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Perinatal exposure to lead alters male reproductive behaviour and immunoreactivity of androgen and oestrogen receptors in the brain
Abstract
Lead (Pb) exposure during perinatal development alters testosterone (T) concentrations and delays puberty in children and laboratory rodents. In addition, exposure to the metal during adult life decreases T and libido in men and affects male reproductive behaviour (MRB) in rats. MRB is regulated by various brain nuclei including the medial preoptic area (MPOa) and the medial amygdala (MeA), in which T and oestradiol (E 2 ) act through their respective androgen (AR) and oestrogen (ER) receptors. However, the mechanism by which MRB is affected by Pb exposure is not known. The objectives of the present study were to evaluate whether perinatal Pb exposure affects MRB and the number of cells immunoreactive to AR and ERα in the MPOa and the MeA. Male Wistar rats exposed to Pb (320 ppm) in drinking water from the beginning of pregnancy until weaning were used. The experimental group experienced significant alterations in MRB, an important decrease in T and E 2 concentrations, and a significant increase in Pb concentrations in the blood, MPOa (hypothalamus) and MeA. In addition, in the studied areas the number of cells immunoreactive to AR and ERα, or detected using the Nissl technique, decreased significantly. These results show that perinatal exposure to Pb alters MRB. This event may be related to a decrease in both the concentrations of sex hormones and the number of cells that express their receptors as well as in the neuronal Nissl staining population. This ultimately affects the quality of life of the individual.
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Aim
The present study evaluated the effect of lead exposure with and without zinc therapy on male sexual and erectile function.
Methods
Twenty male Wistar rats were randomly assigned into four groups; the control, zinc-treated, lead-exposed, lead + zinc-treated groups. Administrations were per os daily for 28 days.
Results
Zinc co-administration significantly improved absolute and relative penile weights and the latencies and frequencies of mount, intromission, and ejaculation in lead-exposed rats. Also, zinc ameliorated lead-induced reductions in motivation to mate and penile reflex/erection. These findings were accompanied by attenuation of lead-induced suppression of circulating nitric oxide (NO), penile cyclic guanosine monophosphate (cGMP), dopamine, serum luteinizing hormone, follicle-stimulating hormone, and testosterone. In addition, zinc alleviated lead-induced upregulation of penile activities of acetylcholinesterase and xanthine oxidase (XO), and uric acid (UA) and malondialdehyde (MDA) levels. Furthermore, zinc ameliorated the lead-induced decline in penile nuclear factor erythroid 2-related factor 2 (Nrf2) and reduced glutathione (GSH) levels, and catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) activities.
Conclusion
This study revealed that co-administration of zinc improves lead-induced sexual and erectile dysfunction by suppressing XO/UA-driven oxidative stress and upregulating testosterone via Nrf2-mediated signaling.
The effect of heavy metals (HMs) has been extensively studied. They cause diverse clinical manifestation through various mechanisms. Male fertility is among the most disturbing effect of HMs affecting family life in human and reproduction in animals. Notably among these effects is interference with the reproductive hormones, morphology and function of reproductive organs, sexual behaviors, and the spermiogram. Quercetin is a dietary flavanoid from edible plants and, has proven pharmacological properties in the treatment and management of many disease conditions. Quercetin ameliorates the adverse effects of HMs on male reproductive hormones by increasing the activity of 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase (17β-HSD) in the synthesis of testosterone. Quercetin chelates HMs, scavenge free radicals, and other cytotoxicant capable of disrupting the morphology and function of the male reproductive system. Apart from it neuroprotective activity on the pituitary gland and increased steroidogenesis, quercetin mitigate neurotransmitter that aid in copulation and improve histopathological changes in the brain due to HMs toxicity to improve sexual behavior. Quercetin was also found to be effective in increasing sperm count, daily sperm production, mortility, viability, and also decreased in the percentage of abnormal sperm morphology due to HMs toxicity. In conclusion quercetin was found to be effective in mitigating HMs toxicity that affects male fertility, and so, it is recommended to be incorporated into the treatment and management of HMs toxicity. Individuals who are at risk of HMs toxicity should take dietary plants that contain quercetin to minimize the effects of these metals.
Manganese (Mn) and lead (Pb) have been associated with the deregulation of the neuroendocrine system, which could potentially favor the appearance of precocious puberty (PP) in environmentally exposed children. This study aims to evaluate the exposure to Mn and Pb and their potential effects in anticipating puberty in school-aged children living near a ferromanganese alloy plant in Bahia, Brazil. Toenail, occipital hair and blood samples were collected from 225 school-aged children. Tanner’s scale was used for pubertal staging. Mn in blood (MnB), toenail (MnTn) and hair (MnH) and blood lead (PbB) levels were measured by graphite furnace atomic absorption spectrometry. Puberty-related hormone concentrations were determined by chemiluminescence. The age at which girls’ breasts began to develop was inversely correlated with weight-for-age, height-for-age and BMI-for-age Z-scores (p < 0.05); pubarche also had similar results. Mn biomarker levels did not present differences among pubertal classification nor among children with potential PP or not. Furthermore, Mn exposure was not associated with the age of onset of sexual characteristics for either girls or boys. However, PbB levels were positively correlated with boys’ pubic hair stages (rho = 0.258; p = 0.009) and associated with the age of onset of girls’ pubarche (β = 0.299, 95%CI = 0.055–0.542; p = 0.017). Testosterone and LH concentrations were statistically higher in boys with an increased PbB (p = 0.09 and p = 0.02, respectively). Prospective studies are needed to better assess the association between exposure to Mn and Pb and the early onset of puberty.
Lead is a prevalent heavy metal that pollutes the environment and accumulates in the human body via absorption, bioavailability, bioconcentration, and biomagnification disrupts the neurological, skeletal, reproductive, hematopoietic, renal, and cardiovascular systems. Lead's distinctive physical and chemical characteristics make it ideal for a variety of uses. It has been linked to human activities for ages and is harmful to health. This review article examines the long-term health consequences of lead exposure in humans. Acute and chronic symptoms of lead poisoning include kidney, brain, reproductive organ, and CNS/PNS damage. Toxic metals have a long half-life in the bone matrix and brain (2-3 years), causing neurological problems and bone loss. The article also shows the problems of high BPb in both men and women during pregnancy. Renal system blood lead levels of 30-60 g/dL may cause kidney failure in severe circumstances. The oxidative stress that occurs in human cells has also been explored. Finally, lead poisoning and lead buildup prevention and therapy have been reviewed. The use of micronutrients and antioxidants has demonstrated a reduction in harmful effects. Adults with BPb >45g/dL should have chelation, whereas children should receive succimer.
Estrogen receptor (ER) α is involved in several estrogen-modulated neural and peripheral functions. To determine its role in the expression of female and male reproductive behavior, a mouse line lacking the ERα in the nervous system was generated. Mutant females did not exhibit sexual behavior despite normal olfactory preference, and had a reduced number of progesterone receptor-immunoreactive neurons in the ventromedial hypothalamus. Mutant males displayed a moderately impaired sexual behavior and unaffected fertility, despite evidences of altered organization of sexually dimorphic populations in the preoptic area. In comparison, males deleted for both neural ERα and androgen receptor (AR) displayed greater sexual deficiencies. Thus, these data highlight a predominant role for neural ERα in females and a complementary role with the AR in males in the regulation of sexual behavior, and provide a solid background for future analyses of neuronal versus glial implication of these signaling pathways in both sexes.
