Prenatal exposure to fenvalerate causes depressive-like behavior in adulthood by inhibiting brain-derived 5-HT synthesis.

The developmental toxicity of fenvalerate, a representative pyrethroid insecticide, is well documented. The present study aimed to explore whether prenatal exposure to fenvalerate causes depression-like behavior in adulthood. Pregnant mice were orally administrated with either corn oil or fenvalerate (2 or 20 mg/kg) during pregnancy. Depressive-like behaviors were assessed by tail suspension test (TST), forced swim test (FST) and sucrose preference test (SPT). Immobility times in TST and FST were increased in offspring whose mothers were exposed to fenvalerate throughout pregnancy. By contrast, sugar preference index, as determined by SPT, was decreased in fenvalerate-exposed offspring. Prefrontal PSD95, a postsynaptic membrane marker, was downregulated in fenvalerate-exposed adulthood offspring. Fenvalerate-induced reduction of prefrontal PSD95 began at GD18 fetal period. Accordingly, prefrontal 5-HT, a neurotransmitter for synaptogenesis, was also reduced in fenvalerate-exposed GD18 fetuses. Tryptophan hydroxylase 2 (TPH2), a key enzyme for 5-HT synthesis, was downregulated in the midbrain of fenvalerate-exposed GD18 fetuses. Additional experiment showed that GRP78 and p-eIF2α, two endoplasmic reticulum stress-related proteins, were increased in the midbrain of fenvalerate-exposed fetal mice. The present results suggest that prenatal exposure to fenvalerate causes depressive-like behavior in adulthood, partially by inhibiting brain-derived 5-HT synthesis.

Gestational 1-nitropyrene exposure causes anxiety-like behavior partially by altering hippocampal epigenetic reprogramming of synaptic plasticity in male adult offspring.

1-Nitropyrene (1-NP), a typical nitro-polycyclic aromatic hydrocarbon, is a developmental toxicant. This study was to evaluate gestational 1-NP-induced anxiety-like behavior in male adult offspring. Pregnant mice were orally administered to 1-NP daily throughout pregnancy. Anxiety-like behaviors, as determined by Elevated Plus-Maze (EPM) and Open-Field Test (OFT), were showed in male adult offspring whose mothers were exposed to 1-NP. Gestational 1-NP exposure reduced dendritic arborization, dendritic length and dendritic spine density in ventral hippocampus of male adult offspring. Additional experiments showed that gephyrin, an inhibitory synaptic marker, was reduced in fetal forebrain and hippocampus in male adult offspring. Nrg1 and Erbb4, two gephyrin-related genes, were reduced in 1-NP-exposed fetuses. Accordingly, 5hmC contents in two CpG sites (32008909 and 32009239) of Nrg1 gene and three CpG sites (69107743, 69107866 and 69107899) of Erbb4 gene were decreased in 1-NP-exposed fetuses. Mechanistically, ten-eleven translocation (TET) activity and alpha-ketoglutarate (α-KG) content were decreased in 1-NP-exposed fetal forebrain. Supplementation with α-KG alleviated 1-NP-induced downregulation of gephyrin-related genes, prevented hippocampal synaptic damage, and improved anxiety-like behavior in male adult offspring. These results indicate that early-life 1-NP exposure causes anxiety-like behavior in male adulthood partially by altering hippocampal epigenetic reprogramming of synaptic plasticity.

Paternal fenvalerate exposure transgenerationally impairs cognition and hippocampus in female offspring.

