT levels correlated positively with ornamentation but negatively with immunocompetence, in particular, measures of innate immunity. Moreover, there was a trend for fish with high 11kT levels to suffer more from oxidative stress. Thus, our data provide support for the ICHH.     

Insight into redox-regulated gene networks in vascular cells

To understand the complex nature of the atherogenic response initiated by oxidative stress in vascular smooth muscle cells (vSMCs), computational prediction methodology was employed to define putative gene-gene and gene-environment interactions in vSMCs subjected to oxidative chemical stress. Computational relationships were derived from the global gene expression profiles of murine cells challenged with a chemical pro-oxidant to cause oxidative stress or cells treated with anti-oxidant prior to oxidative injury. Target clones were chosen based on their biological relevance within the context of the atherogenic response and included lysyl oxidase, matrix metalloproteinase 2, insulin like growth factor binding protein 5, and lymphocyte antigen 6c. Established biological relationships were derived computationally confirming the usefulness of the algorithm in uncovering novel biological relationships worthy of future investigation. Thus, the predictive algorithm can be a useful tool to advance the frontiers of biological discovery.     

An experimental test of the testosterone mediated oxidation handicap hypothesis in a wild bird

The oxidation handicap hypothesis (OHH) proposed that honesty in sexual signals is maintained when testosterone simultaneously promotes the development of elaborate signals and imposes an oxidative cost. Although there is evidence that testosterone enhances display traits in some cases, relatively few studies have tested the prediction that testosterone generates oxidative costs. We tested this prediction experimentally by administering testosterone (n = 14) and control (n = 14) implants to free-living common yellowthroat warblers (Geothlypis trichas) and quantifying testosterone and oxidative state before and 35 ± 15 days after implantation. We interpreted our experimental results in the context of a larger database of 83 unmanipulated males observed over five breeding seasons. In our observational data, testosterone was related to aspects of the carotenoid-based bib, but these relationships were age-dependent. Bib coloration was related to testosterone only for first time breeders, while bib size was positively and negatively associated with testosterone among experienced and inexperienced breeders, respectively. Two measures of oxidative metabolism—damage to DNA and total antioxidant capacity (TAC)—were unrelated to endogenous testosterone. Despite the correlation between endogenous testosterone and plumage, our experimental results failed to support the key prediction of the OHH. Testosterone treated males had higher levels of TAC upon recapture, but oxidative damage to DNA did not differ from controls. Because antioxidants can protect against the harmful effects of oxidative stress, one interpretation of our results is that males physiologically compensated for elevated testosterone, avoiding the honesty enforcing mechanism of the OHH. Taken together, our results suggest that testosterone is not a direct mediator of honest signaling in yellowthroats via its effects on oxidative stress.     

Oxidative damage and anti-oxidant capacity in two migratory bird species at a stop-over site

We quantified in the garden warbler (Sylvia borin) and the barn swallow (Hirundo rustica), two long-distance migratory songbirds, the early oxidative damage (ROMs) and plasma anti-oxidant capacity (OXY) variation of individuals caught at a stop-over site after a sustained flight across the sea, during spring migration. Our main goal was to quantify the oxidative damage and anti-oxidant capacity variation in these two migratory species in relation to fat and muscle stores. The birds were sampled in Ponza, a small island along the migratory route of these species. The levels of ROMs and OXY did not show any differences between the two species and in general were higher in individuals with higher fat and protein stores. Nevertheless, the balance between ROMs and OXY was better in individuals in good condition. These patterns were similar in both species. No sex differences emerged for both ROMs and OXY in the barn swallow, the only species that could be sexed. Both markers of oxidative stress did not show any significant variation across a 30-min restrained experiment. These data are the first of this kind in wild birds in a migratory context and suggest that individuals in better condition are exposed to lower oxidative stress, providing an indirect evidence of the oxidative cost caused by prolonged flights.     