Lead is one of ten hazardous chemicals of public health concern and is used in more than 900 occupations, including the battery, smelting, and mining industries. Lead toxicity accounts for 1.5% (900,000) of deaths annually in the world. In Indonesia, reports of high Blood Lead Level (BLL) were associated with residency in Used Lead Acid Battery (ULAB) recycling sites. The present study aims to investigate the BLL and the evidence of lead toxicity of children living in an ULAB recycling site in Bogor Regency, Indonesia. A cross-sectional study involving 128 children aged 1–5 years was conducted in September-October 2019. The socio-economic factors, BLL, nutritional status, and hematological parameters, were evaluated. Data were analyzed by univariate and bivariate using the Chi-Square test. Socio-economic factors revealed only 2.3% children have pica and 10.9% children have hand-to-mouth habits. Majority of parents had low income, education, and have stayed in the village for years. Analysis on BLL revealed that 69.5% children had BLL of >10 μg/dL, 25% had abnormal BMI, 23.4% had underweight, 53.9% had stunting, 33.6% had anemia, and 22.6% had basophilic stippling. The average BLL and hemoglobin levels of respondents were 17.03 μg/dL and 11.48 g/dL, respectively. Bivariate analysis revealed that children with high BLL had double risk of having underweight and protected from stunting. Analysis on the association between BLL and BMI for age revealed a higher risk to have abnormal BMI. The high BLL also had 1.017 times risk of developing anemia, and almost doubled risk of having basophilic stippling, although they were not statistically significant. In conclusion, the high BLL of children living in the ULAB recycling indicates that lead exposure as well as lead toxicity are still occurring in Cinangka Village, and alerts to the need for a systematic action to mitigate the exposure.
The preoptic area (POA) has long been recognized as a sleep center, first proposed by von Economo. The POA, especially the medial POA (MPOA), is also involved in the regulation of various innate functions such as sexual and parental behaviors. Consistent with its many roles, the MPOA is composed of subregions that are identified by different gene and protein expressions. This review addresses the current understanding of the molecular and cellular architecture of POA neurons in relation to sleep and reproductive behavior. Optogenetic and pharmacogenetic studies have revealed a diverse group of neurons within the POA that exhibit different neural activity patterns depending on vigilance states and whose activity can enhance or suppress wake, non-rapid eye movement (NREM) sleep, or rapid eye movement (REM) sleep. These sleep-regulating neurons are not restricted to the ventrolateral POA (VLPO) region but are widespread in the lateral MPOA and LPOA as well. Neurons expressing galanin also express gonadal steroid receptors and regulate motivational aspects of reproductive behaviors. Moxd1, a novel marker of sexually dimorphic nuclei (SDN), visualizes the SDN of the POA (SDN-POA). The role of the POA in sleep and other innate behaviors has been addressed separately; more integrated observation will be necessary to obtain physiologically relevant insight that penetrates the different dimensions of animal behavior.
The current research was constructed to throw the light on the protective possibility of Chlorella vulgaris (C. vulgaris) and Spirulina platensis (S. platensis) against lead acetate-promoted testicular dysfunction in male rats. Forty rats were classified into four groups: (i) control, (ii) rats received lead acetate (30 mg/kg bw), (iii) rats concomitantly received lead acetate and C. vulgaris (300 mg/kg bw), (vi) rats were simultaneously treated with lead acetate and S. platensis (300 mg/kg bw) via oral gavage for 8 weeks. Lead acetate promoted testicular injury as expressed with fall in reproductive organ weights and gonadosomatic index (GSI). Lead acetate disrupted spermatogenesis as indicated by sperm cell count reduction and increased sperm malformation percentage. Lead acetate-deteriorated steroidogenesis is evoked by minimized serum testosterone along with maximized follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. Testicular oxidative, inflammatory, and apoptotic cascades are revealed by elevated acid phosphatase (ACP) and sorbitol dehydrogenase (SDH) serum leakage, declined testicular total antioxidative capacity (TAC) with elevated total oxidative capacity (TOC), tumor necrosis factor alpha (TNF-α), caspase-3 levels, lessened androgen receptor (AR) expression, and histopathological lesions against control. Our research highlights that C. vulgaris or S. platensis therapy can modulate lead acetate-promoted testicular dysfunction via their antioxidant activity as expressed by elevated TAC and reduced TOC, immunomodulatory effect as indicated by lessened TNF-α level, and anti-apoptotic potential that was revealed by minimized caspase-3 levels. As well as restoration of testicular histoarchitecture, androgen receptor, steroidogenesis, and spermatogenesis were detected with better impacts to S. platensis comparing with C. vulgaris. Therefore, further clinical trials are needed to test S. platensis and C. vulgaris as a promising candidate in treating male infertility.
Objective: To investigate the hepatic and reproductive toxicity of dichlorvos and lead acetate on male Wistar rats.
Methods: Fifteen adult male Wistar rats (170-190 g) were randomly divided into three groups, with 5 rats in each group. Group 1 received 0.5 mL distilled water orally and served as the control group, while groups 2 and 3 were orally treated with 2 mg/kg body weight (b.w.) dichlorvos and 10 mg/kg b.w. lead acetate, respectively, for 55 days. Epididymal sperm, serum follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone concentrations, testicular 17 β-hydroxysteroid dehydrogenase activity (17β-HSD), androgen receptor expression, aspartate aminotransferase (AST), alanine aminotransferase (ALT), testicular oxidant and antioxidant enzymes were evaluated with standard methods.
Results: Sperm count, motility, morphology, FSH, LH, testosterone levels, 17β-HSD, androgen receptor expression, and catalase activity were significantly reduced in the dichlorvos and lead acetate treated groups as compared with the control group (P
Lead (Pb) exposure in early life affects brain development resulting in cognitive and behavioral deficits. Epidemiologic and experimental evidence of sex as an effect modifier of developmental Pb exposure is emerging. In the present study, we investigated Pb effects on behavior and mechanisms of neuroplasticity in the hippocampus and potential sex differences. To this aim, dams were exposed, from one month pre-mating to offspring weaning, to Pb via drinking water at 5 mg/kg body weight per day. In the offspring of both sexes, the longitudinal assessment of motor, emotional, and cognitive end points was performed. We also evaluated the expression and synaptic distribution of N-methyl-D-Aspartate receptor (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits at post-natal day (pnd) 23 and 70 in the hippocampus. Neonatal motor patterns and explorative behavior in offspring were affected in both sexes. Pb effects in emotional response and memory retention were observed in adult females only, preceded by increased levels of GluN2A and GluA1 subunits at the post-synapse at pnd 23. These data suggest that Pb exposure during development affects glutamatergic receptors distribution at the post-synaptic spine in females. These effects may contribute to alterations in selected behavioral domains.
Environmental pollutant effects on fertility sometime are irretrievable. The aim of this study was to investigate the effect of lead acetate and quercetin on tight (claudin 11 and occludin) and gap junctional (connexin 43) proteins and the integrity of the blood–testis barrier status. Experimental groups, including the lead acetate (Pb), quercetin (QE), lead acetate with quercetin (Pb + QE), and control mice, were treated at least one spermatogenic cycle. Gene expression of claudin 11 and occludin decreased in Pb + QE, Pb, and QE compared with the control group. Connexin 43 (Cx43) expression in the control and Pb groups was lower than in Pb + QE and QE. The immunohistochemical data were generally in line with these findings. In conclusion, the results showed that Pb exposure led to disorders in cellular interactions that affect testicular function; however, simultaneous treatment with quercetin did not alleviate these effects.
Graphical Abstract
The objective of this study was to evaluate male pubertal changes associated with environmental low-level lead (Pb) exposure. The study was conducted on 180 boys aged 15 years divided into 3 equal size groups: group 1 from El-Newayrat village, group 2 from Al-Shorafaa (0.5 and 10 km, respectively, from an industrialized area), and group 3 from Talla (25 km). Blood Pb levels (BLLs) were measured and pubertal changes evaluated by measurement of testicular volume (TV), and estimation of the follicle-stimulating hormone, luteinizing hormone, testosterone, estradiol, and prolactin. Blood Pb levels of children of El-Newayrat and Al-Shorafaa were significantly higher (6.38 [1.32] and 3.84 [0.79] μg/dL, respectively) than that of Talla children (1.85 [0.72]; P < 0.001), while height, weight, and TV were lower in boys in groups 1 and 2, compared to group 3. Genitalia and pubarche staging showed greatest retardation and marked bone growth delay in boys of group 1. Hormonal assays reported significant differences in boys of the industrialized areas when compared to that of Talla. Low-level Pb exposure in boys located near an industrial area was accompanied with altered male puberty indicators.