The impairments of maternal fenvalerate exposure have been well documented in previous study, but little was known about the effects of paternal fenvalerate exposure. The current study aimed to assess the effects of paternal fenvalerate exposure on spatial cognition and hippocampus across generations. Adult male mice (F0) were orally administered with fenvalerate (0, 2 or 20 mg/kg) for 5 weeks. F0 males were mated with untreated-females to generate F1 generation. F1 males were mated with F1 control females to generate F2 generation. For F1 and F2 adult offspring, spatial learning and memory were detected by Morris water maze. Results showed that spatial learning and memory were impaired in F1 females but not F1 males derived from F0 males exposed to 20 mg/kg FEN. Furthermore, significant impairment of spatial learning and memory were found in F2 females but not F2 males derived from F0 males exposed to 20 mg/kg FEN. As expected, histopathology showed that neural density in hippocampal CA3 region was reduced in F1 and F2 females but not F1 and F2 males derived from F0 males exposed to 20 mg/kg FEN. Mechanistically, hippocampal thyroid hormone receptor alpha1 (TRα1) was down-regulated in F1 and F2 females derived from F0 males exposed to 20 mg/kg FEN. Correspondingly, hippocampal brain-derived neurotrophic factor, tropomyosin receptor kinase B and p75 neurotrophin receptor, three downstream genes of TR signaling, were down-regulated in F1 and F2 females. Taken together, the present study firstly found that paternal fenvalerate exposure transgenerationally impaired spatial cognition in a gender-dependent manner. Hippocampal TR signaling may, at least partially, contribute to the process of cognitive impairment induced by paternal fenvalerate exposure. Further exploration in the mode of action of fenvalerate is critically important to promote human health and environmental safety.

Pubertal fenvalerate exposure impairs cognitive and behavioral development partially through down-regulating hippocampal thyroid hormone receptor signaling.

Fenvalerate, a synthetic pyrethroid insecticide, is an environmental endocrine disruptor and neurodevelopmental toxicant. An early report found that pubertal exposure to high-dose fenvalerate impaired cognitive and behavioral development. Here, we aimed to further investigate the effect of pubertal exposure to low-dose fenvalerate on cognitive and behavioral development. Mice were orally administered with fenvalerate (0.2, 1.0 and 5.0 mg/kg) daily from postnatal day (PND) 28 to PND56. Learning and memory were assessed by Morris water maze. Anxiety-related activities were detected by open-field and elevated plus-maze. Increased anxiety activities were observed only in females exposed to fenvalerate. Spatial learning and memory were damaged only in females exposed to fenvalerate. Histopathology observed numerous scattered shrinking neurons and nuclear pyknosis in hippocampal CA1 region. Neuronal density was reduced in hippocampal CA1 region of fenvalerate-exposed mice. Mechanistically, hippocampal thyroid hormone receptor (TR)ß1 was down-regulated in a dose-dependent manner in females. In addition, TRα1 was declined only in females exposed to 5.0 mg/kg fenvalerate. Taken together, these suggests that pubertal exposure to low-dose fenvalerate impairs cognitive and behavioral development in a gender-dependent manner. Hippocampal TR signaling may be, at least partially, involved in fenvalerate-induced impairment of cognitive and behavioral development.

Critical time window of fenvalerate-induced fetal intrauterine growth restriction in mice.

Fenvalerate (FEN), a representative type II pyrethroid, is a widely used pyrethroid insecticide and a potential environmental contaminant. Several studies demonstrated that gestational FEN exposure induced intrauterine growth restriction (IUGR). However, the critical time window of FEN-induced fetal IUGR remains obscure. The present study aimed to identify the critical window of FEN-induced fetal IUGR. Pregnant mice were administered corn oil or FEN (20 mg/kg) by gavage daily at the early gestational stage (GD0-GD6), middle gestational stage (GD7-GD12) or late gestational stage (GD13-GD17). The results showed that the rates of fetal IUGR were markedly increased only in the mice exposed to FEN on GD13-GD17 but not in the mice exposed to FEN on GD7-GD12 or GD0-GD6. Further analysis showed that the blood sinusoid area in the placental labyrinth layer was reduced in the mice exposed to FEN on GD13-GD17. In addition, CD34+ microvessel density in the labyrinthine region was decreased in the male and female fetuses whose mothers were exposed to FEN on GD13-GD17. Mechanistic analysis found that the glutathione level was decreased in the FEN-exposed placentas. In contrast, the levels of 3-nitrotyrosine and malondialdehyde, two oxidative stress markers, were increased in FEN-exposed placentas. Heme oxygenase-1, inducible nitric oxide synthase, catalase and peroxiredoxin-3, which are antioxidant enzymes, were upregulated in the FEN-exposed placentas. The present study suggests that the late gestational stage is a critical time window of FEN-induced fetal IUGR. Placental oxidative stress may be, at least partially, involved in the process of FEN-induced placental damage and fetal IUGR.

