|Year : 2022 | Volume
| Issue : 2 | Page : 75-81
Developmental Pb2+-Exposure induces cardiovascular pathologies in adult male rats
Evelyn Okeke1, Lorenz S Neuwirth2, Abdeslem El Idrissi3
1 Department of Biology, The College of Staten Island, City University of New York, Staten Island; Department of Mass Spec Capabilities and Biochemistry, Merck Research Laboratories, Kenilworth, NJ, USA
2 Department of Biology, The College of Staten Island, City University of New York, Staten Island; Department of Psychology, SUNY Old Westbury; Suny Neuroscience Research Institute, Old Westbury; Center for Developmental Neuroscience, The College of Staten Island, City University of New York, Staten Island, NY, USA
3 Department of Biology; Center for Developmental Neuroscience, The College of Staten Island, City University of New York, Staten Island, NY, USA
|Date of Submission||02-Dec-2021|
|Date of Acceptance||08-Mar-2022|
|Date of Web Publication||16-May-2022|
Dr. Lorenz S Neuwirth
Department of Psychology, SUNY Old Westbury, 223 Store Hill Road, Bldg.: NAB, Room: 2059, Old Westbury, New York 11568
Source of Support: None, Conflict of Interest: None
Background: Developmental lead (Pb2+) exposure has been historically shown to alter the pathological functions of the cardiovascular system at high blood lead levels (i.e.,>15 μg/dL). However, given the time that has elapsed in the field (i.e., some 30 years), there is a great need for less clinical and more basic research on the cardiopathology of low blood lead levels (lBLLs; i.e.,<10 μg/dL). Further, most of the prior literature had focused solely on males as they had been reported to be more vulnerable to Pb2+ induced cardiovascular pathology. Aims and Objectives: To generate a model system of Pb2+-induced cardiovascular pathology that would be consistent with past reports, the present study examined male Long–Evans Hooded rats that were perinatally Pb2+ exposed (i.e., via their food with 996 ppm lead acetate in the rat chow) up until weaning (i.e., postnatal day 22; blood lead levels [BLLs]: 10–15 μg/dL) and were then removed from Pb2+ exposure for nearly 1.5 months (i.e., BLLs >3.33 μg/dL). Materials and Methods: Rats were then subjected to cardiovascular measures of systolic and diastolic blood pressures (SBP and DBP) and heart rates. Rats were sacrificed and their hearts were weighed; their thoracic aortas were collected and examined for microstructural and morphological changes through a scanning electron micrograph. Results: The data showed that compared to age matched control rats, the Pb2+ exposed rats have increased SBP, DBP, and heart rate with no differences in heart weight. These data show that early developmental Pb2+ exposure comprising lBLLs can cause significant cardiovascular pathological changes in rats. Conclusion: The present model of developmental Pb2+-exposure occurring early in life caused Pb2+-induced cardiopathology later in life through increased hypertension and reduced elasticity of the aorta media. These cardiovascular pathologies could further increase the likelihood of accelerated fronto executive dysfunctions due to the direct action of Pb2+ on neurons through inhibition of calcium dependent processes and might also contribute to vascular dementias.
Keywords: Aorta, aorta dissection, cardiopathology, cardiovascular diseases, developmental Pb2+-exposures, hypertension, lead (Pb2+) poisoning
|How to cite this article:|
Okeke E, Neuwirth LS, El Idrissi A. Developmental Pb2+-Exposure induces cardiovascular pathologies in adult male rats. Heart Mind 2022;6:75-81
| Introduction|| |
The effects of developmental lea (Pb2+)-exposure in animal models have been extensively studied in regard to its detrimental impacts on the central nervous system over the last three decades,,,,,,,,, in relation to psychopathological symptoms in humans.,,,,,,,,,,,,,,,, Historically, trace metals have been established to cause elevated blood pressure when organisms accumulate small-to-moderate amounts of them within their circulatory system and determine also neurodevelopmental effects in children., Moreover, rodents have proved to be an invaluable preclinical model system to investigate the basic mechanism underlying a wide range of cardiovascular pathologies. Likewise, the associated relationships between human low blood lead levels (lBLLs) (i.e., 5–10 μg/dL) and cardiovascular dysfunctions (i.e., hypertension and increased blood stroke volume, suggest developmental Pb2+ exposure as a risk factor for early and late onset cardiovascular disease) have also been studied exhaustively in adolescents, men while also showing relationships with men at increased risk over women for left ventricular hypertrophy and myocardial infarcts. Moreover, in females aged 40–59 years with BLLs <40 μg/dL show a positive linear relationship with elevated BLLs and increased systolic blood pressure (SBP) and diastolic blood pressure (DBP) causing hypertension that is most pronounced during the postmenopausal period. Additionally, Needleman showed that these BLL risk factors are increased in black men and women. Notably, women are also at increased risk for cardiovascular problems during pregnancy (i.e., preeclampsia) when they are Pb2+-exposed and this increases the vulnerability for the fetus to be subjected to Pb2+-induced developmental neuropathologies., Interestingly, Han et al. showed that treating women with increased dietary calcium prior to becoming pregnant and throughout pregnancy when they were Pb2+-exposed reduced their BLLs and the placental transfer of their BLLs to the fetus, but no long-term follow-up studies have been done to determine whether these children later in life were absent of the predicted psychological and behavioral disorders known to be associated with childhood Pb2+-exposure.,, One solution to this problem could be done by instituting a proactive management plan for women to be screened for BLLs prior to conception (i.e., baseline) at each trimester (i.e., tracking the impacts from organic to later neurodevelopmental systems impacts) and then screening the child upon birth (i.e., regardless of premature or full term as a translational baseline) and subsequently followed up annually until age 3 (i.e., as a postnatal and environmental source assessment screening) or when found to possess a negative BLL.,