Objective:
The aim of this narrative review was to analyze the role played by brain areas, neurohormones and neurotransmitters in the regulation of emotional and sexual behavior in the male.
Methods:
We analyzed the currently available literature dealing with brain structures, neurotransmitters and neurohormones involved in the regulation of emotional and sexual behavior in the male.
Results:
A common brain pathway is involved in these two aspects. The Hippocampus seems to control the signals coming from the external environment, while the amygdala and the hypothalamus control the response to social stimuli. Stimulation of amygdala in the animal models increases sexual performance, while it triggers violent emotional responses. Stimulation of the hypothalamus causes reactions of violent anger and increases sexual activity. Catecholaminergic stimulation of the amygdala and hypothalamus increases emotional and sexual behavior, while serotonin plays an inhibitory role. Cholinergic inhibition leads to a suppression of copulatory activity, while the animal becomes hyperemotive. Opioids, such as β-endorphin and met-enkephalin, reduce copulatory activity and induce impotence. Gonadal steroid hormones, such as estrogen in female and testosterone in male, which play a major role in the control of sexual behavior and gender difference have been highlighted in this review. Vasopressin, oxytocin and their receptors are expressed in high density in the "social behavior neural network" and play a role as signal system controlling social behavior. Finally, the neuropeptide kisspeptin and its receptors, located in the limbic structures, mediate olfactory control of the gonadotropic axis.
Conclusion:
Further studies are needed to evaluate possible implications in the treatment of psychosexual and reproductive disorders.
Environmental exposure to toxic levels of lead (Pb) occurs in a number of industries with potential adverse effects on the reproductive capacity of exposed men. Clinical and animal studies indicate that abnormalities of spermatogenesis result from toxic lead exposure, but eventual histopathologic alterations involved have not been identified. To explore putative abnormalities in the reproductive gonadotropic axis following lead intoxication, experimental animals when exposed to low levels of lead, 65 days old animals were treated with distilled water containing 0, 0 mg (control), 10 mg lead (Pb)/Kg/day and 15 mg lead (Pb)/Kg/day intraperitoneally for 20 days. At the end of treatment, the animals were sacrificed and the blood collected for luteinizing hormone (LH) and testosterone assays. The testis was processed for histological analysis. The results showed a high serum concentration of LH and testosterone in lead-treated animals compared to controls. Histological examination of testis showed deformities in testicular morphology of lead intoxicated animals with gross damage within the somniferous tubules. A strong correlation was established between LH and testosterone suggesting an alteration in the endocrine components of the gonadotropic axis. Histological examination of pituitary gland showed some degenerative changes in endocrine cells of lead group. Changes in LH and testosterone levels suggest that Pb exposure during the critical time of sexual differentiation induces reproductive axis abnormalities in adulthood. In conclusion, lead has a gonadotoxic effect by decreasing LH and testosterone levels and damaging the testis seminiferous tubules. Catalase activity was significantly reduced in the lead group following 65 days of exposure which possibly indicates that lead might had other mechanisms of action, such as increasing oxidative damage.
Aim: This study was designed to evaluate the prophylactic effect of Nigella sativa (NS) treatment on toxic effects induced by lead acetate (LA) on the reproductive hormones, spermiogram and gonadal histology of rats.
Materials and Methods: A total of 20 Sprague-Dawley rats were divided into four groups of five rats each. Group 1 (negative control [NC]) was the NC and was given distilled water, Group 2 served as the positive control (PC) and was administered 10 mg/kg/day of LA per overall survival (OS), Group 3 (T1) was administered 200 mg/kg/daily of NS per OS for a month, and Group 4 (T2) was pretreated with 200 mg/kg/daily of NS per OS for 1 month, followed by 10 mg/kg/daily of LA alone per OS for another. The rats were euthanized at the end of the experimental period for collection of blood and the right caudal epididymis and testis. Serum was used for determination of reproductive hormones by using radioimmunoassay kits. The epididymal segment was cut and homogenized in phosphate-buffered saline, and the homogenate was used for determination of the spermiogram parameters such as sperm concentration, sperm viability, percentage of live sperm, motility and abnormality. Both the epididymis and testis were fixed in 10% buffered formalin for histological processing.
Results: The sperm concentration, general, and individual motilities were higher (p
Background:
In the present study, the oral effect of lead acetate on the parameters related to sexual behavior as well as changes in the level of testosterone hormone in adult male rats have been investigated.
Materials and methods:
Forty adult male Wistar rats were allocated into five equal groups. The control group received nothing, the sham group received distilled water and the experimental groups received 25, 50 and 100mg/kg lead acetate orally, respectively for 28 days. The changes in testosterone hormone level and following sexual behavior parameters were investigated: mount latency (ML), intromission latency (IL), post ejaculatory interval (PEI), mount frequency (MF), ejaculatory latency (EL), intromission frequency (IF), copulatory efficacy (CE) and intercopulatory interval (ICI).
Results:
The levels of testosterone hormone in the groups that received 50 and 100 mg/kg lead acetate showed significant decreases in compared to the control group. Additionally, the same doses of lead acetate caused significant increases in ML, IL, PEI and EL compared to the control group. No significant change was observed in MF, but a significant decrease was detected in IF and CE in the experimental group that received 100 mg/kg lead acetate when compared with the control group. ICI showed significant decreases in the experimental groups that received 50 and 100 mg/kg lead acetate compared to the control group.
Conclusion:
It can be concluded that ingestion of lead acetate affects some behavioral activities and the testosterone level of male rats. These effects might be conducted via the alteration of leydig cells following lead acetate poisoning.
Testosterone (T) profoundly influences central sexual differentiation and functions. In the brain, T signals either directly through androgen receptor (AR) or indirectly through estrogen receptor (ER) following aromatization into E2 (17-beta-estradiol). As T, through AR, also controls peripheral male sexual differentiation, the relative contribution of central AR in T-mediated regulation of behavioral and neuroendocrine responses still remains unclear. To address this question, we generated, by using Cre-loxP technology, mice selectively lacking AR expression in the nervous system. The mutant male urogenital tract was normally developed, and mice were able to produce offspring. Nonetheless, sexual motivation and performance as well as aggressive behaviors were affected. Only a low percentage of males displayed a complete sexual behavior and offensive attacks. The latency to show masculine behaviors was increased and copulation length prolonged. Erectile activity during mating was also altered. These alterations occurred despite increased levels of T and its metabolites, and an unaffected number of ERalpha-immunoreactive cells. Olfactory preference and neuronal activation, mapped by Fos immunoreactivity, following exposure to estrus female-soiled bedding were also normal. At comparable T levels, greater differences in masculine behaviors were observed between gonadectomized control and mutant males. AR invalidation in the nervous system also disrupted the somatotropic axis since mutant males exhibited growth retardation and decreased serum levels of insulin-like growth factor I. Our findings show that central AR is required in T-induced regulation of male-typical behaviors and gonadotrope and somatotropic axes. This genetic model offers a unique opportunity in the understanding of AR's role in cerebral functions of T.