Maternal fenvalerate exposure during pregnancy impairs growth and neurobehavioral development in mouse offspring.

Although use of fenvalerate has increased dramatically over the past decade, little is known about their potential adverse effects on growth and development. The purpose of this study was to examine the effects of maternal fenvalerate exposure during pregnancy on growth and neurobehavioral development in the offspring. Pregnant mice were orally administered to fenvalerate (0.2, 2.0, and 20 mg/kg) daily throughout pregnancy. The tests of growth and neurobehavioral development were performed during lactation period. A series of neurobehavioral tasks were carried out from lactation to puberty. Anxiety-related behaviors were evaluated by open-field and elevated plus maze. Morris Water Maze was used to assess spatial learning and memory ability. Results showed that maternal fenvalerate exposure during pregnancy markedly delayed growth development of neonatal offspring during lactation. In addition, anxiety-like behaviors were increased in fenvalerate-exposed male offspring. Moreover, spatial learning and memory was severely impaired in female offspring. Taken together, maternal fenvalerate exposure during pregnancy delayed growth and neurobehavioral development in a gender-dependent manner. Additional study is required to explore the underlying mechanism through which maternal fenvalerate exposure during pregnancy induces impairment of growth and neurobehavioral development.

Maternal Fenvalerate Exposure Induces Fetal Intrauterine Growth Restriction Through Disrupting Placental Thyroid Hormone Receptor Signaling.

Fenvalerate is an environmental endocrine disruptor that disrupts testosterone and estradiol synthesis. Nevertheless, whether fenvalerate disturbs placental TR signaling remains unclear. The aim of this study was to investigate whether maternal fenvalerate exposure causes fetal intrauterine growth restriction (IUGR) and to explore the role of placental thyroid hormone receptor (TR) signaling. Pregnant mice except controls were orally administered to fenvalerate (0.2, 2.0, or 20 mg/kg) daily throughout pregnancy. As expected, fetal weight was lowered in dams that were administered with 20.0 mg/kg of fenvalerate. Moreover, the rate of IUGR was elevated not only in male fetuses but also in female fetuses of dams exposed to 20.0 mg/kg of fenvalerate. Histopathology showed that the internal space of blood vessels in the labyrinth layer was smaller in placentas of mice exposed to fenvalerate. Mechanistic study found no significant difference on TT4 level in maternal serum, although TT3 level in maternal serum was slightly reduced in dams exposed to 2.0 mg/kg of fenvalerate. Interestingly, placental TRα1 and TRß1 mRNAs were reduced in mice exposed to fenvalerate. Moreover, nuclear translocation of placental TRß1 was suppressed in fenvalerate-exposed mice. Further analysis showed that placental Vegfα and Igf2, several target genes of TR signaling, were down-regulated in fenvalerate-exposed mice. In addition, mRNA level of placental CD36, Snat1, and Snat2, 3 nutrient transporters, were reduced in fenvalerate-exposed mice. These results suggest that maternal fenvalerate exposure induces fetal IUGR through disrupting placental TR signaling. These results provide a novel mechanistic explanation for fenvalerate-induced fetal IUGR.

Maternal lead exposure during lactation persistently impairs testicular development and steroidogenesis in male offspring.