The aforementioned studies have been consistently supported by animal research with lBLLs increasing hypertension while more carefully controlled studies are required to elucidate the precise mechanisms of action by which developmental Pb2+-exposure at low- and high-BLLs causes cardiovascular pathologies to model human cardiovascular disease and their associated psychological and behavioral problems. However, work that began in the 1950s through the 1980s regarding the effects of developmental Pb2+-exposure on hemodynamics has not been re-evaluated given the advancements made in understanding developmental neuropathologies induced by Pb2+-exposure over the last three decades. Only recently has such a reappraisal of the associations between the doubling of BLLs (i.e., reported from the meta analysis ranging from 0.11 to 3.08 μmol/L) and an increase in 1.0 mmHg of SBP and 0.6 mmHg of DBP have been made, while showing no gender differences, and concluding that the meta analysis showed a weak association between elevated BLLs and blood pressure. Telisman et al. reported that in patients with higher BLLs ranging from 25 to 75 μg/dL (i.e., equivalent to 0.4–1.0 μmol/L) an increase in 27 mmHg of SBP and 15 mmHg of DBP suggested a dose-response-like functional positive linear relationship with increasing BLLs with SBP and DBP, respectively. It is important to consider that even through such meta analyses that specific toxicokinetics and Pb2+ accumulation during developmental Pb2+ exposure may not have been known for all patients. Further, if the actual Pb2+-exposure profiles were known, then it would have offered the possibility to parse out more at-risk populations (i.e., acute high Pb2+-exposed, chronic low Pb2+-exposed, and/or chronic high Pb2+-exposed children that were followed into adulthood). This would then serve to elucidate whether the associations between BLLs and blood pressure might show a more refined moderate or strong linear relationship consistent with earlier reports identifying developmental Pb2+-exposure as a risk factor for cardiovascular disease in the present day.
More recently, Benjamin et al. reported that cardiovascular disease is the leading cause of mortality in the US and the field is not very clear how many of those cases were identified with developmental Pb2+-exposure as the sole risk factor and/or a comorbid risk factor. Few reports have indicated a range of cardiovascular pathologies induced by developmental Pb2+-exposure, but many of these reports study the peripheral nervous system and fail to expound on how the brain is negatively impacted by Pb2+-exposure and its associated manifestations through psychological and behavioral symptoms. D'Souza et al. reported that high BLLs in patients exposed to nonoccupational Pb2+-exposure experienced symptoms of weakness and dizziness, abdominal and generalized pain, reduced appetite, and forms of anxiety. Bagchi and Preuss reported that male Sprague Dawley rats exposed to 1% Pb2+ acetate for 40 days during a yearlong study in their drinking water produced an early Pb2+ body burden that resulted in SBP and bone mineral density perturbations that were reversible by chelation therapies. Given the larger body of literature on male rats' cardiovascular evaluation of Pb2+-induced effects, in order to understand more carefully how lBLLs may further cause cardiovascular pathologies, the present study sought to evaluate the effects of developmental Pb2+-exposure on male rats' cardiovascular functions (i.e., SBP, DBP, heart rate, and the ultrastructural integrity of the aorta) later in life following nearly 2-month cessation from Pb2+-exposure. This model permits a more longitudinal assessment of the effects of neurodevelopmental Pb2+-exposure and hemodynamics, along with an understanding of what risks may be associated with it as well as age, and how it subsequently influences other systems such as the risks for vascular dementia and associated dysfunctions that accompany senescence.
| Methods|| |
Long–Evans Norwegian Hooded male and female rats were subjected to triad breeding. Control rats were fed a regular Purina rat chow (Dyets Inc. No. 61212) (containing 970 g/kg Purina RMH 1000 chow and 30 g/kg maltose dextrin), while the Pb2+-rats were fed a diet containing 1.5 g/kg lead acetate (Dyets Inc. No. 612113) (containing 968.4 g/kg Purina RMH 1000 30 g/kg maltose dextrin, 1.5 g/kg lead acetate, and 0.1 g/kg yellow dye) ad libitum from 1 month prior to pairing through parturition and weaning. At postnatal day (PND), 22 male rats were housed to no more than 3 per cage and were taken off the 1.5 g/kg lead acetate diet. Male rats were used as they had more pups evenly distributed across litters when compared to female pups. An (n = 6 male rats) consisting of (n = 2) from 3 separate litters were used for the BLL testing at PND 22, whereas an (n = 9 male rats) consisting of (n = 3) from 3 separate litters were used for the SBP, DBP, heart rate, heart weight, and aorta scanning electron micrograph (SEM) imaging studies that commenced between PND 68 and 88.
