Maternal exposure to triclosan impairs thyroid homeostasis and female pubertal development in Wistar rat offspring

Although the effects of triclosan have been examined in male reproductive functions, it is unknown whether this potent antibacterial agent affects pregnancy and female pubertal development. Effects of maternal exposure to triclosan on thyroid homeostasis (TH) and reproductive-tract development in female Wistar rats were thus studied. Dams were exposed daily to triclosan (0, 1, 10, or 50 mg/kg/d) from 8 d before mating to lactation day 21. Offspring were also exposed after weaning. In vivo triclosan estrogenic activity was screened by uterotrophic assay and vaginal opening (VO), with first estrus and uterus and ovarian weight determined in offspring. Dam blood samples were taken during pregnancy and lactation to examine the effect of triclosan on TH. No apparent external signs of toxicity or differences in mean numbers of implantation sites were observed in treated rats. Triclosan treatment decreased total serum T(4) and T(3) in pregnant rats and also lowered sex ratio, lowered pup body weights on postnatal day (PND) 20, and delayed VO in offspring. In addition, the highest dose of triclosan significantly reduced the live birth index (percentage) and 6-d survival index. Data indicate that triclosan impairs thyroid homeostasis and reproductive toxicity in adult rats and produces fetal toxicity in offspring exposed in utero, during lactation, and after weaning.     

Prenatal exposure to di-n-butyl phthalate (DBP) differentially alters androgen cascade in undeformed versus hypospadiac male rat offspring

This study was to compare the alterations of androgen cascades in di-n-butyl phthalate (DBP)-exposed male offspring without hypospadias (undeformed) versus those with hypospadias. To induce hypospadias in male offspring, pregnant rats received DBP via oral gavage at a dose of 750 mg/kg BW/day during gestational days 14–18. The mRNA expression levels of genes downstream of the androgen signaling pathway, such as androgen receptor (AR) and Srd5a2, in testes of undeformed rat pups were similar to those in controls; in hypospadiac rat pups these levels were significantly lower than those of control pups. In contrast, both undeformed and hypospadiac rats had decreased serum testosterone levels, reduced mRNA expression of key enzymes in the androgen synthetic pathway in the testes, and ablated genes of developmental pathways, such as Shh, Bmp4, Fgf8, Fgf10 and Fgfr2, in the genital tubercle (GT) as compared to those in DBP-unexposed controls, albeit hypospadiac rats had a more severe decrement than those of undeformed rats. Although other possibilities cannot be excluded, our findings suggest that the relatively normal levels of testosterone-AR-Srd5a2 may contribute to the resistance to DBP toxicity in undeformed rats. In conclusion, our results showed a potential correlation between decreased testosterone levels, reduced mRNA expression of AR and Srd5a2 and the occurrence of hypospadias in male rat offspring prenatally exposed to DBP.     

Effects of triclosan on Japanese medaka (Oryzias latipes) during embryo development,early life stage and reproduction

Triclosan has been shown to have endocrine‐disrupting effects in aquatic organisms. In 2016, the US Food and Drug Administration banned the use of triclosan in consumer soaps. Before the ban, triclosan was reported at low concentrations in the aquatic environment, although the effect of triclosan on reproduction in teleost fish species is yet to be clarified. Here we investigated the effects of triclosan on embryo development and reproduction, and during the early life stage, in Japanese medaka (Oryzias latipes) by using Organisation for Economic Co‐operation and Development tests 229, 212 and 210, with minor modifications. In adult medaka, exposure to 345.7 μg l^–1 suppressed fecundity and increased mortality but had no effect on fertility. Exposure to 174.1 or 345.7 μg l^–1 increased liver vitellogenin concentration in females but decreased liver vitellogenin concentration in males. With triclosan exposure, mortality was increased dose dependently during the embryonic and early larval stages, and a particularly steep increase in mortality was observed soon after hatching. The lowest observed effect concentrations of triclosan in Japanese medaka obtained in the present study (mortality [embryonic and larval stages, 276.3 μg l^–1; early life stage, 134.4 μg l^–1; adult stage, 174.1 μg l^–1], growth [134.4 μg l^–1], vitellogenin [174.1 μg l^–1], fecundity [345.7 μg l^–1] and fertility [>345.7 μg l^–1]) were at least 55 times (compared with the USA) and up to 13 400 times (compared with Germany) greater than the detected triclosan levels in the aquatic environment. These results suggest that triclosan may not be affecting fish populations in the aquatic environment.     