Lead (Pb) is a testicular toxicant. In the present study, we investigated the effects of maternal Pb exposure during lactation on testicular development and steroidogenesis in male offspring. Maternal mice were exposed to different concentration of lead acetate (200 or 2000 ppm) through drinking water from postnatal day (PND) 0 to PND21. As expected, a high concentration of Pb was measured in the kidneys and liver of pups whose mothers were exposed to Pb during lactation. In addition, maternal Pb exposure during lactation elevated, to a less extent, Pb content in testes of weaning pups. Testis weight in weaning pups was significantly decreased when maternal mice were exposed to Pb during lactation. The level of serum and testicular T was reduced in Pb-exposed pups. The expression of P450scc, P450(17α) and 17ß-HSD, key enzymes for T synthesis, was down-regulated in testes of weaning pups whose mothers were exposed to Pb during lactation. Interestingly, the level of serum and testicular T remained decreased in adult offspring whose mothers were exposed to Pb during lactation. Importantly, the number of spermatozoa was significantly reduced in Pb-exposed male offspring. Taken together, these results suggest that Pb could be transported from dams to pups through milk. Maternal Pb exposure during lactation persistently disrupts testicular development and steroidogenesis in male offspring.

Endoplasmic reticulum stress is involved in hepatic SREBP-1c activation and lipid accumulation in fructose-fed mice.

A link between fructose drinking and nonalcoholic fatty liver disease (NAFLD) has been demonstrated in human and rodent animals. The aim of the present study was to investigate whether endoplasmic reticulum (ER) stress is mediated in the development of fructose-induced NAFLD. Female CD-1 mice were fed with 30% fructose solution for eight weeks. Hepatic lipid accumulation was assessed. Hepatic nuclear sterol regulatory element-binding protein (SREBP)-1c was measured. Results showed that hepatic SREBP-1c was activated in mice fed with fructose solution. Fatty acid synthase (fas) and acetyl-CoA carboxylase (acc), two target genes of SREBP-1c, were up-regulated. Fructose-evoked hepatic SREBP-1c activation seemed to be associated with insulin-induced gene (Insig)-1 depletion. An ER stress and unfolded protein response (UPR), as determined by an increased glucose-regulated protein (GRP78) expression and an increased eIF2α and PERK phosphorylation, were observed in liver of mice fed with fructose solution. Phenylbutyric acid (PBA), an ER chemical chaperone, not only significantly attenuated ER stress, but also alleviated fructose-induced hepatic Insig-1 depletion. PBA inhibited fructose-evoked hepatic SREBP-1c activation and the expression of SREBP-1c target genes, and protected against hepatic lipid accumulation. In conclusion, ER stress contributes, at least in part, to hepatic SREBP-1c activation and lipid accumulation in fructose-evoked NAFLD.

Ascorbic acid protects against cadmium-induced endoplasmic reticulum stress and germ cell apoptosis in testes.

Cadmium (Cd) is a testicular toxicant which induces endoplasmic reticulum (ER) stress and germ cell apoptosis in testes. This study investigated the effects of ascorbic acid on Cd-evoked ER stress and germ cell apoptosis in testes. Male mice were intraperitoneally injected with CdCl(2) (2.0 mg/kg). As expected, a single dose of Cd induced testicular germ cell apoptosis. Interestingly, Cd-triggered testicular germ cell apoptosis was almost completely inhibited in mice treated with ascorbic acid. Interestingly, ascorbic acid significantly attenuated Cd-induced upregulation of GRP78 in testes. In addition, ascorbic acid significantly attenuated Cd-triggered testicular IRE1α and eIF2α phosphorylation and XBP-1 activation, indicating that this antioxidant counteracts Cd-induced unfolded protein response (UPR) in testes. Finally, ascorbic acid significantly attenuated Cd-evoked upregulation of CHOP and JNK phosphorylation, two components in ER stress-mediated apoptotic pathway. In conclusion, ascorbic acid protects mice from Cd-triggered germ cell apoptosis via inhibiting ER stress and UPR in testes.

