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Review
. 2021 Oct:201:111558.
doi: 10.1016/j.envres.2021.111558. Epub 2021 Jul 2.

Sex-specific neurotoxic effects of heavy metal pollutants: Epidemiological, experimental evidence and candidate mechanisms

Meethila Gade  1 , Nicole Comfort  1 , Diane B Re  2
Affiliations
Review

Sex-specific neurotoxic effects of heavy metal pollutants: Epidemiological, experimental evidence and candidate mechanisms

Meethila Gade et al. Environ Res. 2021 Oct.

Abstract

The heavy metals lead (Pb), mercury (Hg), and cadmium (Cd) are ubiquitous environmental pollutants and are known to exert severe adverse impacts on the nervous system even at low concentrations. In contrast, the heavy metal manganese (Mn) is first and foremost an essential nutrient, but it becomes neurotoxic at high levels. Neurotoxic metals also include the less prevalent metalloid arsenic (As) which is found in excessive concentrations in drinking water and food sources in many regions of the world. Males and females often differ in how they respond to environmental exposures and adverse effects on their nervous systems are no exception. Here, we review the different types of sex-specific neurotoxic effects, such as cognitive and motor impairments, that have been attributed to Pb, Hg, Mn, Cd, and As exposure throughout the life course in epidemiological as well as in experimental toxicological studies. We also discuss differential vulnerability to these metals such as distinctions in behaviors and occupations across the sexes. Finally, we explore the different mechanisms hypothesized to account for sex-based differential susceptibility including hormonal, genetic, metabolic, anatomical, neurochemical, and epigenetic perturbations. An understanding of the sex-specific effects of environmental heavy metal neurotoxicity can aid in the development of more efficient systematic approaches in risk assessment and better exposure mitigation strategies with regard to sex-linked susceptibilities and vulnerabilities.

Keywords: brain; heavy metals; metals; neurotoxic effects; neurotoxicity; sex-specific; sexual dimorphism.

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Conflict of interest statement

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.. Flow diagram for inclusion and exclusion of studies.
*Records excluded after initial screening of all titles and abstracts **Records excluded if 1) missing information regarding: dose of exposure, period of exposure, biomarker of interest, domain assessed; 2) conducted in vivo in a non-rodent species; 3) published in languages other than English, except for one study for Cd written in Chinese
Figure 2.
Figure 2.. Geometric means (95% confidence intervals, CIs) of whole blood concentrations of Pb, Cd, Mn, and Hg (total Hg and MeHg) stratified by sex, NHANES 2015–2016.
Symbols represent the unadjusted geometric means and bars represent 95% CIs. ***p < 0.001, NS: not significant. (A) Blood lead, Pb; (B) Blood cadmium, Cd; (C) Blood manganese, Mn; (D) Blood mercury, Hg (total Hg and methyl mercury, MeHg). N = 4,987 for Pb, Cd, Mn, and total Hg; N = 4,937 for MeHg. See Supplementary Table 3 for exact values.
Figure 3.
Figure 3.. Geometric means (95% confidence intervals, CIs) of whole blood concentrations of Pb, Cd, Mn, and Hg (total Hg and MeHg) stratified by life stage and sex, NHANES 2015–2016.
Symbols represent unadjusted geometric means and bars represent 95% CIs. (A) Lead, Pb; (B) Cadmium, Cd; (C) Manganese, Mn; (D) Total Mercury, Hg; (E) Methyl mercury, MeHg. N = 4,987 for Pb, Cd, Mn, and total Hg; N = 4,937 for MeHg. See Supplemental Table 4 for exact values. The life stages are defined as follows: child, age < 12 years; adolescent, age 12–21 years; adult, age 22–65 years; elderly, age > 65 years.
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