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 17β‐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. Copyright © 2012 John Wiley & Sons, Ltd.     

Maternal exposure to di-(2-ethylhexyl)phthalate alters kidney development through the renin-angiotensin system in offspring

Di-(2-ethylhexyl)phthalate (DEHP) is a widely used industrial plasticizer to which humans are widely exposed. We investigated the consequences of maternal exposure to DEHP on nephron formation, examined the programming of renal function and blood pressure and explored the mechanism in offspring. Maternal rats were treated with vehicle, 0.25 and 6.25mg/kg body weight/day DEHP respectively from gestation day 0 to postnatal day 21. Maternal DEHP exposure resulted in lower number of nephrons, higher glomerular volume and smaller Bowman's capsule in the DEHP-treated offspring at weaning, as well as glomerulosclerosis, interstitial fibrosis and effacement of podocyte foot processes in adulthood. In the DEHP-treated offspring, the renal function was lower and the blood pressure was higher. The renal protein expression of renin and angiotensin II was reduced at birth day and increased at weaning. Maternal DEHP exposure also led to reduced mRNA expression of some renal development involved genes at birth day, including Foxd1, Gdnf, Pax2 and Wnt11. While, the mRNA expression of some genes was raised, including Bmp4, Cdh11, Calm1 and Ywhab. These data show that maternal DEHP exposure impairs the offspring renal development, resulting in a nephron deficit, and subsequently elevated blood pressure later in life. Our findings suggest that DEHP exposure in developmental periods may affect the development of nephrons and adult renal disease through inhibition of the renin-angiotensin system.     

Perinatal exposure to androgen excess and the effects on the rat uterine estradiol responsiveness

Androgen exposure during sexual development induces alterations in steroidal target tissues. The objective of this study was to evaluate the uterine responsiveness to estradiol after perinatal androgenization. Pregnant Wistar rats were exposed to corn oil or testosterone propionate at 0.05, 0.1, or 0.2 mg/kg from gestational day 12 until postnatal day 21. Female offspring was challenged with estradiol (E₂) after weaning (0.4 mg/kg) and at adulthood (10 or 100 µg/day), when the pituitary response was also evaluated. At adulthood, control and 0.05 mg/kg groups presented a uterine weight increment when exposed to 100 µg/day of E₂, 0.1 mg/kg group only responded to 10 µg/day of E₂, and the 0.2 mg/kg group showed increased uterine weight at both doses. The pituitary weight was similarly increased after estradiol stimulation in all experimental groups. In conclusion, testosterone propionate exposure induced an abnormal stimulation of uterine tissue growth by estrogen stimulus without affecting pituitary response. More studies are needed to clarify whether these alterations are capable of impairing the reproductive capacity of the female tract. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1460–1468, 2016.     

In utero exposure to chloroquine alters sexual development in the male fetal rat

Chloroquine (CQ), a drug that has been used extensively for the prevention and treatment of malaria, is currently considered safe for use during pregnancy. However, CQ has been shown to disrupt steroid homeostasis in adult rats and similar compounds, such as quinacrine, inhibit steroid production in the Leydig cell in vitro. To explore the effect of in utero CQ exposure on fetal male sexual development, pregnant Sprague-Dawley rats were given a daily dose of either water or chloroquine diphosphate from GD 16-18 by oral gavage. Chloroquine was administered as 200 mg/kg CQ base on GD 16, followed by two maintenance doses of 100 mg/kg CQ base on GD 16 and 18. Three days of CQ treatment resulted in reduced maternal and fetal weight on GD 19 and increased necrosis and steatosis in the maternal liver. Fetal livers also displayed mild lipid accumulation. Maternal serum progesterone was increased after CQ administration. Fetal testes testosterone, however, was significantly decreased. Examination of the fetal testes revealed significant alterations in vascularization and seminiferous tubule development after short-term CQ treatment. Anogenital distance was not altered. Microarray and RT-PCR showed down-regulation of several genes associated with cholesterol transport and steroid synthesis in the fetal testes. This study indicates that CQ inhibits testosterone synthesis and normal testis development in the rat fetus at human relevant doses.     