Yolk testosterone reduces oxidative damages during postnatal development

Conditions experienced during early life can influence the development of an organism and several physiological traits, even in adulthood. An important factor is the level of oxidative stress experienced during early life. In birds, extra-genomic egg substances, such as the testosterone hormone, may exert a widespread influence over the offspring phenotype. Interestingly, testosterone can also upregulate the bioavailability of certain antioxidants but simultaneously increases the susceptibility to oxidative stress in adulthood. However, little is known about the effects of maternally derived yolk testosterone on oxidative stress in developing birds. Here, we investigated the role of yolk testosterone on oxidative stress of yellow-legged gull chicks during their early development by experimentally increasing yolk testosterone levels. Levels of antioxidants, reactive oxygen species and lipid oxidative damage were determined in plasma during nestlings'' growth. Our results revealed that, contrary to control chicks, birds hatched from testosterone-treated eggs did not show an increase in the levels of oxidative damage during postnatal development. Moreover, the same birds showed a transient increase in plasma antioxidant levels. Our results suggest that yolk testosterone may shape the oxidative stress-resistance phenotype of the chicks during early development owing to an increase in antioxidant defences and repair processes.     

Yolk testosterone, postnatal growth and song in male canaries

Avian eggs contain substantial amounts of maternal yolk androgens, which have been shown to modulate offspring phenotype. The first studies on the functional consequences of maternal yolk androgens have focused on early life stages and their role in sibling competition. However, recent longitudinal studies reported long-lasting effects of maternal yolk androgens on offspring phenotype, mostly concerning traits that are sensitive to androgens. This suggests that maternal yolk androgens could play an important role in sexual selection, since the expression of many male sexual characters is testosterone-dependent. Using male canaries as a model, we examined the consequences of an experimental elevation of yolk testosterone concentrations on early development as well as long-lasting effects particularly on song, which is one of the most important sexual characters in male songbirds. Elevated yolk testosterone concentrations inhibited male growth, possibly in interaction with an existent ectoparasite exposure. Males hatched from testosterone-treated eggs (T-males) did not have enhanced competitive skills, in contrast to previous studies. The elevation of yolk testosterone concentrations delayed song development but did not affect adult song phenotype. This is intriguing, as yolk testosterone possibly induced developmental stress, which is known to reduce song quality. We hypothesize that yolk testosterone has either no direct effect on adult song phenotype, or that positive effects are merged by the negative effects of developmental stress. Finally, females mated with T-males invested more in their clutch indicating that females either assess T-males as more attractive (differential allocation hypothesis) or compensated for lower offspring viability (compensation hypothesis).     

Fat-loaded HepG2 spheroids exhibit enhanced protection from Pro-oxidant and cytokine induced damage

The mechanisms by which steatosis renders hepatocytes susceptible to damage in non-alcoholic steatohepatitis (NASH) are unclear although fat accumulation is believed to increase hepatocyte susceptibility to inflammatory cytokines and oxidative stress. We therefore investigated the susceptibility of steatotic, hepatocyte-derived cells to TNFalpha and the pro-oxidant, t-butylhydroperoxide (TBH). HepG2 spheroids rendered steatotic by fat-loading with 0.15 mM oleic or palmitic acid for 48 h and treated with TNFalpha or TBH for 18 h exhibited surprisingly lower levels of cytotoxicity, and increased anti-oxidant activity (superoxide dismutase (SOD)) compared with non fat-loaded controls. The protective effect of steatosis was significantly reversed by the inhibition of AMP-activated kinase (AMPK) since spheroids transfected with a kinase-dead AMPKalpha2 subunit, exhibited a significant increase in TBH-induced cytotoxicity when fat-loaded. In conclusion, our findings suggest that fat-loaded hepatocyte-derived cells are surprisingly less susceptible to cytokine and pro-oxidant induced damage via an adaptive mechanism dependent, in part, on AMPK activity.     

Regulation of immunocompetence by different androgen metabolites in a blenny with alternative reproductive tactics