Sprague-Dawley dams were administered lead acetate (0.1%) in their drinking water from Day 14 of gestation to parturition to determine whether exposure of the fetus to elevated lead (Pb) levels during a period of rapid differentiation of the hypothalamic-pituitary-gonadal (HPG) axis would disrupt HPG function in adulthood. At birth, offspring from 20 Pb-treated and 10 control dams were weighed and 2 litter representatives from each sex were fostered to untreated dams. Animals were weaned at 26 days of age and subsequently group housed by sex and treatment. Blood Pb levels in prenatally exposed pups were below the limits of detectability at weaning. Female offspring from Pb-treated dams were found to have a significant delay in the day of vaginal opening. In a sample of lead exposed females, 50% were found to exhibit prolonged and irregular periods of diestrous which was accompanied by an absence of observable corpora lutea when they were euthanized at 83 days of age. Male offspring from these dams were found to have decreased sperm counts at 70 and 160 days of age and to exhibit significantly less territorial scent marking and masculine sex behavior in adulthood compared to controls. Azoospermia was observed in 1 lead exposed animal at 70 days of age and 2 animals at 160 days. Enlarged prostates were observed in Pb-exposed males measured at 160 days, but other sex organ weights were normal. Volume of the sexually dimorphic nucleus of the preoptic area of the hypothalamus in adulthood was significantly reduced by approximately 35% in Pb-exposed males. Pulsatile release of gonadotropins, measured in castrated adult animals of both sexes, revealed irregular release patterns of both FSH and LH in some Pb animals which were not observed in controls. The overall pattern of results suggests that multiple levels of the HPG axis can be affected by exposure to Pb during a period of gestation when structures related to the HPG axis are undergoing rapid proliferation. These data indicate that lead exposure during this period places the exposed animal at significant risk for reduced reproductive capacity in adulthood.
The use of the D1/D2 dopamine receptor agonist apomorphine SL for the treatment of erectile dysfunction provides a strong support in favour of a participation of the dopaminergic system in the control of sexual function. However, the exact involvement of dopamine in sexual motivation and in the control of genital arousal in humans is unknown. In contrast, experimental data suggest an implication of dopamine at all these stages of the copulatory behaviour in rodents. The release of dopamine at the level of the nucleus accumbens, which is innervated by the mesolimbic dopaminergic pathway originating in the ventral tegmental area, is positively implicated in the pre-copulatory or appetitive phase in male rats. There is also a permissive role in the copulatory or consumatory phase for dopamine released at the level of the median pre-optic area, which receives projection from the dopaminergic incertohypothalamic pathway within the hypothalamus. It is noteworthy that these participations of the dopaminergic system are not specific to sexual behaviour but rather reflect the more general involvement of dopamine in the regulation of cognitive, integrative and reward processes. Due to its role in the control of locomotor activity, the integrity of the nigrostriatal dopaminergic pathway is also essential for the display of copulatory behaviour. Somehow more specific to sexual function, it is likely that dopamine can trigger penile erection by acting on oxytocinergic neurons located in the paraventricular nucleus of the hypothalamus, and perhaps on the pro-erectile sacral parasympathetic nucleus within the spinal cord. The counterpart of such regulation of the genital arousal by dopamine has not yet been established in females. In conclusion, the central dopaminergic system is a key element of the control of sexual function.
Lead is a male reproductive toxicant. Data suggest that rats dosed with relatively high levels of lead acetate for short periods of time induced changes in the hypothalamic gonadotropin-releasing hormone (GnRH) at the molecular level, but these changes were attenuated with increased concentration of exposure. The current study evaluated whether exposure to low levels of lead acetate over longer periods of time would produce a similar pattern of adaptation to toxicity at the molecular and biologic levels. Adult 100-day-old Sprague-Dawley male rats were dosed with 0, 0.025, 0.05, 0.1, and 0.3% lead acetate in water. Animals were killed after 1, 4, 8, and 16 weeks of treatment. Luteinzing hormone (LH) and GnRH levels were measured in serum, and lead levels were quantified in whole blood. Hypothalamic GnRH mRNA levels were also quantified. We found no significant differences in serum LH and GnRH among the groups of animals treated within each time period. A significant dose-related increase of GnRH mRNA concentrations with lead dosing occurred in animals treated for 1 week. Animals treated for more than 1 week also exhibited a significant increase in GnRH mRNA, but with an attenuation of the increase at the higher concentrations of lead with increased duration of exposure. We conclude that the signals within and between the hypothalamus and pituitary gland appear to be disrupted by long-term, low-dose lead exposure.
The interface of sexual behavior and evolutionary psychology is a rapidly growing domain, rich in psychological theories and data as well as controversies and applications. With nearly eighty chapters by leading researchers from around the world, and combining theoretical and empirical perspectives, The Cambridge Handbook of Evolutionary Perspectives on Sexual Psychology is the most comprehensive and up-to-date reference work in the field. Providing a broad yet in-depth overview of the various evolutionary principles that influence all types of sexual behaviors, the handbook takes an inclusive approach that draws on a number of disciplines and covers nonhuman and human psychology. It is an essential resource for both established researchers and students in psychology, biology, anthropology, medicine, and criminology, among other fields. Volume 2: Male Sexual Adaptations addresses theory and research focused on sexual adaptations in human males.
Lead (Pb), is an environmental toxicant, causes multi-organ dysfunction including reproductive impairments. This study designed to investigate the prospective antioxidative, anti-inflammatory and anti-apoptotic effects of ellagic acid (EA) on Pb-mediated testicular and hepato-renal toxicity. Four experimental groups of five male Long-Evans rats each were used: control, Pb (60 mg/kg), EA (30 mg/kg), and Pb + EA groups. All groups were given their respective treatment orally for 30 days. Pb exposure altered body and organs weight, food and water consumption, rectal temperature, Pb residue levels in tissues, liver and kidney function, sperm quality parameters, serum metabolic and hematology profiles, and impaired the oxidative/antioxidative balance in the testicular and hepato-renal tissue, as shown by the decreased antioxidant proteins (superoxide dismutase, catalase, glutathione peroxidase, and reduced glutathione) and increased the oxidative (MDA, lipid hydroperoxides, conjugated dienes, protein carbonyl, fragmented DNA and GSH:GSSG ratio) stress and inflammatory (IL-1, IL-6, TNF-α, prostaglandin, LTB4, NO, myeloperoxidase, LDH) markers. Moreover, a dysregulation in the stress response (HSP-70) and apoptotic-regulating proteins (BAX, BCL-2, and active Caspase-3) were recorded upon Pb exposure. Remarkably, EA oral administration reduced the Pb residue levels in tissues, improved the liver and kidney function, revived the spermatogenesis and sperm quality, restored redox homeostasis, suppressed the oxidative stress, inflammatory and apoptotic responses in the liver, kidney and testis tissue. Our findings point out that EA can be used as a phyto-chelator to overcome the adverse effects of Pb exposure due to its potent antioxidant, anti-inflammatory, and anti-apoptotic effects.
Male sexual behavior is subject to learning, resulting in increased efficiency of experienced males compared to naive ones. The improvement in behavioral parameters is underpinned by cellular and molecular changes in the neural circuit controlling sexual behavior, particularly in the hypothalamic medial preoptic area. This review provides an update on the mechanisms related to the sexual experience in male rodents, emphasizing the differences between rats and mice.
Chronic lead (Pb) exposure affects the circadian physiological processes regulated by suprachiasmatic nucleus (SCN), which is synchronized (entrainment) by light. Disorders in the entrainment capacity of an organism alter its performance to interact with the environment, thus affecting its health status. The objectives of the present study were to evaluate whether chronic early Pb exposure affects the entrainment of the circadian rhythm of locomotor activity by light and to explore the possible mechanisms involved. Adult male Wistar rats, control and chronically exposed to Pb (320 ppm) in drinking water from gestation to adult age, were used. Assessment of the metal level showed a significant increase of Pb in the blood, hypothalamus and prefrontal cortex of the experimental rats. Continuous registrations of locomotor activity (12h:12 h light-dark cycle) depicted that Pb induces important delay of this activity when the light was turned off. The Pb exposed animals entrained faster with a photoperiod delay of 6 h, (lights on at 13:00 h), which was maintained at onset of activity at lights out. In continuous darkness, the animals were exposed to a light pulse at circadian time 23. This resulted in a significant decrease of photo-stimulated neurons (immunoreactivity to c-Fos) in the SCN of the metal-exposed animals. These results show that chronic early Pb exposure alters the photic entrainment of the rhythm of locomotor activity, which is evidenced by a significant decrease in both the number of photo-stimulated neurons and neuronal population (Nissl stain) of the SCN.