Effects of prenatal exposure to Tityus bahiensis scorpion venom on rat offspring development

Scorpion envenoming is a public health problem. In Brazil, the scorpion Tityus serrulatus is considered the most dangerous, but a large number of exposures also occur with Tityus bahiensis. There are quite a few studies in literature about the toxic effects of this venom but it is not known if the venom causes malformations or behavioral defects to the offspring of mothers exposed to the venom during pregnancy. The objective of this work was to determine, in rats, the possible toxic effects of T. bahiensis venom on offspring when injected into rats during different periods of fetal development. Rats were assigned to one of three groups: one control group and two experimental groups that were subcutaneously injected with venom (2.5 mg/kg) on the 10th (GD10) or on 16th day (GD16) of gestation. Pups were evaluated for changes in physical and behavioral development. GD10 treatment group offspring showed an increase in body weight gain, earlier ear unfolding, incisor tooth eruption and vaginal opening. A decrease in the time of palmar grasp and surface-righting reflexes was observed only for males. In GD16 treatment group, earlier ear unfolding, incisor tooth eruption, and delay in eye opening were observed in the offspring. In female pups a decrease in weight gain and in time for palmar grasp reflex, and an increase in time for negative geotaxis were observed. In male pups a delay in the testis descent, decrease in the time of palmar grasp, increase in the time of negative geotaxis reflex and in the general and locomotor activities could be noticed. Therefore, we concluded that a moderate dose of scorpion venom administered to pregnant rats was able to elicit alterations in physical and behavioral development in the offspring during the postnatal period.     

Maternal nicotine exposure and fetal programming of vascular oxidative stress in adult offspring

Despite the well-known harmful effects, many women continue to smoke throughout pregnancy. Consequently, nicotine replacement therapy (NRT) - which has been developed as a pharmacotherapy for smoking cessation - has been used as an alternative to smoking during pregnancy. However, like cigarette smoking, NRT results in biologically significant levels of nicotine crossing the placenta, leading to both fetal and neonatal exposure to nicotine, and yet, NRT safety during pregnancy has not been extensively evaluated. There is now evidence from studies in rats that maternal nicotine exposure throughout gestation results in fetal programming of vascular oxidative stress in the offspring during adulthood. This phenomenon involves vascular dysfunction mediated by reactive oxygen species in association with decreased superoxide dismutase activity and increased Nox2-NADPH oxidase expression in the vascular wall. If this phenomenon also occurs in humans, either smoking or NRT use during pregnancy may represent a novel risk factor for the unborn that results in accelerated cardiovascular disease in their adulthood.     

Changes in androgen-mediated reproductive development in male rat offspring following exposure to a single oral dose of flutamide at different gestational ages.

Previous studies have indicated that the androgen receptor antagonist, flutamide, can produce a suite of reproductive malformations in the male rat when orally administered daily on gestation days (GD) 12-21. The objective of this study was to investigate the gestation time dependence for the induction of these malformations to establish a robust animal model for future studies of gene expression related to specific malformations. Groups of timed-pregnant Sprague-Dawley rats (GD 0 = day of mating) were administered flutamide as a single gavage dose (50 mg/kg) on GD 16, 17, 18, or 19 with 10 dams per group. Control animals (5 dams per time per group) were administered corn oil vehicle (2 ml/kg). Dams were allowed to litter, and their adult male offspring were killed at postnatal day (PND) 100 +/- 10. Anogenital distance was measured at PND 1 and 100. Areolae were scored at PND 13, and permanent nipples evaluated at PND 100. No reproductive tract malformations were found in control male offspring. In the treated groups, malformations were noted following exposure at every GD, although the incidence of specific malformations varied by GD. At GD 16, the highest incidence was noted for permanent nipples (46% pups, 60% litters), epispadias (12% pups, 30% litters), and missing epididymal components (5% pups, 20% litters). The highest incidences for hypospadias (58% pups, 80% litters), vaginal pouch (49% pups, 70% litters), cleft prepuce (29% pups, 60% litters), and missing prostate lobes (12% pups, 60% litters) were noted at GD 17. At GD 18 the highest incidence of malformations noted were epispadias (5% pups, 30% litters), reduced prostate size (32% pups, 90% litters), and abnormal kidneys (3% pups, 30% litters) and bladders (7% pups, 30% litters), while on GD 19 70% of the litters had animals with abnormal seminal vesicles. Testicular and epididymal morphological changes were noted at all GDs and were consistent with the gross observations and peaked in incidence and severity on GD17. The major discrepancy between this study and previous multiple-dose studies was in the very few numbers of animals presenting with cryptorchidism (only one each on GDs 16 and 17), suggesting that exposure over multiple days may be required to induce this malformation. Thus, a single gestational exposure of flutamide induced numerous reproductive tract malformations consistent with previously reports following multiple exposures, with the timing of the exposure producing marked tissue selectivity in the response noted in adult offspring.     