Cadmium-induced teratogenicity: association with ROS-mediated endoplasmic reticulum stress in placenta.

The placenta is essential for sustaining the growth of the fetus. An increased endoplasmic reticulum (ER) stress has been associated with the impaired placental and fetal development. Cadmium (Cd) is a potent teratogen that caused fetal malformation and growth restriction. The present study investigated the effects of maternal Cd exposure on placental and fetal development. The pregnant mice were intraperitoneally injected with CdCl(2) (4.5mg/kg) on gestational day 9. As expected, maternal Cd exposure during early limb development significantly increased the incidences of forelimb ectrodactyly in fetuses. An obvious impairment in the labyrinth, a highly developed tissue of blood vessels, was observed in placenta of mice treated with CdCl(2). In addition, maternal Cd exposure markedly repressed cell proliferation and increased apoptosis in placenta. An additional experiment showed that maternal Cd exposure significantly upregulated the expression of GRP78, an ER chaperone. Moreover, maternal Cd exposure induced the phosphorylation of placental eIF2α, a downstream molecule of PERK signaling. In addition, maternal Cd exposure significantly increased the level of placental CHOP, another target of PERK signaling, indicating that the unfolded protein response (UPR) signaling was activated in placenta of mice treated with CdCl(2). Interestingly, alpha-phenyl-N-t-butylnitrone, a free radical spin-trapping agent, significantly alleviated Cd-induced placental ER stress and UPR. Taken together, these results suggest that reactive oxygen species (ROS)-mediated ER stress might be involved in Cd-induced impairment on placental and fetal development. Antioxidants may be used as pharmacological agents to protect against Cd-induced fetal malformation and growth restriction.

Melatonin alleviates cadmium-induced cellular stress and germ cell apoptosis in testes.

Increasing evidence demonstrates that melatonin has an anti-apoptotic effect in somatic cells. However, whether melatonin can protect against germ cell apoptosis remains obscure. Cadmium (Cd) is a testicular toxicant and induces germ cell apoptosis. In this study, we investigated the effects of melatonin on Cd-evoked germ cell apoptosis in testes. Male ICR mice were intraperitoneally (i.p.) injected with melatonin (5 mg/kg) every 8 hr, beginning at 8 hr before CdCl(2) (2.0 mg/kg, i.p.). As expected, acute Cd exposure resulted in germ cell apoptosis in testes, as determined by terminal dUTP nick-end labeling (TUNEL) staining. Melatonin significantly alleviated Cd-induced testicular germ cell apoptosis. An additional experiment showed that spliced form of XBP-1, the target of the IRE-1 pathway, was significantly increased in testes of mice injected with CdCl(2). GRP78, an endoplasmic reticulum (ER) chaperone, and CHOP, a downstream target of the PERK pathway, were upregulated in testes of Cd-treated mice. In addition, acute Cd exposure significantly increased testicular eIF2α and JNK phosphorylation, indicating that the unfolded protein response (UPR) pathway was activated by CdCl(2). Interestingly, melatonin almost completely inhibited Cd-induced ER stress and the UPR in testes. In addition, melatonin obviously attenuated Cd-induced heme oxygenase (HO)-1 expression and protein nitration in testes. Taken together, these results suggest that melatonin alleviates Cd-induced cellular stress and germ cell apoptosis in testes. Melatonin may be useful as pharmacological agents to protect against Cd-induced testicular toxicity.

Crosstalk between endoplasmic reticulum stress and mitochondrial pathway mediates cadmium-induced germ cell apoptosis in testes.