Exposure to heavy metals contributes to most of the unexplained male infertility. Lead (Pb) is a well- known heavy metal, which disrupt the male reproductive system. This study was conducted to investigate the therapeutic and protective effects of green tea active principle, epigallocatechin gallate (EGCG), on the lead toxicity-induced infertility in male rats. Male albino rats receiving lead acetate (PbAc, 50 mg/l) once a daily in drinking water showed reduction of spermatozoa count and motility, diminishing the weights of testes, seminal vesicle and epididymis, low level of serum testosterone and 17β-estradiol (E2), and degenerative changes in seminiferous tubules. Additionally, the Pb exposure caused a testicular oxidative stress with a decrease in the activities of superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT) enzymes, a remarkable rising in malondialdehyde (MDA) levels, as well as a downregulation in P450 aromatase gene expression (Cyp19) in the rats’ testicular tissues. These adverse effects of Pb were ameliorated by EGCG treatment, which increased testosterone, E2 serum level, and aromatase P450 gene expression, and improved testicular architecture and semen picture. Additionally, EGCG decreased the tissue levels of MDA and retained the levels of antioxidative enzymes. In conclusion, EGCG administration can provide a significant protection against testicular toxicity caused by pb, indicating the beneficial roles of EGCG on the male reproductive system.
Lead is a neurotoxin that produces long-term, perhaps irreversible, effects on health and well-being. This article summarizes clinical and preclinical studies that have employed a variety of research techniques to examine the neurotoxic effects of low levels of lead exposure. A historical perspective is presented, followed by an overview of studies that examined behavioral and cognitive outcomes. In addition, a short summary of potential mechanisms of action is provided with a focus on calcium-dependent processes. The current level of concern, or reference level, set by the CDC is 5 μg/dL of lead in blood and a revision to 3.5 μg/dL has been suggested. However, levels of lead below 3 μg/dL have been shown to produce diminished cognitive function and maladaptive behavior in humans and animal models. Because much of the research has focused on higher concentrations of lead, work on low concentrations is needed to better understand the neurobehavioral effects and mechanisms of action of this neurotoxic metal.
Lead is a heavy metal. It is used in lead-acid battery, as a coloring agent, paints, and metal alloyed as shielding materials, smelters, printing press, and so on. It is a toxic metal affecting various organs, and developing fetus and young children are more vulnerable to toxicity of lead. This overview is based on the information of toxic potential of lead to human reproduction and reproductive outcome. Exposure to lead may affect libido, semen quality by declining sperm count, motility, viability, integrity, elevation in morphological abnormalities, and sperm DNA integrity. These alterations led to reducing fertility potential and chances of miscarriages, preterm birth, and so on in a partner. Lead exposure impairs hormonal synthesis and regulations in both sexes. Lead exposure also affects female reproduction by impairing menstruations, reducing fertility potential, delaying conception time, altering the hormonal production, circulation, affecting pregnancy and its outcome, and so on. At present, the safe dose of lead cannot be advocated as more and more data are generated in recent years which indicate the toxic potential of lead to human reproduction at a low level that was previously thought not to have such effect. Hence, use of lead should be stopped/avoided or restricted to safeguard human reproduction.
Lead is a heavy metal. It is used in lead-acid battery, as a coloring agent, paints, and metal alloyed as shielding materials, smelters, printing press, and so on. It is a toxic metal affecting various organs, and developing fetus and young children are more vulnerable to toxicity of lead. This overview is based on the information of toxic potential of lead to human reproduction and reproductive outcome. Exposure to lead may affect libido, semen quality by declining sperm count, motility, viability, integrity, elevation in morphological abnormalities, and sperm DNA integrity. These alterations led to reducing fertility potential and chances of miscarriages, preterm birth, and so on in a partner. Lead exposure impairs hormonal synthesis and regulations in both sexes. Lead exposure also affects female reproduction by impairing menstruations, reducing fertility potential, delaying conception time, altering the hormonal production, circulation, affecting pregnancy and its outcome, and so on. At present, the safe dose of lead cannot be advocated as more and more data are generated in recent years which indicate the toxic potential of lead to human reproduction at a low level that was previously thought not to have such effect. Hence, use of lead should be stopped/avoided or restricted to safeguard human reproduction. © 2018 Indian Journal of Occupational and Environmental Medicine | Published by Wolters Kluwer - Medknow.
The effects of lead exposure on to the mammals are reported to be devastating. Lead is present in all the abiotic environmental components such as brass, dust, plumbing fixtures, soil, water, and lead mixed imported products. Its continuous use for several industrial and domestic purposes has caused rise in its levels thereby posing serious threats to human health. The mechanisms involved in lead-induced toxicity primarily include free radical mediated generation of oxidative stress which directly imbalance the prooxidants and the antioxidants in body. The toxicity of lead involves damage primarily to major biomolecules (lipid, protein and nucleic acids) and liver (hepatotoxicity), nervous system (neurotoxicity), kidney (nephrotoxicity) and DNA (genotoxicity), present in animals and humans. The activation of c-Jun NH2-terminal kinase (JNK), Phosphoinositide (PI) 3-kinase or Akt and p38 mitogen activated protein kinase (MAPK) signaling pathways are important for lead cytotoxicity. Lead increased apoptosis through signaling cascade and associated factors and significantly impairs cell differentiation and maturation. In addition, lead has the great impact on metabolic pathways such as heme synthesis thereby leading the onset of anemia in lead exposed people. This review encompasses an updated account of varied aspects of lead induced oxidative stress and their biomolecular consequences such as perturbations in physiological processes, apoptosis, carcinogenesis, hormonal imbalance and loss of vision and reduced fertility and their possible remediation through synthetic (chelators) and natural compounds (plant-based principles). This communication primarily concerns with the biomedical implications of lead induced generation of free radical and their toxicity management in mammalian system.
In the field of behavioral neuroscience, it is essential to use the appropriate animal models for the topic of investigation. The danger of using the wrong model can result in false interpretation of the results. In this review we will discuss the animal models used to study sexual behavior, with a focus on rats. We will discuss the potentials and pitfalls of the different paradigms and try to make recommendations on how research in this field could be optimized. Both male and female sexual behavior are discussed, in addition to sexual motivation.
This study was conducted to investigate the mechanism of lead (Pb)-induced testicular toxicity. We examined the impact of Pb toxicity on 17β-oestradiol (E2), oestrogen receptors (ERs) and aromatase P450 which are key factors in spermatogenesis. Treatment of rats with Pb acetate (PbAc, 50 mg/L in drinking water) significantly reduced sperm count, motility, viability and increased sperm abnormalities along with degenerative changes in seminiferous tubules and Leydig cells. Additionally, administration of PbAc resulted in a significant reduction in serum testosterone, serum and testicular E2 as well as increased level of testicular testosterone. Pb also induced testicular oxidative stress as evidenced by a significant decrease in the activities of superoxide dismutase, glutathione peroxidase and catalase antioxidant enzymes, and increased malondialdehyde level in the testis. At the molecular level, Pb treatment downregulated the mRNA expression of P450 arom (Cyp19) and ERα. In conclusion, Pb induces testicular oxidative damage and disrupts spermatogenesis, at least in part, via downregulation of Cyp19 and ERα expression, which further decrease E2 level. These data, therefore, provide insight into the mechanism of lead-induced testicular toxicity.