Blood pressure studies
The present study employed the methods consistent with El Idrissi et al., Briefly, 1–2 weeks prior to testing, rats were habituated to a commercial holding chamber with an external warming blanket surrounding the holding chamber to increase the rat's comfortability (i.e., providing warmth and a dark interior space to remain calm). At the end of the holding chamber, there was an opening from which the rat's tail could be accessed and a rat vein occlusion cuff could be slid onto the rat's tail (Rat Cuff Kit-M; Kent Scientific; Torrington, CT) to record physiological parameters of cardiovascular function (i.e., SBP and DBP measured as mmHg and heart rate measured as beats per minute [BPM]). Rats were habituated for 15 min for 3 sessions/day for 3 days prior to testing. This was done to increase the comfortability of the rat and to decrease any stress-induced or novelty-induced artifacts that may have otherwise served as an extraneous variable that could compromise the integrity of the study. Once this internal validity was established, the physiological measures were recorded from the rats using a CODA® Monitor Noninvasive Blood Pressure System (Kent Scientific; Torrington, CT) for ten repeated trials from a single test session conducted in 1 day. From these ten trials, the first three and last three trials were eliminated due to priming (i.e., acclimating to the cuff noise and pressure) and longevity effects (i.e., preventing additional extraneous variables that may increase all physiological measures as a function of repeated stressors to test). As such, the middle four trials were then averaged to obtain a single mean value for the SBP, DBP, and heart rate for each rat. In between testing, the rat holding chambers were cleaned with 70% ethyl alcohol and soap and warm water and then wiped dry, prior to testing the next rat. All tests were conducted at the same time of day between 11:00 am and 3:00 pm to ensure time/phase-locked cardiovascular rhythm that may otherwise be influenced by daily changes to circadian rhythms.
Blood lead levels and transcardial perfusion
Following completion of all blood pressure studies, rats were sacrificed by way of transcardial perfusion and blood samples were collected using ethylenediaminetetraacetic acid-coated S-Monovette® syringes (Sarstedt, Germany) and immediately frozen on dry ice. Blood samples were then sent out for BLL determination to Magellan Diagnostics (North Billerica, MA), formerly known as ESA Laboratories; BLLs were determined by atomic absorption spectrophotometry with a lower sensitivity detection level limit of 1 μg/dL. Immediately following blood sample collection, the rats were exsanguinated with 3 purges of 60 mL × 1 phosphate-buffered saline (PBS; P3813 Sigma Aldrich; St. Louis, MO) pH 7.4, followed by excising the hearts for immediately determining its weight and then excising the thoracic aortas, and placed in 2.5% glutaraldehyde in 0.1 M PBS for subsequent SEM imaging.
Scanning electron micrograph thoracic aorta sample preparation
Thoracic aortas were harvested from Long–Evans rats at the indicated ages. Any adherent tissue (i.e., fat or other connective tissues) was cleaned off and aortas were rinsed in ×1 PBS. Subsequently, the aortas were then cross-sectioned into 3.0 mm samples and placed into glass vials with two samples per vial.
In a chemical fume hood, a generous volume of 2.5% glutaraldehyde in 0.1 M PBS pH 7.4 was added to each vial to submerge all sections in the fixative. Samples were incubated in the fixative at room temperature (RT) in the fume hood for 1 h followed by 3 min × 10 min washes in 0.1 M PBS pH 7.4.
Samples were dehydrated through ascending steps of ethanol. All ethanol incubations were performed for 1 h at RT unless indicated otherwise. First, samples were submerged in 25% ethanol and then they were placed in 50% ethanol followed by 75% ethanol and 95% ethanol. Finally, samples were submerged in 100% ethanol for 24 h. Ethanol was removed from the glass vial and samples were allowed to air dry in a chemical fume hood for 5-min.
A small colorless double-sided adhesive patch was placed in the center of the SEM stub with premounted tabs. Cross sections were placed on the patch accordingly so that the cross section faced upright. Samples were then coated with a mixture of gold and palladium (Au/Pd) with a 60:40 concentration ratio using a Med20 high vacuum sputter coater.
Scanning electron micrograph imaging
Images of the Au/Pd (60/40 ratio)-coated samples aortas were captured using an AMRAY 1910 Field Emission Scanning Electron Microscope, with the capability of 3-axis stage motorization, 4” load lock for faster transfer of samples for samples sizes up to 4” maximum with 100 mm X/Y, equipped with energy dispersive spectrometers and wavelength dispersive spectrometers, and able to capture digital images at a resolution of 7 nm at 1 kV and 1.5 nm at 30 kV. The aorta images collected were taken at a resolution of 7 nm at 5 kV at ×50, ×100, ×250, and ×500 magnifications to determine qualitatively any structural and/or morphological changes as a function of neurodevelopmental Pb2+-exposure, respectively.