In Parablennius parvicornis, small reproductive males with relatively low expression of secondary sexual characters (M- morphotype) parasite on the parental investment of the larger nest-holder males which have fully developed secondary sexual characters (M+ morphotype). In comparison with M+ males, M- males have relatively low levels of androgens while having high blood cell percentages of lymphocytes and antigen responsiveness. Here we test the hypothesis that androgens are a causal factor for these differences in immunocompetence between morphotypes. After drawing an initial blood sample, males received a silastic implant containing either oil only (C), or oil with testosterone (T) or 11-ketotestosterone (KT). Males were re-caught 2 weeks later for drawing of the final blood sample. KT but not T induced the development of secondary sexual characters in M- males. M- males treated with KT showed lower swimming activity than the males treated with T or C implants, suggesting that KT also mediates behavioral changes in M- males. As expected, blood cell percentages of lymphocytes, but not of granulocytes, were higher in M- males than in M+ males. Overall, lymphocyte percentages increased in the C group which might have been a response to the surgery/treatment. In concordance with the hypothesis, lymphocyte percentages were suppressed in males treated with T in comparison with controls. However, no significant change was found in KT-treated males. This suggests that androgens modulate central, morphological and immunological traits by partly independent androgen mechanisms in P. parvicornis.     

Effect of testosterone on oxidative stress and cell damage induced by 3-nitropropionic acid in striatum of ovariectomized rats

This paper evaluates the effects of testosterone (0.5 mg/kg subcutaneously (s.c.) for 8 days) on oxidative stress and cell damage induced by 3-nitropropionic acid (20 mg/kg intraperitoneally (i.p.) for 4 days) in ovariectomized rats. Gonadectomy triggered oxidative damage and cell loss, evaluated by the detection of caspase-3, whereas 3-nitropropionic acid increased the levels of oxidative stress induced by ovariectomy and prompted cell damage characterized by enhanced levels of lactate dehydrogenase. These changes were blocked by testosterone administration. Our results support the following conclusions: i) ovariectomy triggers oxidative and cell damage via caspase-3 in the striatum; ii) 3-nitropropionic acid exacerbates oxidative stress induced by ovariectomy and leads to cell damage characterized by increased levels of lactate dehydrogenase; iii) testosterone administration decreases oxidative stress and cell damage. Additionally, these data support the hypothesis that testosterone might play an important role in the onset and development of neurodegenerative diseases.     

Honest sexual signalling mediated by parasite and testosterone effects on oxidative balance

Extravagant ornaments evolved to advertise their bearers'' quality, the honesty of the signal being ensured by the cost paid to produce or maintain it. The oxidation handicap hypothesis (OHH) proposes that a main cost of testosterone-dependent ornamentation is oxidative stress, a condition whereby the production of reactive oxygen and nitrogen species (ROS/RNS) overwhelms the capacity of antioxidant defences. ROS/RNS are unstable, very reactive by-products of normal metabolic processes that can cause extensive damage to key biomolecules (cellular proteins, lipids and DNA). Oxidative stress has been implicated in the aetiology of many diseases and could link ornamentation and genetic variation in fitness-related traits. We tested the OHH in a free-living bird, the red grouse. We show that elevated testosterone enhanced ornamentation and increased circulating antioxidant levels, but caused oxidative damage. Males with smaller ornaments suffered more oxidative damage than those with larger ornaments when forced to increase testosterone levels, consistent with a handicap mechanism. Parasites depleted antioxidant defences, caused oxidative damage and reduced ornament expression. Oxidative damage extent and the ability of males to increase antioxidant defences also explained the impacts of testosterone and parasites on ornamentation within treatment groups. Because oxidative stress is intimately linked to immune function, parasite resistance and fitness, it provides a reliable currency in the trade-off between individual health and ornamentation. The costs induced by oxidative stress can apply to a wide range of signals, which are testosterone-dependent or coloured by pigments with antioxidant properties.     

Testosterone and oxidative stress: the oxidation handicap hypothesis

Secondary sexual traits (SST) are usually thought to have evolved as honest signals of individual quality during mate choice. Honesty of SST is guaranteed by the cost of producing/maintaining them. In males, the expression of many SST is testosterone-dependent. The immunocompetence handicap hypothesis has been proposed as a possible mechanism ensuring honesty of SST on the basis that testosterone, in addition to its effect on sexual signals, also has an immunosuppressive effect. The immunocompetence handicap hypothesis has received mixed support. However, the cost of testosterone-based signalling is not limited to immunosuppression and might involve other physiological functions such as the antioxidant machinery. Here, we tested the hypothesis that testosterone depresses resistance to oxidative stress in a species with a testosterone-dependent sexual signal, the zebra finch. Male zebra finches received subcutaneous implants filled with flutamide (an anti-androgen) or testosterone, or kept empty (control). In agreement with the prediction, we found that red blood cell resistance to a free radical attack was the highest in males implanted with flutamide and the lowest in males implanted with testosterone. We also found that cell-mediated immune response was depressed in testosterone-treated birds, supporting the immunocompetence handicap hypothesis. The recent finding that red blood cell resistance to free radicals is negatively associated with mortality in this species suggests that benefits of sexual signalling might trade against the costs derived from oxidation.     