Cadmium (Cd) is associated with male infertility and poor semen quality in humans. Increasing evidence demonstrates that Cd induces testicular germ cell apoptosis in rodent animals. However, the molecular mechanisms of Cd-induced testicular germ cell apoptosis remain poorly understood. In the present study, we investigated the role of endoplasmic reticulum (ER) stress on Cd-evoked germ cell apoptosis in testes. We show that spliced form of XBP-1, the target of the IRE1 pathway, was significantly increased in testes of mice injected with CdCl(2). GRP78, an ER chaperone, and CHOP, a downstream target of the PERK pathway, were upregulated in testes of Cd-treated mice. In addition, acute Cd exposure significantly caused eIF2α and JNK phosphorylation in testes, indicating that the unfolded protein response pathway in testes was activated by Cd. Interestingly, phenylbutyric acid (PBA), an ER chemical chaperone, attenuated Cd-induced ER stress and protected against germ cell apoptosis in testes. In addition, PBA significantly attenuated Cd-evoked release of cytochrome c from mitochondria to cytoplasm in testes. Taken together, these results suggest that crosstalk between ER stress signaling and mitochondrial pathway mediates Cd-induced testicular germ cell apoptosis.

Gender-specific impairments on cognitive and behavioral development in mice exposed to fenvalerate during puberty.

In human and rodent models, endocrine disrupting chemicals (EDCs) interfere with the development of cognition and behaviors. Fenvalerate is a potential EDC. The purpose of this study was to examine whether pubertal fenvalerate exposure altered behavioral development. Mice were orally administered with either vehicle or fenvalerate (7.5 or 30 mg/kg/day) from postnatal day (PND) 28 to PND56. Learning and memory were assessed by Morris Water Maze. Aggressive performance was evaluated by aggressive behavior test. Anxiety-related activities were detected by three tests: open-field, plus-maze and black-white alley. Sensorimotor function was analyzed using beam walking and tightrope. Results found that the impairment for spatial learning and memory was more severe in fenvalerate-exposed female mice than in male mice. In addition, pubertal fenvalerate exposure inhibited aggressive behavior in males. Moreover, pubertal fenvalerate exposure increased anxiety activities in females. Altogether, these results suggest that pubertal fenvalerate exposure impairs spatial cognition and behavioral development in a gender-dependent manner. These findings identify fenvalerate as candidate environmental risk factors for cognitive and behavioral development, especially in the critical period of development.

Melatonin alleviates lipopolysaccharide-induced placental cellular stress response in mice.

Melatonin protects mice from lipopolysaccharide (LPS)-induced fetal death and intra-uterine growth retardation. Nevertheless, its molecular mechanism remains obscure. In the present study, we investigated the effects of melatonin on LPS-induced cellular stress in placenta. Pregnant mice were given with melatonin [5.0 mg/kg, intraperitoneal (i.p.)] 30 min before and 150 min after LPS (300 µg/kg, i.p.) on gestational day 15. Oxidative stress, endoplasmic reticulum (ER) stress, hypoxic stress, and heat stress in placenta were analyzed at 4 hr after LPS. As expected, maternal LPS administration resulted in placental glutathione (GSH) depletion and up-regulated the expression of placental antioxidative enzymes. In addition, LPS significantly increased the level of inducible nitric oxide synthase (iNOS) and enhanced the intensity of placental 3-nitrotyrosine residues. An ER stress, as determined by a decreased GRP78 expression, an obvious eIF2α and JNK phosphorylation, and an increased CHOP expression, were observed in placenta of pregnant mice injected with LPS. In addition, LPS significantly increased mRNA level of placental HIF-1α, VEGF, and ET-1, the markers of hypoxic stress. Heme oxygenase (HO)-1, a marker of heat stress, was also up-regulated in placenta of LPS-treated pregnant mice. Interestingly, LPS-induced placental oxidative stress, hypoxic stress, and ER stress were significantly alleviated when pregnant mice were given with melatonin, whereas melatonin had little effect on LPS-evoked placental HO-1 expression. In conclusion, maternally administered melatonin alleviates LPS-induced cellular stress in the placenta. Melatonin may be useful as pharmacological agents to protect the fetuses against LPS-induced intra-uterine fetal death and intra-uterine growth restriction.