All statistical analyses were carried out by using the SPSS version 24 (IBM®, Armonk, New York, USA). The criteria for statistical significance were set at α ≤0.05 with a confidence interval of 95% (95%). To assess the normality of the participant sample distribution, the Levene's test was used to assess the equality of variances, where unequal variances were reported the degree of freedom was adjusted accordingly to ensure appropriate statistical comparisons where applicable. This was followed by an independent samples t-test that was used to evaluate the differences between the two treatment groups for the SBP, DBP, and heart rate, and finally, a Cohen's d was used for determining the effect size of the differences between the two treatment groups.
The procedures outlined in the manuscript were approved by The College of Staten Island of The City University of New York Institutional Animal Care and Use Committe. All procedures abided to the ethical care and welfare of the animals in accordance with the IACUC policies. The CSI-08-015 protocol was first approved on 12/12/10 and continued thereafter.
| Results|| |
Blood lead levels caused by developmental exposure
The control rats (0 ppm) exhibited BLLs that were below the lower detectable limit (i.e., 3.3 μg/dL). In contrast, the Pb2+ rats developmentally exposed to 1000 ppm lead acetate through their food supply produced a MBLLs = 13.99 (standard deviation [SD] = 3.37; range: 10–15 μg/dL). These BLLs were comparable to the moderate BLLs found in the pediatric population within the levels of actionable concern, making them physiologically relevant and a good model for biomedical translational research.
Effects of developmental Pb2+-exposure on age and heart weight
The rats in the present study were evaluated for cardiovascular pathologies 1½ months following the cessation of developmental Pb2+-exposure. Between PND 70 and 75, rats used in this study had no significant differences in age MControl = 75.56 PND (SD = 8.96) and MPb2+ = 70.58 PND (SD = 10.49). Additionally, the early developmental effects of Pb2+-exposure did not exhibit any significant differences in heart weight MControl = 1.05 g (SD = 0.13) and MPb2+ = 1.05 g (SD = 0.09). Thus, no effects of age or heart weight could have contributed to any cardiovascular pathology observed in the present study.
Developmental effects of Pb2+ on blood pressure
The control rats showed a MSBP = 127.53 (SD = 13.40), a MDBP = 94.55 (SD = 12.10), and a MHeart Rate = 353.58 (SD = 38.48), whereas the Pb2+ rats showed a MSBP = 137.65 (SD = 11.83), a MDBP = 105.23 (SD = 11.06), and a MHeart Rate = 399.47 (SD = 25.71), respectively [Figure 1]a. The early developmental effects of Pb2+-exposure revealed a significant effect of SBP t (16) = −1.700, P < 0.05*, with a Cohen's d of −0.802 showing a strong effect size [Figure 1]a. Moreover, the early developmental effects of Pb2+-exposure revealed a significant effect of DBP t (15.873) = −1.954, P < 0.05*, with a Cohen's d of −0.921 showing a strong effect size [Figure 1]a. Further, the early developmental effects of Pb2+-exposure revealed a significant effect of heart rate t (16) = −2.975, P < 0.01**, with a Cohen's d of −1.402 showing a strong effect size that the difference between the two means is larger than one and a half SD [Figure 1]b.
|Figure 1: The systolic (solid bars) and diastolic blood pressure (striped bars; a) and the heart rate measured as beats per minute for the control (light gray bars) and the Pb2+ rats (dark gray bars), respectively. The data show a significant increase in systolic and diastolic blood pressure (a; *P < 0.05) and heart rate (b; **P < 0.01) in neurodevelopmental Pb2+-exposed rats, when compared to age-matched control rats. The data suggest that developmental Pb2+-exposure causes early-onset hypertension and cardiovascular pathologies in male rats. Data are presented as the mean ± scanning electron micrograph|
Click here to view
Developmental Pb2+-induced morphological changes to the aorta
The lifelong impacts of developmental Pb2+-exposure were examined in the aorta through SEM imaging of the aortic wall (i.e., to examine any morphological changes to the adventitia, media, and intima layers of the aortic wall) as well as the smooth muscle and endothelial cells, respectively. In [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d, from the intimal flap (i.e., the internal elastic membrane), moving inward to the media (i.e., the smooth muscle), and then toward the adventitia (i.e., the external elastic membrane), the SEM images show morphologically a thinning of the smooth muscle with less layers pronounced at both ×50 (a and b) and ×100 (c and d) magnifications. This observation is made further apparent in [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d, as the smooth muscle in the tunica media is present with more elastic fibers (i.e., determined by increased contractions across the inner lumen) in the control rat's aorta, whereas in the Pb2+-exposed rats, aorta exhibits the opposite morphological microstructural details. This suggests the developmental Pb2+-exposure may create a parallel cardiopathological condition similar to aortic dissection patients with intimal tears, forms of medial weakness, and/or earlier than typically acquired elastic fiber and/or elastin abnormalities with the possibility to be accompanied by cystic medial necrosis (i.e., degeneration observed by the reduction of and/or disappearance of elastic fibers in the arterial media.