The many faces of the octahedral ferritin protein

Iron is an essential trace nutrient required for the active sites of many enzymes, electron transfer and oxygen transport proteins. In contrast, to its important biological roles, iron is a catalyst for reactive oxygen species (ROS). Organisms must acquire iron but must protect against oxidative damage. Biology has evolved siderophores, hormones, membrane transporters, and iron transport and storage proteins to acquire sufficient iron but maintain iron levels at safe concentrations that prevent iron from catalyzing the formation of ROS. Ferritin is an important hub for iron metabolism because it sequesters iron during times of iron excess and releases iron during iron paucity. Ferritin is expressed in response to oxidative stress and is secreted into the extracellular matrix and into the serum. The iron sequestering ability of ferritin is believed to be the source of the anti-oxidant properties of ferritin. In fact, ferritin has been used as a biomarker for disease because it is synthesized in response to oxidative damage and inflammation. The function of serum ferritin is poorly understood, however serum ferritin concentrations seem to correlate with total iron stores. Under certain conditions, ferritin is also associated with pro-oxidant activity. The source of this switch from anti-oxidant to pro-oxidant has not been established but may be associated with unregulated iron release from ferritin. Recent reports demonstrate that ferritin is involved in other aspects of biology such as cell activation, development, immunity and angiogenesis. This review examines ferritin expression and secretion in correlation with anti-oxidant activity and with respect to these new functions. In addition, conditions that lead to pro-oxidant conditions are considered.     

环境污染物对水生生物产生氧化压力的分子生物标志物

为了能够建立一种简单、快速、准确的环境污染监测预警体系,人们进行了广泛的研究,其中有关环境污染物对分子生物标志物的影响已成为研究热点。生物体内的氧自由基和其它活性氧分子（ROS）对组织和细胞成分造成的伤害,称之为氧化压力,环境中的有毒物质能够对生物体产生不同程度的氧化压力。生物体内的强氧化剂或体外因素（如环境污染物）引起的强氧化物与抗氧化防御系统之间的平衡能够用于评估环境压力对生物体产生影响的程度,尤其适合于评估不同种化学物质引起氧化损伤的程度。这些抗氧化防御系统及其对氧化压力的敏感性在环境毒物学研究中占有非常重要的地位,大量研究结果表明：过渡金属、多环芳烃、有机氯和有机磷农药、多氯联苯、二氧芑和其它异型物质都能够对生物体产生氧化压力。这些有毒物质能够引起各种有害影响,如对膜脂、DNA和蛋白产生损伤;改变抗氧化酶的活性等。总结了这种氧化压力的研究进展情况,并讨论了这些分子生物标志物在水生生物中的应用。     

Relationship between oxidative stress and circulating testosterone and cortisol in pre-spawning female brown trout

Reproduction in vertebrates is an energy-demanding process that is mediated by endogenous hormones and potentially results in oxidative stress. The primary aim of this study was to quantify the relationship between oxidative stress parameters (antioxidant capacity and levels of reactive oxygen metabolites) and circulating testosterone and cortisol in a common and widespread teleost fish, the brown trout (Salmo trutta, L.). Results show that trout with higher testosterone levels prior to spawning have higher levels of oxidative damage at the time that they spawn (although by the time of spawning testosterone levels had dropped, leading to a negative relationship between testosterone and oxidative damage at that time). Cortisol levels were not directly related to oxidative damage or antioxidant capacity, but concentrations of this hormone were positively related to levels of fungal infection, which was itself associated both with lower antioxidant capacity and lower levels of oxidative damage. These results highlight the complexity of interactions between different components of the endocrine system and metabolism and suggest that caution be used in interpreting relationships between a single hormone and indicators of oxidative balance or other fitness proxies.     