Perinatal exposure to PCB 153, but not PCB 126, alters bone tissue composition in female goat offspring

The aim of this study was to investigate if environmentally relevant doses of the putative estrogenic non dioxin-like PCB 153 and the dioxin-like PCB 126 caused changes in bone tissue in female goat offspring following perinatal exposure. Goat dams were orally dosed with PCB 153 in corn oil (98 microg/kg body wt/day) or PCB 126 (49 ng/kg body wt/day) from day 60 of gestation until delivery. The offspring were exposed to PCB in utero and through mother's milk. The suckling period lasted for 6 weeks. Offspring metacarpal bones were analysed using peripheral quantitative computed tomography (pQCT) after euthanisation at 9 months of age. The diaphyseal bone was analysed at a distance of 18% and 50% of the total bone length, and the metaphyseal bone at a distance of 9%. Also, biomechanical three-point bending of the bones was conducted, with the load being applied to the mid-diaphyseal pQCT measure point (50%). PCB 153 exposure significantly decreased the total cross-sectional area (125 mm(2)+/-4) versus non-exposed (142 mm(2)+/-5), decreased the marrow cavity (38 mm(2)+/-4) versus non-exposed (50 mm(2)+/-3) and decreased the moment of resistance (318 mm(3)+/-10) versus non-exposed (371 mm(3)+/-20) at the diaphyseal 18% measure point. At the metaphyseal measure point, the trabecular bone mineral density (121 mg/cm(3)+/-5) was increased versus non-exposed (111 mg/cm(3)+/-3). PCB 126 exposure did not produce any observable changes in bone tissue. The biomechanical testing of the bones did not show any significant changes in bone strength after PCB 153 or PCB 126 exposure. In conclusion, perinatal exposure to PCB 153, but not PCB 126, resulted in altered bone composition in female goat offspring.     

Effects of perinatal exposure to low doses of tributyltin chloride on pregnancy outcome and postnatal development in mouse offspring

Tributyltin (TBT), an endocrine‐disrupting chemical, is well known to induce imposex in female gastropods. In this study, we assessed the effects of low doses of tributyltin chloride (TBTCl) on dams and their offspring. Pregnant mice were administered by gavage with 0, 1, 10, or 100 μg TBTCl/kg body weight/day from day 6 of pregnancy through the period of lactation. There were no TBT treatment‐related deaths or clinical signs of toxicity for dams, and no treatment‐related effects on body weight, litter sizes, gestational length of dams, and sex ratio, lactational body weight, postnatal survival, age at eruption of incisors, and eye opening of pups. However, at 100 μg/kg, TBTCl retarded the testes descent of male offspring. Behavioral tests showed a significant delay in cliff‐drop aversion response in offspring of 10 and 100 μg/kg groups, but no significant difference in the righting reflex between control and TBT‐exposed offspring was detectable. These results indicate that neurobehavioral toxicity seems to be one sensitive indicator to assess the risk of low doses of TBT. © 2011 Wiley Periodicals, Inc. Environ Toxicol, 2012.     

Maternal protein restriction during pregnancy and lactation alters central leptin signalling,increases food intake,and decreases bone mass in 1 year old rat offspring

The effects of perinatal nutrition on offspring physiology have mostly been examined in young adult animals. Aging constitutes a risk factor for the progressive loss of metabolic flexibility and development of disease. Few studies have examined whether the phenotype programmed by perinatal nutrition persists in aging offspring. Persistence of detrimental phenotypes and their accumulative metabolic effects are important for disease causality. This study determined the effects of maternal protein restriction during pregnancy and lactation on food consumption, central leptin sensitivity, bone health, and susceptibility to high fat diet‐induced adiposity in 1‐year‐old male offspring. Sprague‐Dawley rats received either a control or a protein restricted diet throughout pregnancy and lactation and pups were weaned onto laboratory chow. One‐year‐old low protein (LP) offspring exhibited hyperphagia. The inability of an intraperitoneal (i.p.) leptin injection to reduce food intake indicated that the hyperphagia was mediated by decreased central leptin sensitivity. Hyperphagia was accompanied by lower body weight suggesting increased energy expenditure in LP offspring. Bone density and bone mineral content that are negatively regulated by leptin acting via the sympathetic nervous system (SNS), were decreased in LP offspring. LP offspring did not exhibit increased susceptibility to high fat diet induced metabolic effects or adiposity. The results presented here indicate that the programming effects of perinatal protein restriction are mediated by specific decreases in central leptin signalling to pathways involved in the regulation of food intake along with possible enhancement of different CNS leptin signalling pathways acting via the SNS to regulate bone mass and energy expenditure.     