|Figure 2: The scanning electron micrograph images of the control (a and c) and the Pb2+ rat's (b and d) aorta taken at ×50 (a and b) and ×100 (c and d) low magnifications to inspect the morphological microstructures of the aorta lumen via the adventitia, media, and intima layers of the aortic wall. The aorta morphology of the control rat shows increased elasticity/elastic fibers in the tunica media (a and c) with a decreased elasticity in the tunica media of the Pb2+ rat's aorta with potential thinning or degeneration (c and d)|
Click here to view
|Figure 3: The scanning electron micrograph images of the control (a and c) and the Pb2+ rat's (b and d) aorta taken at ×250 (a and b) and ×500 (c and d) high magnifications to further inspect the morphological alterations in the elastic fibers of the media as a function of developmental Pb2+-exposure. The aorta morphology of the control rat confirms an increased presence of elastic fibers in the tunica media (a and c) with a decrease in elastic fibers along with potential tearing (i.e., dissection) and/or degeneration of the smooth muscle within the tunica media of the Pb2+ rat's aorta (c and d)|
Click here to view
| Discussion|| |
The present study evaluated the effects of developmental Pb2+ exposure consisting of the perinatal time-period in male rats and later life cardiovascular pathologies. The data obtained from this study provide evidence that perinatal Pb2+ exposed rats, even following nearly 1.5–2 months of being absent of Pb2+ exposure, produced persistent increases in SBP, DBP, and heart rate as well as altering the microstructure of the aorta tunica media elastic fibers and the smooth muscle. These findings suggest that perinatal Pb2+ exposure can cause an early developmental profile of hypertension and a reduction in the smooth muscle elasticity which is consistent with tearing (i.e., dissection,) and degeneration of the aorta lumen, specifically the tunica media. The alterations of the cardiovascular system induced by developmental Pb2+-exposure are significant as the aorta is responsible for supplying blood from the heart to all other organs including the brain, which may also increase the risk for vascular dementia and when disrupted can be fatal. Moreover, recent studies in men have shown that low-level Pb2+-exposure can cause resistant hypertension in which the tibia bone lead levels are able to predict an increased risk of 19% for hypertension.
These observations are also consistent with developmental Pb2+-exposure causing cardiovascular pathology early during the aging process in rats. This finding is consistent with other studies that have systematically reviewed aorta morphological changes as a function of aging in humans. Consistent with these reports, it is reasonable to postulate the perinatal Pb2+ exposure might also alter the hemodynamic load on the cardiovascular system contributing to a broad range of biomechanical vulnerabilities for later life cardiovascular pathologies (i.e., shear stress, calcification, and inflammation) consistent with reports of Bäck et al., Teo et al., Vandeputte et al., Reyes et al., and Benson and Price. Although the present study only examined male rats to determine whether the data would corroborate with prior reports, examination of female perinatal Pb2+-exposed rats is also required to elucidate sex-dependent effects on Pb2+-induced cardiopathology. Further, considering the cardiovascular pathology induced by developmental Pb2+-exposure, considerations for longitudinal studies of patients diagnosed with low-level Pb2+-exposure from childhood may benefit from increased dietary Vitamin D, calcium, and taurine,,,,, as well as the potential use of beta-blockers and calcium channel blockers, as proactive cardiovascular pharmacological and neuropsychopharmacological treatment interventions. This latter point is important as the positive linear relationship between BLLs (5 μg/dL) and coronary artery stenosis suggesting early risk for cardiovascular pathology and further serves as an additional risk factor for negative neurocognitive and psychosocial symptoms to manifest and persist across the lifespan. These recent reports provide yet another mechanism of action (i.e., cardiovascular) of Pb2+-induced long-term brain insult that would cause fronto-executive dysfunctions consistent with neurodevelopmental Pb2+-exposures.,,
| Conclusion|| |
In summary, the present study showed that male rats developmentally exposed to Pb2+ poisoning exhibited cardiopathology by way of increased hypertension and reduces elasticity of the aorta media and that they can be used as a comparative model with high reliability and construct validity. These findings corroborate with emerging work in the clinical areas following children that were Pb2+-exposed within their youth and later into adulthood as early cardiopathological risk factors. These Pb2+-induced risk factors may further increase the risk of vascular pathology of the brain and, in turn, sensitize children that were Pb2+-poisoned to develop fronto-executive dysfunctions earlier in life than what would otherwise neurotypically occur. Thus, the early screening of children that are Pb2+-exposed should be more consistently done and should also include cardiovascular assessments if and when needed.
E.O., L.S.N., and A.E. conceived the experiments. E.O. and L.S.N. completed all blood pressure behavioral experiments. L.S.N. conducted all the perfusions. E.O. prepared all samples for SEM and collected all the SEM images. E.O., L.S.N., and A.E. completed the statistical analyses for the manuscript and approved the final manuscript for publication.
Financial support and sponsorship
The authors have no funding to declare.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Yang DM, Chang YF. Versatile Cell and Animal Models for Advanced Investigation of Lead Poisoning. Biosensors (Basel) 2021;11:371.
Neuwirth LS, Lopez OE, Schneider JS, Markowitz ME. Low-level lead exposure impairs fronto-executive functions: A call to update the DSM-5 with lead poisoning as a neurodevelopmental disorder. Psychol Neurosci 2020;13:299-325.