The actions of androgens such as testosterone and dihydrotestosterone are mediated via the androgen receptor (AR), a ligand-dependent nuclear transcription factor and member of the steroid hormone nuclear receptor family. Given its widespread expression in many cells and tissues, the AR has a diverse range of biological actions including important roles in the development and maintenance of the reproductive, musculoskeletal, cardiovascular, immune, neural and haemopoietic systems. AR signalling may also be involved in the development of tumours in the prostate, bladder, liver, kidney and lung. Androgens can exert their actions via the AR in a DNA binding-dependent manner to regulate target gene transcription, or in a non-DNA binding-dependent manner to initiate rapid, cellular events such as the phosphorylation of 2(nd) messenger signalling cascades. More recently, ligand-independent actions of the AR have also been identified. Given the large volume of studies relating to androgens and the AR, this review is not intended as an extensive review of all studies investigating the AR, but rather as an overview of the structure, function, signalling pathways and biology of the AR as well as its important role in clinical medicine, with emphasis on recent developments in this field.
The aim of the present study was to investigate the molecular effects of perinatal exposure to lead (Pb) on protein and mRNA expression of purine receptors: P2X4, P2X7, adenosine receptor A1; and astrocytes (GFAP mRNA expression) and on microglia activation (Iba1 mRNA expression) in several structures of the mesolimbic system (striatum, hippocampus, prefrontal cortex) in rats expressing tolerance to the antinociceptive effect of morphine. Rat mothers were orally treated with 0.1% lead acetate from conception, through gestation, and postnatally, as well as to offspring up to day (PND) 28; subsequently molecular studies were conducted on adult (PND 60) male rats. Morphine tolerance developed more strongly in rats perinatally exposed to Pb.
Neuropsychological studies in children who are exposed to lead during their early brain development have shown to develop behavioural and cognitive deficit. The aim of the present study was to assess the cellular damage in hippocampus, amygdala and cerebellum of rat pups exposed to lead during different periods of early brain development. Five groups of rat pups were investigated. (a) Control group (n = 8) (mothers of these rats were given normal drinking water throughout gestation and lactation), (b) pregestation lead-exposed group (n = 8) (mothers of these rats were exposed to 0.2% lead acetate in the drinking water for one month before conception), (c) gestation lead-exposed group (n = 8) (exposed to 0.2% lead acetate in the drinking water through the mother throughout gestation [gestation day 01 to day 21]), (d) lactation lead-exposed group (n = 8) (exposed to 0.2% lead acetate in the drinking water through the mother throughout lactation [postnatal day 01 to day 21]) and (e) gestation and lactation lead-exposed group (n = 8) (exposed to 0.2% lead acetate throughout gestation and lactation). On postnatal day 30, rat pups of all the groups were killed. Numbers of surviving neurons in the hippocampus, amygdala and cerebellum regions were counted using cresyl violet staining technique. Histological data indicate that lead exposure caused significant damage to neurons of hippocampus, amygdala and cerebellum regions in all lead-exposed groups except lactation lead-exposed group. The extent of damage to neurons of hippocampus, amygdala and cerebellum regions in lactation lead-exposed group was comparable to gestation and lactation groups even though the duration of lead exposure was much less in lactation lead-exposed group. To conclude, the postnatal period of brain development seems to be more vulnerable to lead neurotoxicity compared to prenatal period of brain development.
Roles for oestrogens in brain masculinization/sexual behaviour, regulation of follicle-stimulating hormone (FSH)secretion and Leydig cell development and function are well established. However, the widespread distribution of oestrogen receptors α and β in reproductive and other tissues of the male, and findings from human males or transgenic animals in which the genes coding for these receptors or for aromatase are non-functional, are changing our perception of the roles of oestrogen in the male. Aspects of pubertal development in boys (growth of the long bones, their mineralization and epiphyseal closure) attributed to the actions of androgens are now recognized as being mediated in part by oestrogens. Oestrogens also play a role (probably vasodilatatory) in the cardiovascular system of the male. Within the reproductive system, oestrogens have been shown to play a role in the regulation of fluid resorption from the efferent ducts and appear to be important in the structural and functional development of the Wolffian/excurrent duct system, as well as that of the prostate; inappropriately low or high oestrogen exposure during development can cause permanent changes to these tissues, which may lead to disorders of spermatogenesis and infertility. Sertoli cells and certain germ cells in the testis are also targets for oestrogen action. Many other tissues (adipose, kidney, thymus/immune system, skin, gut and muscle) are oestrogen targets in the male. Based on these findings and the widespread distribution of aromatase, it is argued that many of the effects of oestrogens in the male might stem from its local production and action and, furthermore, that the balance in action between androgens and oestrogens might be of central importance at many oestrogen target sites.
This study investigated the effects of gestational and lactational exposure to lead and cadmium on testicular steroidogenesis, antioxidant system and male accessory gland functions in F1 generation rats to understand the biochemical mechanisms involved in endocrine disruptions. Pregnant rats were subcutaneously administered with 0.05 mg kg(-1) body wt\ day(-1) of sodium acetate (control), lead acetate, cadmium acetate and (lead acetate + cadmium acetate) throughout the gestational-lactational period, and all animals from each of the experimental groups were sacrificed by decapitation on post-natal day 56 for performing various biochemical assays. We observed significant reduction in the activities of testicular key steroidogenic enzymes and serum testosterone concentration along with significant depletion in cholesterol, ascorbic acid and reduced glutathione contents in all the metal-treated groups. Reductions in the activities of catalase and superoxide dismutase with concomitant increase in the levels of thiobarbituric acid reactive substance were observed in experimental groups. Both sperm contents and sperm motility patterns were significantly altered in all the metal-treated groups, suggesting the direct/indirect spermotoxic effects of lead and cadmium. The inhibitory effects of lead, cadmium and combined exposure on testicular steroidogenesis machinery, along with the male accessory gland functions, are indicative of multiple targets of lead and cadmium to disrupt male reproductive functions.
Lead (Pb) exposure alters the temporal organization of several physiological and behavioural processes in which the suprachiasmatic nucleus (SCN) of the hypothalamus plays a fundamental role. In this study, we evaluated the effects of chronic early Pb exposure (CePbe) on the morphology, cellular density and relative optical density (OD) in the cells of the SCN of male rats. Female Wistar rats were exposed during gestation and lactation to a Pb solution containing 320 ppm of Pb acetate through drinking water. After weaning, the pups were maintained with the same drinking water until sacrificed at 90 days of age. Pb levels in the blood, hypothalamus, hippocampus and prefrontal cortex were significantly increased in the experimental group. Chronic early Pb exposure induced a significant increase in the minor and major axes and somatic area of vasoactive intestinal polypeptide (VIP)- and vasopressin (VP)-immunoreactive neurons. The density of VIP-, VP- and glial fibrillary acidic protein (GFAP)-immunoreactive cells showed a significant decrease in the experimental group. OD analysis showed a significant increase in VIP neurons of the experimental group. The results showed that CePbe induced alterations in the cells of the SCN, as evidenced by modifications in soma morphology, cellular density and OD in circadian pacemaker cells. These findings provide a morphological and cellular basis for deficits in circadian rhythms documented in Pb-exposed animals.
To assess lipid peroxidation and ultrastructural modifications in rat brains following perinatal exposure to lead (Pb) and/or cadmium (Cd).
Female rats were divided into four groups: control group, Pb (300 mg/L) group, Cd group (10 mg/L) and Pb+Cd (300 mg/L, 10 mg/L) group. The compounds were delivered in the drinking water throughout pregnancy and lactation.
The levels of compounds in blood and brain of the Pb+Cd group were similar to those of other groups, but the effects of Pb+Cd on pups' body and brain weights were higher than on other compounds. Electron microscopy revealed that Pb and Cd had effects on mitochondrial swelling, disruption and cristae loss, Nissl body dissolution, degenerated organelles and vacuoles, cytomembrane disappearance, and nuclear chromoplasm concentration. The activity of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), acetylcholinesterase (AChE) was decreased, whereas the activity of maleic dialdehyde (MDA) was increased.
