Year: 2018
Type: letter
Abstract: A large body of data from the epidemiologic studies conducted in the U.S, Finland, China and Russia [Hemminki et al., 1980; Hemminki et al., 1983; Remy et al., 2017; Shmitova, 1980; Yang et al., 2013], have established concerns regarding adverse reproductive outcomes in women and their children who were exposed to hexavalent chromium (Cr(VI)) through the environmental and occupational sources. These women suffer from various gynecological illnesses, including preterm labor or premature abortion [Hemminki et al., 1980; Yang et al., 2013]. Cr(VI) toxicity in female [Banu et al., 2008; Mishra et al., 2008; Murthy et al., 1996; Rao et al., 2009; Sivakumar et al., 2014; Stanley et al., 2013] and male [Aruldhas et al., 2004; Kumar et al., 2017; Marouani et al., 2017; Wise et al., 2008] animals is evident from wide range of investigations. Our previous study identified that regulatory dose of Cr (100 ppb or 0.1 ppm) causes germ cell apoptosis in an ex vivo fetal ovarian culture model [Stanley et al., 2015]. Although it is clear that Cr(VI) is a reproductive toxicant in females and males, information regarding the pharmacokinetics and mechanisms of Cr toxicity are unknown, in particular in humans. Our preliminary study published in Toxicological Sciences identified a “positive association” between Cr accumulation, oxidative stress and apoptosis in human placenta collected from de-identified human placental samples from Michigan [Banu et al., 2018]. Although we continue to further explore the mechanisms (by incorporating more samples) and possibilities to identify biomarkers for Cr(VI) and other heavy metal(s) exposure, this article is a response to Thompson et al regarding critiques and comments about our and other published data and its interpretation. Some of the questions, critiques and comments by Thompson et al., are valuable and reasonable, and these points are addressed here, and will be carefully considered in future reports. Comment 1: “The findings in Banu et al. (2018) are undermined by methodological issues. Environmental monitoring and pharmacokinetic data also limit biological plausibility”. Response: It is conceivable that the environmental monitoring and pharmacokinetic data could limit biological plausibility. This is because we used tissue samples from the repository. However, the methodologies used were validated and accurate, peer reviewed and published [Banu et al., 2016; Sivakumar et al., 2014; Stanley et al., 2013; Wang et al., 2005; Zadorozhnaja et al., 2000]. Comment 2: “Cr(VI) in Michigan (0.0015 ppm) are 30 000 times lower than those that caused placental effects in rodents (50 ppm)”. Response: As Thompson et al indicates, the maximum reported detection of Cr(VI) in Michigan water is 0.0015 ppm (less than the approved safety limits). However, there are multiple other sources besides water such as, from the food, lifestyle factors (such as smoking), vitamin supplements, and exposure from the air. The placenta is one of the organs with highest vasculature [Pretorius et al., 1998]. It is not known how much Cr could possibly be periodically accumulated in the placental tissue or Cr-DNA-adducts during the course of pregnancy. The erythrocyte has a high capacity for Cr(VI) uptake and binding. Cr(VI) enters the erythrocyte through a sulfate ion channel; once inside the cell, it is rapidly reduced to reactive intermediates Cr(V) and Cr(IV) and binds to the beta chain of human hemoglobin [Kerger et al., 1997] and Cr-hemoglobin complex is stable and remains sequestered within the cell over the lifespan of the erythrocyte [Paustenbach et al., 2003]. A recent study indicate that estimation of Cr in erythrocyte is a direct indicator of Cr(VI) exposure [Devoy et al., 2016]. Another study from our lab indicated that regulatory dose of Cr(VI) (0.1 ppm) causes germ cell death in rat fetal ovaries [Stanley et al., 2015]. Comment 3: “Banu et al., omitted 30 of the 50 placental samples…” Response: The report in Tox Sci [Banu et al., 2018] is a preliminary study. Although we had incorporated 50 placentas for Cr estimation, 20 placentas were included for other analyses on the basis of high and low Cr burden. We agree that the results would be much stronger if all 50 samples were incorporated for all analyses. We have 540 samples in our repository. Our future studies will incorporate more samples to validate our findings and conclusions. Comment 4: “Use of stainless steel surgical instruments could be a source of Cr”. Response: We recognized that stainless steel surgical instruments could affect Cr levels in tissue. Therefore also evaluated concentrations of Nickel (Ni), an element that is also high in stainless steel. A positive relationship between high Cr and high Ni would have been interpreted as contamination from stainless steel. None of the samples (n = 50) showed this relationship, allowing us to discount the possibility of Cr contamination from surgical instruments. Comment 5: Other misleading statements include “environmental exposure to Cr(VI) is increasing and is a growing concern”…. Response: On the contrary, several studies and reports including the devastated town of Hinkley [Banks, 2002], and San Fernando Valley, CA [Melvin et al., 2003]; as well as Garfield NJ [US-EPA, 2016] due to Cr(VI) contamination exist to strongly support our statement that environmental exposure to Cr(VI) is increasing and a concern, as listed in the references [Kalahasthi et al., 2006; Khan et al., 2013; Li et al., 2001; Qian et al., 2013; Remy et al., 2017; Wang et al., 2014; Zhitkovich 2011]. Comment 6: “Significant contamination with Cr(VI) has been found in approximately 30% of the drinking water sources in California”, however, it is unclear what is meant by “significant” in this context. Response: This statement stems from previous publications and reports [Cone, 2009; Dunn et al., 2009; N.T.P, 2008; Salnikow et al., 2008]. Detectable levels of Cr(VI) have been reported in 30% of the drinking water sources monitored in California, which has a 1 μg/l detection limit for purposes of reporting [N.T.P, 2008]; 87% of those sources had concentrations ranging from 1 to 10 μg/l. Comment 7: Comments about mRNA and western blots. Response: As clearly indicated in the paper, fold-change comparison was made between low Cr and High Cr group. Normalization of western blot and mRNA expression was performed with beta actin protein or mRNA, respectively. Comment 8: Time from delivery to sample stabilization. Response: Time duration ranged from 20 to 45 min. Comment 9: “Effects of other metals and endocrine disruptors….” Response: We have appropriately concluded the study in our published paper as follows: “Although the focus of this study was on Cr metals such as Cd, Ni, As, and Mn and other endocrine disruptors in the placenta may have also played a role in the development of such adverse effects. These studies need to be expanded to address mixture effects” [Banu et al., 2018]. Comment 10: Western blot quantification. Response: Please refer Banu et al., (2018, p. 379). Supplementary data are available at Toxicological Sciences online. This work was partly supported by National Institute of Environmental Health Sciences grants R01ES025234 (Sakhila K. Banu), ES017500 (Vasantha Padmanabhan (V.P)), P01 ES022844 (V.P.), and the United States Environmental Protection Agency (US EPA) Grant RD 83543601 (V.P.).
Source: Toxicological Sciences
Author: Sakhila K Banu
Institution: Texas A&M University
Language: English
Subfield: Health, Toxicology and Mutagenesis
Field: Environmental Science
Domain: Physical Sciences
Open Access status: bronze
OpenAlex ID: W2805215905