Neuwirth LS, Masood S, Anderson DW, Schneider JS. The attention set-shifting test is sensitive for revealing sex-based impairments in executive functions following developmental lead exposure in rats. Behav Brain Res 2019;366:126-34.
Onalaja AO, Claudio L. Genetic susceptibility to lead poisoning. Environ Health Perspect 2000;108 Suppl 1:23-8.
Laughlin NK. Animal models of behavioral effects of early lead exposure. In: Riley EP, Vorhees CV, editors. Handbook of Behavioral Teratology. Boston MA: Springer; 1986. p. 291-319.
Bornschein R, Pearson D, Reiter L. Behavioral effects of moderate lead exposure in children and animal models: Part 1, clinical studies. Crit Rev Toxicol 1980;8:43-99.
Clasen RA, Hartmann JF, Coogan PS, Pandolfi S, Laing I, Becker RA. Experimental acute lead encephalopathy in the juvenile rhesus monkey. Environ Health Perspect 1974;7:175-85.
Michaelson IA, Sauerhoff MW. Animal models of human disease: Severe and mild lead encephalopathy in the neonatal rat. Environ Health Perspect 1974;7:201-25.
Silbergeld EK, Goldberg AM. Hyperactivity: A lead-induced behavior disorder. Environ Health Perspect 1974;7:227-32.
Scharding NN, Oehme FW. The use of animal models for comparative studies of lead poisoning. Clin Toxicol 1973;6:419-24.
Lanphear B. Still treating lead poisoning after all these years. Pediatrics 2017;140:e20171400.
Mason LH, Harp JP, Han DY. Pb neurotoxicity: Neuropsychological effects of lead toxicity. Biomed Res Int 2014;2014:84047.
Canfield RL, Kreher DA, Cornwell C, Henderson CR Jr. Low-level lead exposure, executive functioning, and learning in early childhood. Child Neuropsychol 2003;9:35-53.
Bellinger DC. Very low lead exposures and children's neurodevelopment. Curr Opin Pediatr 2008;20:172-7.
Cecil KM, Brubaker CJ, Adler CM, Dietrich KN, Altaye M, Egelhoff JC, et al
. Decreased brain volume in adults with childhood lead exposure. PLoS Med 2008;5:e112.
Woolf AD, Goldman R, Bellinger DC. Update on the clinical management of childhood lead poisoning. Pediatr Clin North Am 2007;54:271-94.
Surkan PJ, Zhang A, Trachtenberg F, Daniel DB, McKinlay S, Bellinger DC. Neuropsychological function in children with blood lead levels <10 microg/dL. Neurotoxicology 2007;28:1170-7.
Lidsky TI, Schneider JS. Adverse effects of childhood lead poisoning: The clinical neuropsychological perspective. Environ Res 2006;100:284-93.
Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P, Bellinger DC, et al.
Low-level environmental lead exposure and children's intellectual function: An international pooled analysis. Environ Health Perspect 2005;113:894-9.
Weisskopf MG, Hu H, Mulkern RV, White R, Aro A, Oliveira S, et al.
Cognitive deficits and magnetic resonance spectroscopy in adult monozygotic twins with lead poisoning. Environ Health Perspect 2004;112:620-5.
Lidsky TI, Schneider JS. Lead neurotoxicity in children: Basic mechanisms and clinical correlates. Brain 2003;126:5-19.
Gioia GA, Isquith PK, Guy SC. Assessment of executive functions in children with neurological impairment. In. Simeonsson RJ, Rosenthal SL, editors. Psychological and Developmental Assessment: Children with Disabilities and Chronic Conditions. New York: Guilford Press. The Guildford Press; 2001. p. 317-56.
Trope I, Lopez-Villegas D, Cecil KM, Lenkinski RE. Exposure to lead appears to selectively alter metabolism of cortical gray matter. Pediatrics 2001;107:1437-42.
Dietrich KN, Berger OG, Bhattacharya A. Symptomatic lead poisoning in infancy: A prospective case analysis. J Pediatr 2000;137:568-71.
Lanphear BP, Dietrich K, Auinger P, Cox C. Cognitive deficits associated with blood lead concentrations <10 microg/dL in US children and adolescents. Public Health Rep 2000;115:521-9.
Bellinger D. Neuropsychologic function in children exposed to environmental lead. Epidemiology 1995;6:101-3.
White RF, Diamond R, Proctor S, Morey C, Hu H. Residual cognitive deficits 50 years after lead poisoning during childhood. Br J Ind Med 1993;50:613-22.
Saltman P. Trace elements and blood pressure. Ann Intern Med 1983;98:823-7.
Riccio CA, Drake MB, Sullivan JR. Neurotoxins and neurodevelopment. In: Riccio C, Sullivan J, editors. Pediatric Neurotoxicology. Specialty Topics in Pediatric Neuropsychology. Cham: Springer; 2016. p. 1-11.
Lidsky TI, Heaney AT, Schneider JS, Rosen JF. Neurodevelopmental effects of childhood exposure to heavy metals: Lessons from pediatric lead poisoning. In: Mazzocco MM, Ross JL, editors. Neurogenetic Developmental Disorders: Variations in the Manifestation in Childhood. Cambridge, MA: MIT Press; 2007. p. 335-63.
