Effects of Cadmium Exposure on Lactating Mice and Rats: A Systematic Review of Breastfeeding Experiments

Round 1

Reviewer 1 Report

The current review article is dealing with the presentation of Cd-mediated effects on biological models, closely related to human effects, focusing on lactating rats and mice and breast feeding experimentation. The organization of the systematic review, regarding the data presented seem welldone and both Figures and Tables are clear in overall. However, authors should reconsider Fig. 2 clarification into the text and proceed to minor corrections throughout the text (i.e. see line 186: the review articles aimed...). Moreover, regarding the Discussion section, authors should provide more evidence on Cd mediated effects, taking into account the presented data, using a merged section (Results and Discussion) for better explaining and arguing.

Author Response

Responses are in a pdf archive

Author Response File: Author Response.pdf

Reviewer 2 Report

Please, do consider following remarks. The studies are well analysed, but presentation of the results is lacking precision and seems shallow. Discussion is scarce and it requires major improvement.

Abstract

Line 18 – please use „mechanisms are“ or „mechanism is“.

Introduction

Line 39 – Smoking contributes to uptake of Cd by smokers rather to its introduction into the environment.

Line 43-44 – Please, be more specific – what did the studies indicate; was the level of Cd in the breast milk increased and who has been included in the control group. What are the facts based on which the conclusion was reached that the breast-milk may be contaminated by Cd_

Line 49 – Please do not use the same sentence as in the Abstract bearing the same typo. Please, include what is the mechanism of Cd detoxication and refer to the literature source indicating whether it is developped in newborns or when in the postnatal period it develops. Is it realy the reason why newboens are more prone to adverse effects of Cd?

Results

Line 130 – If Cd was administred by drinking water which was available ad libidum, what was the daily intake of Cd per dam? If this was not reported than actual dose of exposure is not known. How do the authors reason inclusion of this study into analysis? Same issue for the inhalation study, and studies refering to in lines 150-151 and studies cited in the Table 3 based on the Cd administration by drinking water. For the accurate analysis information on the Cd uptake in those studies is crucial.

Is there any difference between tables 1, 2, 3 in the manuscripta and in the supplementary materials. They seem as same. Is there any particular reason for duplicating them?

Lines 198-199 - Please provide more details regarding the way in which did Cd alter acetylcholinesterase, Na+ -, K+ -and Mg2+ ATPase activities.

Lines 211 – 213 – What is the consequence/relevance of the transferrin receptor up-regulation in brain tissue of Cd-exposed pups and other brain elements such as Zn, Cu, lipids and cholesterol reduction?

In which group of pups were neurodevelopmental toxicity biomarkers most and least pronounced: exposed during gestation, lactation, gestation+lactation? The same question relates to other categories of observed adverse effects.

Line 220 – Please, could you be more specific – what type of cells in testicles mor frequently underwent apoptosis?

Line 222 – 223 It is not clear in which way was the genetic regulation of cystoskeleton related proteins (CORO1A, cofilin 1 and profilin) affected. Please, provide more details on that regard.

Lines 225 – 235 – Please, based on the records on administration route, dosage, and period of exposure, how would you explain discrepancies and conversed results regarding the sexual development parameters in female pups?

Line 245 – In which way was secretion of insulin affected?

Line 274 – typo “alivary gland”.

Line 276 – In which way did Cd alter heart morphology?

Figure 3 in the manuscript shows the same if not more detailed data as the Figure 1 in the supplementary file. Are they both necessary?

Figure 2 shows that Cross-fostering (CF) strategy was in pregnancy and pregnancy-lactation schemes were also included in the analysis. Results obtained by that approach should be separately presented and emphasized. Yet, there is no mentioning of them in the Results chapter.

Discussion

Discussion is not what a discussion should be. The authors provided a summary of already presented results. Based on the analysis of the studies some conclusions should be made regarding the range of doses which were adverse and which did not trigger any effect. Differences between effects in regard to the period of exposure, route of exposure, what are the target organs in each of the exposure period, the relevance of these studies for the human exposure, possibility of the extrapolation of the results, how to improve elimination or prevent absorption of the Cd by pups gut. The authors mentioned retention of the Cd; where does it occur, what is the effect, except on sexual maturation, of Cd exposure in pups observed after the weaning? There are so many points to be discussed based on the analysis of the published studies and many indications to be proposed. Unfortunately, the discussion is to scarce.

Author Response

responses are in a pdf archive

Author Response File: Author Response.pdf