Embryonic and posthatching treatments with sex steroids demasculinize the motivational aspects of crowing behavior in male Japanese quail

Demasculinizing action of embryonic estrogen on crowing behavior in male Japanese quails was examined. Eggs were treated with either 20 μg of estradiol benzoate (EB) or vehicle on the 10th day of incubation. Chicks hatched from both groups of eggs were injected daily with either testosterone propionate (TP; 10 μg/g b.w.), 5α-dihydrotestosterone (DHT, a non-aromatizable androgen; 10 μg/g b.w.), or vehicle from 11 to 50 days after hatching, and during this period their calling behaviors were observed. Irrespective of embryonic treatments, all birds received posthatching treatment with either TP or DHT, but not with vehicle, emitted crows in place of distress calls in a stress (non-sexual) context of being isolated in a recording chamber. The posthatching TP, but not posthatching DHT, induced crowing in a sexual context (crowing in their home-cages) from much earlier age than posthatching vehicle in the birds received control embryonic treatment with vehicle. The same TP treatment, however, completely eliminated the crowing in a sexual context in the birds received EB during their embryonic life. In the birds treated with either posthatching DHT or posthatching vehicle, the crowing in a sexual context was only slightly decreased by embryonic EB treatment. These data suggest that posthatching estrogen, derived from testosterone aromatization, enhances the demasculinizing action of embryonic estrogen, and thus strongly reduces the sexual motivation for crowing behavior. This demasculinizing action, however, would not influence vocal control system which generates acoustic pattern of crowing in the presence of androgens allowing the birds to crow in a non-sexual context.     

Oxidative stress,circulating antioxidants,and dietary preferences in songbirds

Oxidative stress is an unavoidable consequence of metabolism and increases during intensive exercise. This is especially problematic for migratory birds that metabolize fat to fuel long-distance flight. Birds can mitigate damage by increasing endogenous antioxidants (e.g. uric acid) or by consuming dietary antioxidants (e.g. tocopherol). During flight, birds may increase protein catabolism of lean tissue which may increase circulating uric acid and many birds also consume an antioxidant-rich frugivorous diet during autumn migration. We evaluated three related hypotheses in a migratory passerine: (1) protein consumption is positively related to circulating antioxidants, (2) a dietary oxidative stressor [i.e. polyunsaturated fatty acid (PUFA)] influences antioxidant capacity and oxidative damage, and (3) oxidative stress influences dietary antioxidant preferences. White-throated Sparrows (Zonotrichia albicollis) consuming a high protein diet increased circulating uric acid; however, uric acid, antioxidant capacity, and oxidative stress did not differ between birds consuming a high PUFA versus a low PUFA diet, despite increased oxidative damage in high PUFA birds. Birds did not prefer antioxidant-rich diets even when fed high PUFA, low protein. We conclude that White-throated Sparrows successfully mitigated oxidative damage associated with a high PUFA diet and mounted an endogenous antioxidant response independent of uric acid, other circulating antioxidants, and dietary antioxidants.     

Androgens exacerbate motor asymmetry in male rats with unilateral 6-hydroxydopamine lesion

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopamine neuron loss in the nigrostriatal pathway that shows greater incidence in men than women. The mechanisms underlying this gender bias remain elusive, although one possibility is that androgens may increase dopamine neuronal vulnerability to oxidative stress. Motor impairment can be modeled in rats receiving a unilateral injection of 6-hydroxydopamine (6-OHDA), a neurotoxin producing nigrostriatal degeneration. To investigate the role of androgens in PD, we compared young (2 months) and aged (24 months) male rats receiving gonadectomy (GDX) and their corresponding intact controls. One month after GDX, rats were unilaterally injected with 6-OHDA, and their motor impairment and asymmetry were assessed 2 weeks later using the cylinder test and the amphetamine-induced rotation test. Plasma samples were also collected to assess the concentration of testosterone and advanced oxidation protein products, a product of oxidative stress. GDX decreased lesion-induced asymmetry along with oxidative stress and increased amphetamine-induced rotations. These results show that GDX improves motor behaviors by decreasing motor asymmetry in 6-OHDA-treated rats, an effect that may be ascribed to increased release of striatal dopamine and decreased oxidative stress. Collectively, the data support the hypothesis that androgens may underlie the gender bias observed in PD.