Perinatal exposure to low doses of Pb and Cd can produce alterations in lipid peroxidation and ultrastructural modifications in rat brains, and exposure to both metals can result in greater damages.
The aim of the present study was to determine blood lead levels in a group of Egyptian school-age children and assess its relationship to pubertal development.
Forty-one children were recruited from high- and low-pollution areas in Cairo, Egypt. Sexual maturation was evaluated using Tanner score. Measurements of blood lead and serum levels of follicle stimulation hormone (FSH), luteinizing hormone (LH), estradiol in girls and testosterone in boys were performed for included subjects.
A total of 51.2% of children had high blood lead levels (>or=10 microg/dL). Boys with high lead levels had delayed pubertal maturation compared to those with low lead levels. Breast staging of sexual maturation was significantly delayed in girls with high lead levels. FSH and LH were significantly reduced in children of both sexes, and testosterone levels were reduced in boys with high lead.
These findings consolidate the cumulative medical evidence of the deleterious effect of high lead levels on pubertal development, possibly through the hypothalamic-pituitary-gonadal axis.
In our earlier investigations, we have demonstrated the alteration of antioxidant enzymes in adult rat brain exposed to lead. This study was carried out to investigate the effect of lead on inducing apoptosis by choosing poly (ADP-ribose) polymerase (PARP), bcl-2 and caspase-3 expression as marker proteins in the cerebellum, the hippocampus, the brain stem and the frontal cortex. Adult male rats were treated with lead acetate (500ppm) through drinking water for a period of 8 weeks and parallel controls were maintained on sodium acetate. Both control and exposed rats were sacrificed at intervals of 4 and 8 weeks, brains were isolated and different regions namely the cerebellum, the hippocampus, the frontal cortex and the brain stem were separated and processed to investigate PARP, bcl-2 and caspase-3 expression using western blotting. The results suggest that lead induces region-specific response of expression in apoptotic proteins of rat brain showing more effect in hippocampus and cerebellum and less effect in frontal cortex and brain stem and it is tissue specific. However, results appear to conclude that PARP induced expression in hippocampus and cerebellum was more followed by mitochondrial and cytosolic damage.
Intact male rats were tested on two successive weekly tests with females to determine their level of sexual activity. Nuclear estrogen receptor content was measured in specific brain regions of individual sexually responsive and sexually nonresponsive males. Sexually nonresponsive male rats had significantly reduced nuclear estrogen receptor levels in the preoptic area compared to sexually responsive males. Sexually active males did not differ from inactive males in nuclear estrogen receptors in the medialbasal hypothalamus.
Sprague-Dawley rats were injected sc with lead acetate in suspension, or with sodium acetate (controls) on the d 9 of pregnancy and every 3-4 d thereafter until the pups were 13 or 21 d of age. At termination, testicular homogenates or isolated Sertoli cells were used to study steroidogenesis and gonadotropin binding. Lead had no significant effect on the mother's water and food consumption, on the pup's body or testis weights, on the number of pups and the time of birth, and on the seminiferous tubule diameter. Homogenates of testes of the lead-treated group converted significantly less (p less than 0.01) labeled progesterone (14C or 3H) to 5 alpha-pregnane-3,20-dione, 3 alpha-hydroxy-5 alpha-pregnan-20-one, 17 beta-hydroxy-5 alpha-androstan-3-one (DHT), 3(alpha, beta)-hydroxy-5 alpha-androstan-17-one, testosterone/17 alpha-hydroxyprogesterone, and androstenedione. Sertoli cells from lead-treated animals converted significantly less (p less than 0.01) progesterone to 5 alpha-pregnane-3 alpha, 20 alpha-diol, 3 alpha-hydroxy-5 alpha-pregnan-20-one, DHT, and 20 alpha-hydroxy-4-pregnen-3-one. These data and direct spectrophotometric assays indicated that 3 alpha-hydroxysteroid oxidoreductase (3 alpha-HSO), 3 beta-HSO, 20 alpha-HSO, 5 alpha-reductase, and C17-20-lyase had been affected. The receptor studies showed that the binding of [125I]rFSH to testicular receptors was significantly reduced from 35,600 (control) to 25,980 cpm/mg protein (lead). This is the first evidence that lead exposure (in utero and via mother's milk) significantly reduces steroid production and hormone binding in the testis at the onset of puberty.
The reproductive toxicity and growth effects of developmental lead exposure were assessed using a rat model in which 0.6% (w/v) lead acetate was administered in the drinking water ad libitum. Three series of experiments were conducted in which lead exposure was initiated beginning in utero, prepubertally, or postpubertally. Lead effects were measured on reproductive physiology and endocrinology, sexually dimorphic hepatic testosterone hydroxylation, and growth rates in both male and female animals. In male animals secondary sex organ weights were significantly decreased only in animals exposed prepubertally. In addition, serum testosterone levels were significantly suppressed, most severely in animals exposed from in utero (in the in utero group). Little effect was observed in adult female rats. However, in female animals exposed prepubertally, delayed vaginal opening and disrupted estrus cycling was observed. More severe reproductive disruption was accompanied by suppression of circulating estradiol in the in utero group. Effects on circulating sex steroids were accompanied by variable effects on circulating luteinizing hormone (LH) levels, pituitary LH, and pituitary LH beta mRNA, suggesting a dual site of lead action: (a) at the level of the hypothalamic pituitary unit, and (b) directly at the level of gonadal steroid biosynthesis. Prepubertal growth in both sexes was suppressed 25% in the in utero group. However, pubertal growth rates were significantly suppressed only in male animals and postpubertal growth was not significantly different from controls in any of the experiments, despite continued exposure to high lead levels in the drinking water. In addition, at age 85 days, male-specific hepatic hydroxylation of testosterone at positions 2 alpha and 16 alpha, which is catalyzed by a cytochrome P450 isozyme CYP 2C11, itself regulated by sexually dimorphic growth hormone secretion, was unaffected. This suggests that the growth effects of lead are possibly due to a delay in the development of sex-specific pituitary growth hormone secretion patterns rather than a persistent developmental defect. Thus, the reproductive and growth effects of lead are complex and sex-dependent, and appear to involve multiple sites on the hypothalamic-pituitary-gonadal axis.
In view of conflicting results in literature concerning lead exposure associated with behavioural alterations, this study investigated behaviour in the open-field and shuttle avoidance, for as well as tissue lead burdens of pre- and postnatally lead-exposed rats. Rats were exposed to the metal from conception to weaning by giving the dams 0.5, 2.0 or 4.0 mM lead acetate in drinking water. This regimen did not affect body weight gain of dams or offspring development and had no effect on cerebral weights nor on haematological parameters of 23-day-old rats. In 1-day-old rats, lead accumulated in the blood but not in the brain, whereas both in 23-day-old rats and in dams lead accumulated in blood, kidney and cerebral cortex. In the open-field, lead-exposed groups showed higher locomotor activity in the test session as compared to controls and did not show any decrease in rearing responses in the test, indicating less habituation. Lead-treated rats subjected to a shuttle avoidance task showed no significant increase in avoidance responses between sessions as compared to control, indicating less retention. Moreover, only the control group presented a significant reduction of the footshock escape latency along testing session, suggesting a lead effect on footshock escape acquisition. In the shuttle box, intertrial crossing responses were not affected by lead treatment. The behavioural alterations occurred in animals with blood lead levels in the range 11-50.6 micrograms/dl.