Doggrell SA, Brown L. Rat models of hypertension, cardiac hypertrophy and failure. Cardiovasc Res 1998;39:89-105.
Harlan WR. The relationship of blood lead levels to blood pressure in the U.S. population. Environ Health Perspect 1988;78:9-13.
Harlan WR, Landis JR, Schmouder RL, Goldstein NG, Harlan LC. Blood lead and blood pressure. Relationship in the adolescent and adult US population. JAMA 1985;253:530-4.
Schwartz J. Lead, blood pressure, and cardiovascular disease in men. Arch Environ Health 1995;50:31-7.
Schwartz J. Lead, blood pressure, and cardiovascular disease in men and women. Environ Health Perspect 1991;91:71-5.
Nash D, Magder L, Lustberg M, Sherwin RW, Rubin RJ, Kaufmann RB, et al.
Blood lead, blood pressure, and hypertension in perimenopausal and postmenopausal women. JAMA 2003;289:1523-32.
Needleman H. Lead poisoning. Annu Rev Med 2004;55:209-22.
Bogden JD, Oleske JM, Louria DB. Lead poisoning –
One approach to a problem that won't go away. Environ Health Perspect 1997;105:1284-7.
Cantor AG, Hendrickson R, Blazina I, Griffin J, Grusing S, McDonagh MS. Screening for elevated blood lead levels in childhood and pregnancy: Updated evidence report and systematic review for the US preventive services task force. JAMA 2019;321:1510-26.
Neuwirth LS. Resurgent lead poisoning and renewed public attention towards environmental social justice issues: A review of current efforts and call to revitalize primary and secondary lead poisoning prevention for pregnant women, lactating mothers, and children within the U.S. Int J Occup Environ Health 2018;24:86-100.
Han S, Pfizenmaier DH, Garcia E, Eguez ML, Ling M, Kemp FW, et al.
Effects of lead exposure before pregnancy and dietary calcium during pregnancy on fetal development and lead accumulation. Environ Health Perspect 2000;108:527-31.
Nie LH, Wright RO, Bellinger DC, Hussain J, Amarasiriwardena C, Chettle DR, et al.
Blood lead levels and cumulative blood lead index (CBLI) as predictors of late neurodevelopment in lead poisoned children. Biomarkers 2011;16:517-24.
Bellinger DC. Neurological and behavioral consequences of childhood lead exposure. PLoS Med 2008;5:e115.
Pabello NG, Bolivar VJ. Young brains on lead: Adult neurological consequences? Toxicol Sci 2005;86:211-3.
Fine BP, Vetrano T, Skurnick J, Ty A. Blood pressure elevation in young dogs during low-level lead poisoning. Toxicol Appl Pharmacol 1988;93:388-93.
Victery W. Evidence for effects of chronic lead exposure on blood pressure in experimental animals: An overview. Environ Health Perspect 1988;78:71-6.
Nawrot TS, Thijs L, Den Hond EM, Roels HA, Staessen JA. An epidemiological re-appraisal of the association between blood pressure and blood lead: A meta-analysis. J Hum Hypertens 2002;16:123-31.
Telisman S, Jurasović J, Pizent A, Cvitković P. Blood pressure in relation to biomarkers of lead, cadmium, copper, zinc, and selenium in men without occupational exposure to metals. Environ Res 2001;87:57-68.
Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al.
Heart disease and stroke statistics-2018 update: A report from the American Heart Association. Circulation 2018;137:e67-492.
D'souza HS, Dsouza SA, Menezes G, Venkatesh T. Diagnosis, evaluation, and treatment of lead poisoning in general population. Indian J Clin Biochem 2011;26:197-201.
Bagchi D, Preuss HG. Effects of acute and chronic oval exposure of lead on blood pressure and bone mineral density in rats. J Inorg Biochem 2005;99:1155-64.
El Idrissi A, Okeke E, Yan X, Neuwirth LS. Taurine regulation of blood pressure and vasoactivity. In: El Idrissi A, L'Amoreaux W, editors. Taurine 8: Physiological Roles and Mechanisms of Action, Advances in Experimental Medicine and Biology. Vol. 775. New York, NY: Springer Press; 2013. p. 407-25. Available from: https://doi.org/10.1007/978-14614-6103-1_31
El Idrissi A, Okeke E, Yan X, Neuwirth LS. Taurine regulation of blood pressure and vascular resistance. In: El Idrissi A, L'Amoreaux W, editors. Taurine in Health and Disease. Kerla, India: Transworld Research Network; 2012. p. 53-74.
Nakashima Y. Pathogenesis of aortic dissection: Elastic fiber abnormalities and aortic medial weakness. Ann Vasc Dis 2010;3:28-36.
Nienaber CA, Clough RE, Sakalihasan N, Suzuki T, Gibbs R, Mussa F, et al
. Aortic dissection. Nat Rev Dis Primers 2016;2:16053.
Juang D, Braverman AC, Eagle K. Cardiology patient pages. Aortic dissection. Circulation 2008;118:e507-10.
Schofield P. Dementia associated with toxic causes and autoimmune disease. Int Psychogeriatr 2005;17:S129-47.