Effects of pubertal fenvalerate exposure on testosterone and estradiol synthesis and the expression of androgen and estrogen receptors in the developing brain.

Fenvalerate is a potential endocrine disruptor. Several studies have demonstrated that fenvalerate disrupts testosterone (T) synthesis in testes. T and estradiol (E(2)) are de novo synthesized in the developing brain. Thus, the aim of the present study was to investigate the effects of pubertal fenvalerate exposure on the synthesis of T and E(2) and the expression of androgen receptor (AR) and estrogen receptors (ERs) in cerebral cortex. CD-1 mice were orally administered daily with either vehicle or fenvalerate (7.5 or 30 mg/kg) from postnatal day (PND) 28 to PND56. The level of T and E(2) in cerebral cortex was significantly decreased in males exposed to fenvalerate. In agreement with the decrease in T and E(2) syntheses, the expression of 17ß-HSD, a key enzyme for T synthesis, was significantly reduced in cerebral cortex of fenvalerate-exposed males. Conversely, in females, the expression of 17ß-HSD in cerebral cortex was mildly up-regulated by fenvalerate and the level of T and E(2) was mildly increased. Pubertal fenvalerate exposure had no effect on the expression of StAR, P450(17α) and P450scc, the key enzymes for T synthesis, and P450 aromatase, the key enzyme for E(2) synthesis, in cerebral cortex of males and females. Interestingly, the expression of AR in cerebral cortex was up-regulated in male and female mice exposed to fenvalerate, whereas pubertal fenvalerate exposure did not affect the level of ERα and ERß in cerebral cortex. Taken together, these results suggest that pubertal fenvalerate exposure disrupts T and E(2) synthesis and the expression of AR in cerebral cortex. These changes of steroid status in the developing brain might be deleterious for neurobehavioral development.

Maternal cypermethrin exposure during lactation impairs testicular development and spermatogenesis in male mouse offspring.

Within the last decade, numerous epidemiological studies have demonstrated that endocrine disruptors are a possible cause for a decline in semen quality. Cypermethrin is a widely used pyrethroid insecticide, but little is known about its potentially adverse effects on male reproduction. In the present study, we investigated the effects of maternal cypermethrin exposure during lactation on testicular development and spermatogenesis in male offspring. Maternal mice were administered with cypermethrin (25 mg/kg) by gavage daily from postnatal day 0 (PND0) to PND21. Results showed that the weight of testes at PND21 was significantly decreased in pups whose mothers were exposed to cypermethrin during lactation. Maternal cypermethrin exposure during lactation markedly decreased the layers of spermatogenic cells, increased the inside diameter of seminiferous tubules, and disturbed the array of spermatogenic cells in testes of pups at PND21. In addition, maternal cypermethrin exposure during lactation markedly reduced mRNA and protein levels of testicular P450scc, a testosterone (T) synthetic enzyme. Correspondingly, the level of serum and testicular T at weaning was significantly decreased in pups whose mothers were exposed to cypermethrin during lactation. Although the expression of testicular T synthetic enzymes and serum and testicular T in adulthood had restored to control level, the decreased testicular weight and histological changes were irreversible. Importantly, the number of spermatozoa was significantly decreased in adult male offspring whose mothers were exposed to cypermethrin during lactation. In conclusion, maternal cypermethrin exposure during lactation permanently impairs testicular development and spermatogenesis in male offspring, whereas cypermethrin-induced endocrine disruption is reversible.

Coping as a mechanism linking stressful life events and mental health problems in adolescents.