The male rat's sexual behavior constitutes a highly ordered sequence of motor acts involving both striate and smooth muscles. It is spontaneously displayed by most adult made rats in the presence of a sexually receptive female. Although the behavior is important for the survival of the species it is not necessary for survival of the individual. In that way it is different from other spontaneous behaviors such as eating, drinking, avoidance of pain, respiration or thermoregulation. Among other things, this means that it is difficult to talk about sexual deprivation or need. Nevertheless, studies of male sex behavior distinguish sexual motivation (the ease by which behavior is activated, "libido") from the execution of copulatory acts (performance, "potency") (Meisel, R.L. and Sachs, B.D., The physiology of male sexual behavior. In: E. Knobil and J.D. Neill (Eds.), The Physiology of Reproduction, 2nd Edn., Vol. 2, Raven Press, New York, 1994, pp. 3-105 [13]). The hormonal control of male sexual behavior has been extensively studied. It is clear that steroid hormones, androgens and estrogens, act within the central nervous system, modifying neuronal excitability. The exact mechanism by which these hormones activate sex behavior remains largely unknown. However, there exists a considerable amount of knowledge concerning the brain structures important for sexual motivation and for the execution of sex behavior. The modulatory role of some non-steroid hormones is partly known, as well as the consequences of manipulations of several neurotransmitter systems.
A dose-response study was conducted to examine the growth suppression associated with developmental lead exposure in a rat model and to determine the endocrine mechanisms underlying these effects. Ad libitum intake of lead acetate (0.05% to 0.45% w/v) was initiated in time-impregnated female Sprague-Dawley rats (n = 10-15/group) at gestational day 5. At birth, pups were culled to four male and four females per litter. Lead exposure of dams continued until weaning, following which lead exposure of pups was continued until sacrifice at age 2 , 35, 55, and 85 days. Birth weight and prepubertal and pubertal growth rates were significantly suppressed. Growth rates were suppressed to a much greater degree in male as compared to female pups. Decreased growth rates were accompanied by a significant decrease in plasma insulin-like growth factor 1 (IGF1) concentrations and (1) a significant increase in pituitary growth hormone (GH) content during puberty in pups of both sexes, (2) a delay in the developmental profiles of the GH-dependent male-specific liver enzymes cytochrome P-450 CYP2C11 and N-hydroxy-2-acetylaminofluorene sulfotransferase, and (3) continued suppression of these enzymes in lead-exposed adult male pups. In addition, significant decreases in plasma sex steroids, testosterone (male) and 17beta-estradiol (female), were observed during puberty. Postpuberty, at age 85 d, both IGF1 and sex steroid levels were indistinguishable from control pups despite continued lead exposure. Growth rates were also similar in control and lead-exposed pups between age 57 and 85 d. Data suggest that the mechanism underlying lead-induced sex-independent suppression of growth observed in these studies involves disruption of GH secretion during puberty. It is possible that the mechanisms underlying the greater suppression of somatic growth observed at puberty in lead-exposed male offspring may be due to the additional hypoandrogenization produced by the action of lead on the hypothalamic-pituitary-testicular axis.
The messenger role of nitric oxide (NO) in immobilization stress-induced inhibition of testicular steroidogenesis has been previously suggested. In accord with this, here, we show that the intratesticular injection of isosorbide dinitrate (ISDN; 2x2.5 mg/testis), an NO donor, mimicked the action of stress on serum testosterone concentrations and hCG-stimulated testosterone production in rat testicular tissue. When added in vitro, ISDN inhibited testicular 3beta-hydroxysteroid dehydrogenase and 17alpha-hydroxylase/lyase. Immobilization stress and injections of ISDN also decreased the activity of catalase, glutathione peroxidase, glutathione transferase, and glutathione reductase in the interstitial compartment of testis. When stressed rats were treated concomitantly with bilateral intratesticular injections of N(omega)-nitro-L-arginine methyl ester, a non-selective NOS inhibitor (2x600 microg/testis), the activities of antioxidative enzymes, as well as serum testosterone concentration, were partially normalized. These results indicate that stress-induced stimulation of the testicular NO signalling pathway leads to inhibition of both steroidogenic and antioxidant enzymes.
The effects of maternal exposure to lead (Pb) during the perinatal (1% and 0.1% Pb) periods of sexual brain differentiation were studied in adult male offspring. Maternal Pb levels were measured after treatment. Behavioral (open field and sexual behavior), physical (sexual maturation, body and organ weights), and biochemical (testosterone levels and hypothalamic monoamine and respective metabolite levels) data were assessed in perinatally exposed offspring. The effects of gonadrotopin-releasing hormone (GnRH) administration to pups at birth on puberty and sexual behavior were also investigated in offspring postnatally exposed to the metal. Results showed that perinatal administration of the two Pb concentrations did not modify maternal weight gain; 1% Pb exposure reduced offspring body weight during the 7 days of treatment while no changes were observed after 0.1% Pb exposure; neither Pb concentration altered offspring sexual maturation; the higher Pb concentration improved sexual behavior while the 0.1% concentration reduced it; exposure to 0.1% Pb caused decrease in testis weight, an increase in seminal vesicle weight and no changes in plasma testosterone levels; hypothalamic VMA levels were increased compared to the control group; GnRH administration reversed the effects of 0.1% Pb administration on male sexual behavior. These results show that perinatal exposure to Pb had a dose-dependent effect on the sexual behavior of rats and that a decrease in GnRH source in the offspring was probably involved in the reduction of their sexual performance.
Lead (Pb) can delay sexual maturation; however, the mechanism and critical time of insult are not clearly defined. Therefore, we assessed maternal Pb levels during low-level gestational and/or lactational exposure, as well as blood and tissue Pb in developing fetuses in relation to the subsequent detrimental effects of Pb on puberty-related hormones and the onset of female puberty. Adult Fisher 344 female rats were gavaged daily with either a 1-ml solution of PbAc containing 12 mg/ml Pb or an equal volume of sodium acetate (NaCl), for the controls, from 30 days prior to breeding until their pups were weaned at 21 days. By cross-fostering at the time of birth, the pups were either exposed to PbAc or NaAc during gestation only, lactation only, or during both gestation and lactation. Pb delayed the timing of puberty and this delay was associated with suppressed serum levels of insulin-like growth factor-1 (IGF-1), luteinizing hormone (LH), and estradiol (E(2)). Liver IGF-1 mRNA was not affected, suggesting that Pb altered translation and/or secretion of IGF-1. We reported previously that peripherally derived IGF-1 acts at the hypothalamic level to facilitate LH release at puberty; hence, we suggest that the action of Pb in decreasing circulating IGF-1 contributes to the delayed puberty. The detrimental effects occurred regardless of the developmental time of exposure, although gestational exposure appeared more sensitive to the effects of Pb. Also, the effects noted were with blood Pb levels less than previously reported and these levels are relevant to human health concerns.
The effect of lead (Pb) intoxication during pregnancy and lactation on the male reproductive system was studied to evaluate the alterations caused by Pb in the development of pups. The investigations covered the effect of lead on the course of spermatogenesis and the development of the epididymis and reproductive glands. For this purpose, dams were intoxicated with 300 mg/L Pb during the gestational period and through lactation. Pups were sacrificed on Postnatal (PN) Days 12 and 21. Blood lead (PbB) and plasma iron concentrations were measured, and blood cells counted. Biochemical studies as well as histochemical analyses were performed on testes and accessory glands of the reproductive system. Lead intoxication resulted in a decrease in testis and seminal vesicle weights and an increase in DNA and RNA levels on PN Day 21. Total protein was significantly decreased by the toxicant, and alkaline and acid phosphatase levels of the gonads were reduced. Effects were also reflected in the reduction of the thickness of epithelium and of seminiferous tubule diameter (STD) as a consequence of the action of lead in the reduction in numbers of prospermatogonia and spermatocytes. Results indicate that the reproductive system targets of lead intoxication are not only the testes; lead intoxication results in the inhibition of testicular, epididymal, and seminal vesicle function, altering the biochemical composition of these organs, and consequently, affecting the normal development of germinal cells.