Zheutlin AR, Hu H, Weisskopf MG, Sparrow D, Vokonas PS, Park SK. Low-level cumulative lead and resistant hypertension: A prospective study of men participating in the veterans affairs normative aging study. J Am Heart Assoc 2018;7:e010014.
Komutrattananont P, Mahakkanukrauh P, Das S. Morphology of the human aorta and age-related changes: Anatomical facts. Anat Cell Biol 2019;52:109-14.
Bäck M, Gasser TC, Michel JB, Caligiuri G. Biomechanical factors in the biology of aortic wall and aortic valve diseases. Cardiovasc Res 2013;99:232-41.
Teo JG, Goh KY, Ahuja A, Ng HK, Poon WS. Intracranial vascular calcifications, glioblastoma multiforme, and lead poisoning. AJNR Am J Neuroradiol 1997;18:576-9.
Vandeputte DF, Jacob WA, Van Grieken RE. Phosphorus, calcium and lead distribution in collagen in lead induced soft tissue calcification. An ultrastructural and X-ray microanalytical study. Matrix 1990;10:33-7.
Reyes PF, Gonzalez CF, Zalewska MK, Besarab A. Intracranial calcification in adults with chronic lead exposure. AJR Am J Roentgenol 1986;146:267-70.
Benson MD, Price J. Cerebellar calcification and lead. J Neurol Neurosurg Psychiatry 1985;48:814-8.
Shah KR, Runyon MS, Beuhler MC. Calcium carbonate for elemental lead ingestions: Effect of alkalinization on elemental lead solubility in a simulated gastric environment. J Med Toxicol 2021;17:185-9.
Neuwirth LS, Emenike BU. Compositions and methods of treating a subject with taurine and derivatives thereof. Inv. Ref. 200-2067US01. Serial No. 16/880,796 U.S. Patent Application; 2020.
Neuwirth LS, Emenike BU, Barrera E, Hameed N, Rubi S, Dacius TF Jr., et al
. Assessing the anxiolytic properties of taurine-derived compounds in rats exposed to lead: A neurodevelopmental and behavioral pharmacological study. In: Hu J, Fengyuan P, Schaffer SW, El Idrissi A, Wu JY, editors. Taurine 11, Advances in Experimental Medicine & Biology. Vol. 1155. New York, NY: Springer Press; 2019. p. 801-19. Available from: https:/doi.org/10.1007/978-981-13-8023-5_69
Neuwirth LS, Kim Y, Barrera E, Jo C, Chrisphonte JM, Hameed N, et al
. Early neurodevelopmental exposure to low lead levels induces frontoexecutive dysfunctions that are recovered by the co-treatment of taurine in the rat attention set-shift test: Implications for taurine as a psychopharmacotherapy against neurotoxicants. In: Hu J, Fengyuan P, Schaffer SW, El Idrissi A, Wu JY, editors. Taurine 11, Advances in Experimental Medicine & Biology. Vol. 1155. New York, NY: Springer Press; 2019. p. 821-46. Available from: https:/doi.org/10.1007/978-981-13-8023-5_70
Neuwirth LS, Volpe NP, Corwin C, Ng S, Madan N, Ferraro AM, et al
. Taurine recovery of learning deficits induced by developmental Pb2+
exposure. In: Lee DH, Shaffer S, Park E, Kim HW, editors. Taurine 10: Taurine and Brain Health, Advances in Experimental Medicine & Biology. Vol. 975. New York, NY: Springer Press; 2017. p. 39-55. Available from: https://doi.org/10.1007/978-94-024-1079-2_4
Neuwirth LS. The characterization of Pb2+
toxicity in rat neural development: An assessment of Pb2+
effects on the GABA shift in neural networks and implications for learning and memory disruption. UMI Proquest Dissertations & Theses 3612469. DAI/B 75-06(E); Apr 2014.
Kok SN, Tweet MS. Recurrent spontaneous coronary artery dissection. Expert Rev Cardiovasc Ther 2021;19:201-10.
Tweet MS, Gulati R. Chapter 5 – Spontaneous coronary artery dissection. In: Sex Differences in Cardiac Diseases: Pathophysiology, Presentation, Diagnosis, and Management. New York, Elsevier; 2021. p. 75-92. https://doi.org/10.1016/b978-0-12-819369-3.00026-5
Kim S, Kang W, Cho S, Lim DY, Yoo Y, Park RJ, et al.
Associations between blood lead levels and coronary artery stenosis measured using coronary computed tomography angiography. Environ Health Perspect 2021;129:27006.
Kovacs AH, Bellinger DC. Neurocognitive and psychosocial outcomes in adult congenital heart disease: A lifespan approach. Heart 2021;107:159-67.
Jackson WM, Davis N, Calderon J, Lee JJ, Feirsen N, Bellinger DC, et al.
Executive functions in children with heart disease: A systematic review and meta-analysis. Cardiol Young 2021;31:1914-22.
Davis JM, Otto DA, Weil DE, Grant LD. The comparative developmental neurotoxicity of lead in humans and animals. Neurotoxicol Teratol 1990;12:215-29.
[Figure 1], [Figure 2], [Figure 3]