Effect of oral and inhalation exposure to cadmium on the oestrous cycle in rats

Female rats were administered by gavage an aqueous solution of CdCl2 for 14 weeks, 5 days per week, at doses of 0.04, 0.4, 4 and 40 mg Cd/kg/day or exposed by inhalation to CdO for 20 weeks (5 h per days, 5 days per week) at concentrations of 0.02, 0.16 and 1 mg Cd/m3. A pronounced increase in the mean duration of the oestrous cycle mainly due to lengthening of dioestrus was noted already 6 weeks after treatment of females given per os 40 mg Cd/kg or exposed to a concentration of 1 mg Cd/m3. No changes in the mean duration of the oestrous cycle were found in other experimental groups, although in the 0.16 mg Cd/m3 group an increased percentage of females with oestrous cycles lasting over 6 days was shown 18 weeks after exposure. Since Cd-induced lethality and decrease in body weight gain were observed in females given by gavage 40 mg Cd/kg or exposed by inhalation to a concentration of 1 mg Cd/m3, it is concluded that exposure to cadmium does not affect the sexual cycle unless other overt signs of Cd-toxicity are induced.     

Prenatal exposure to permethrin influences vascular development of fetal brain and adult behavior in mice offspring

Pyrethroids are one of the most widely used classes of insecticides and show neurotoxic effects that induce oxidative stress in the neonatal rat brain. However, little is still known about effects of prenatal exposure to permethrin on vascular development in fetal brain, central nervous system development, and adult offspring behaviors. In this study, the effects of prenatal exposure to permethrin on the development of cerebral arteries in fetal brains, neurotransmitter in neonatal brains, and locomotor activities in offspring mice were investigated. Permethrin (0, 2, 10, 50, and 75 mg/kg) was orally administered to pregnant females once on gestation day 10.5. The brains of permethrin‐treated fetuses showed altered vascular formation involving shortened lengths of vessels, an increased number of small branches, and, in some cases, insufficient fusion of the anterior communicating arteries in the area of circle of Willis. The prenatal exposure to permethrin altered neocortical and hippocampus thickness in the mid brain and significantly increased norepinephrine and dopamine levels at postnatal day 7 mice. For spontaneous behavior, the standing ability test using a viewing jar and open‐field tests showed significant decrease of the standing ability and locomotor activity in male mice at 8 or 12 weeks of age, respectively. The results suggest that prenatal exposure to permethrin may affect insufficient development of the brain through alterations of vascular development. © 2011 Wiley Periodicals, Inc. Environ Toxicol 28:617–629, 2013.     

Maternal exposure to di-n-butyl phthalate (DBP) induces combined anorectal and urogenital malformations in male rat offspring

Anorectal malformations in combination with hypospadias (ARMs & hypospadias) are a type of complex congenital malformations. The underlying mechanisms of this deformity are largely unknown. In this study, we comprehensively characterized the dysplasia, histological malformations, and genetic changes of ARMs & hypospadias in male rats after maternal exposure to di-n-butyl phthalate (DBP) by gastric intubation at doses of 850 mg/kg bw/day during GD11-15. On postnatal day 1, anatomical and histopathological analysis confirmed combined malformations of the genital tubercle (GT), terminal rectum (TR) and testes. DBP-induced dysplasia was also seen in the kidney, lung, spleen, heart and liver of ARMs & hypospadias male rats. Moreover, decreased levels of serum testosterone, as well as reduced expression of genes related to the androgen signaling pathway (Cyp11a1, Hsd3b, Scarb1, Star, AR, Srd5a2) were found in the testes of ARMs & hypospadias male rats after DBP exposure as compared to untreated controls. Further, decreased mRNA levels of Shh, Fgf10, Gli2, Gli3, Bmp4, Wnt5a, Hoxa13, Hoxd13, Fgfr2 and AR were observed in TR and GT in the ARMs & hypospadias group. These results provide evidence that prenatal exposure to DBP can lead to combined anorectal and urogenital malformations as well as dysplasia of the testes.     