OBJECTIVE: Although stressful life events represent an etiologic factor of mental health problems in adolescents, few studies have been conducted to address mechanisms linking the stress-psychopathology relation. The present study was designed to examine coping as a mediate factor on the relationship between stressful life events and symptoms of anxiety and depression. METHODS: The participants were 13 512 students from eight cities of China, who participated in a school-based survey. Data were collected by a questionnaire comprising coping, stressful life events, anxiety, and depressive symptoms. As a model, a series of regression equations were used to examine whether coping mediated the association between stressful life events and symptoms of anxiety and depression. RESULTS: Each dimension of stressful life events showed significant correlation with anxiety, depression and coping (all P<0.001). In the model to analyze mediate effects, all standardized coefficients (ß) were significant (all P<0.01), indicating marked mediator effects. Furthermore, negative coping might account for more mediate effects than positive coping on this relationship. CONCLUSION: Coping partially mediated the relationship between stressful life events and mental health during adolescence. This study highlighted an important public health priority for preventive interventions targeting stress-related psychopathology, and for further promoting adolescents' mental health.

Pubertal and early adult exposure to fenvalerate disrupts steroidogenesis and spermatogenesis in mice at adulthood.

Fenvalerate, a pyrethroid insecticide used worldwide, has been shown to have a potentially adverse effect on male reproduction. Our earlier study showed that maternal fenvalerate exposure during lactation impaired testicular development in male offspring. In this study, we investigated the effects of pubertal and early adult exposure to fenvalerate on steroidogenesis and spermatogenesis in mice. Male mice were administered fenvalerate (60 mg/kg) by gavage daily from postnatal day 35 (PND35) to PND63. Results showed that sperm count was significantly decreased in fenvalerate-treated mice. In addition, fenvalerate markedly decreased the layers of spermatogenic cells, disturbed the array of spermatogenic cells and increased the number of apoptotic cells in testes. The adverse effects of fenvalerate on male reproduction seemed to be associated with a decrease in serum and testicular testosterone (T). Although pubertal and early adult exposure to fenvalerate had little effect on the number of Leydig cells in testes, mRNA and protein levels of testicular T biosynthetic enzymes including P450(17alpha) and P450scc were significantly downregulated in fenvalerate-treated mice. In conclusion, pubertal and early adult fenvalerate exposure induces a deleterious effect on steroidogenesis and spermatogenesis in adulthood. The decreased testicular T synthesis partially contributes to fenvalerate-induced impairment on spermatogenesis.

Age- and gender-dependent impairments of neurobehaviors in mice whose mothers were exposed to lipopolysaccharide during pregnancy.

Lipopolysaccharide (LPS)-induced intrauterine infection has been associated with neurodevelopmental injury in rodents. The purpose of the present study was to analyze the dynamic changes of neurobehaviors in mice whose mothers were exposed to LPS during pregnancy. The pregnant mice were intraperitoneally (i.p.) injected with LPS (8 microg/kg) daily from gestational day (gd) 8 to gd 15. A battery of neurobehavioral tasks was performed in mice at postnatal day (PND) 70, 200, 400 and 600. Results showed that the spatial learning and memory ability, determined by radial six-arm water maze (RAWM), were obviously impaired in two hundred-day-old female mice and four hundred-day-old male mice whose mothers were exposed to LPS during pregnancy. Open field test showed that the number of squares crossed and peripheral time, a marker of anxiety and exploration activity, were markedly increased in two hundred-day-old female mice following prenatal LPS exposure. In addition, prenatal LPS exposure significantly shortened the latency to the first grid crossing in six hundred-day-old female offspring. Moreover, sensorimotor impairment in the beam walking was observed in two hundred-day-old female mice whose mothers were exposed to LPS during pregnancy. Species-typical behavior examination showed that prenatal LPS exposure markedly increased weight burrowed in seventy-day-old male offspring and six hundred-day-old female offspring. Correspondingly, prenatal LPS exposure significantly reduced weight hoarded in two hundred-day-old female offspring. Taken together, these results suggest that prenatal LPS exposure induces neurobehavioral impairments at adulthood in an age- and gender-dependent manner.