Life‐cycle exposure to the estrogenic mycotoxin zearalenone affects zebrafish (Danio rerio) development and reproduction

Zearalenone (ZON) is one of the worldwide most common mycotoxin and exhibits estrogenic activity in the range of natural steroid estrogens. The occurrence of ZON has been reported in soil, drainage water, wastewater effluents, and rivers, but its ecotoxicological effects on fish have hardly been investigated. The consequences of continuous long‐term ZON exposure, including a subsequent depuration period, as well as transgenerational effects of F0 short‐term exposure on F1 generation were investigated. Effects on growth, reproduction activity, physiology, and morphology of zebrafish (Danio rerio) were examined in a 182 day live‐cycle experiment. Life‐long exposure to ZON for 140 days increased wet weight, body length, and condition factor of female fish at 1000 ng/L, and sex ratio was shifted toward female from 320 ng/L ZON. Only females at 1000 ng/L ZON revealed a 1.5‐fold induction of plasma vitellogenin (VTG). Relative fecundity at 1000 ng/L recovered significantly during the depuration period. An increased condition factor in adult female F1 fish implies that exposure of F0 generation to 1000 ng/L ZON affected growth of F1 generation. A negative correlation between relative fecundity in the F1 generation (all groups exposed to 320 ng/L ZON) and the nominal ZON concentrations of the F0 exposure might indicate an influence of F0 exposure on reproductive performance of F1 generation. No exposure scenario affected fertility, hatch, embryo survival, and gonad morphology of zebrafish. Evaluating the environmental relevance of this data, the risk for fish to be harmed by exposure to ZON solely seems rather marginal, but ZON might contribute to the overall estrogenicity in the environment. © 2011 Wiley Periodicals, Inc. Environ Toxicol 2013.     

Maternal exposure to arsenic and cadmium and the risk of congenital heart defects in offspring

Hair arsenic and cadmium from 339 women with congenital heart defect (CHD)-affected pregnancies (case women) and 333 women with normal live births (control women) in China were estimated using inductively coupled plasma mass spectrometry. The median levels of hair arsenic and cadmium in the case women were 98.30 (74.30–136.30) ng/g and 14.60 (8.30–32.50) ng/g, respectively, which were significantly higher than the levels in the control group (P < 0.05). Arsenic concentrations ≥62.03 ng/g were associated with increased risk for almost every CHD subtype, with a dose-response relationship. However, only the group with the highest cadmium levels (≥25.85 ng/g) displayed an increased risk of CHDs (AOR 1.96; 95% CI 1.24–3.09), with a 2.81-fold increase found for the occurrence of conotruncal defects in their offspring. Furthermore, an interaction between arsenic and cadmium was observed. Our findings suggest that maternal exposure to arsenic and cadmium may be a significant risk factor for CHDs in offspring. Cadmium may have an enhancing effect on the association between arsenic and the risk of CHDs in offspring.     

Maternal nicotine exposure leads to decreased cardiac protein disulfide isomerase and impaired mitochondrial function in male rat offspring

Smoking throughout pregnancy can lead to complications during gestation, parturition and neonatal development. Thus, nicotine replacement therapies are a popular alternative thought to be safer than cigarettes. However, recent studies in rodents suggest that fetal and neonatal nicotine exposure alone results in cardiac dysfunction and high blood pressure. While it is well known that perinatal nicotine exposure causes increased congenital abnormalities, the mechanisms underlying longer‐term deficits in cardiac function are not completely understood. Recently, our laboratory demonstrated that nicotine impairs placental protein disulfide isomerase (PDI) triggering an increase in endoplasmic reticulum stress, leading us to hypothesize that this may also occur in the heart. At 3 months of age, nicotine‐exposed offspring had 45% decreased PDI levels in the absence of endoplasmic reticulum stress. Given the association of PDI and superoxide dismutase enzymes, we further observed that antioxidant superoxide dismutase‐2 levels were reduced by 32% in these offspring concomitant with a 26–49% decrease in mitochondrial complex proteins (I, II, IV and V) and tissue inhibitor of metalloproteinase‐4, a critical matrix metalloprotease for cardiac contractility and health. Collectively, this study suggests that perinatal nicotine exposure decreases PDI, which can promote oxidative damage and mitochondrial damage, associated with a premature decline in cardiac function.