Developmental neurotoxicants and the vulnerable male brain: a systematic review of suspected neurotoxicants that disproportionally affect males

Abstract

The prevalence of neurodevelopmental disorders (NDs), including autism spectrum disorder, attention-deficit/hyperactivity disorder, tic disorder, obsessive-compulsive disorder, and emotional disturbances, has increased notably in the past few decades.To date, debate continues as to the origins of NDs. Increases in widespread exposure to and bioaccumulation of chemical neurotoxicants have paralleled the upsurge in NDs, and are suggested to be causal agents for NDs. One consistent aspect of NDs is the male preponderance. This review considers the issue of male preponderance by reviewing the gender-specific neurotoxic effects of recognized neurotoxicant chemicals to assess their possible etiology in NDs. This investigation consisted of a systematic literature review of original studies published from 1970-2016 on suspected neurotoxicants, to examine whether they have a disproportionate adverse effect based on gender. Based on that review, the neurotoxicants exhibiting consistent gender-specific effects, with exposed males being more affected (than similarly exposed females), were: lead, Thimerosal/ethylmercury, some organochlorine pesticides (e.g., dieldrin, endosulfan, and heptachlor), and air pollution. The next group identified were neurotoxicants exhibiting gender-specific neurotoxic effects, with males being somewhat (but not consistently) more affected than females: mercury vapor, polychlorinated biphenyls (PCBs), and organophosphate pesticides. Finally, there was a group of studies in which the neurotoxicants exhibited apparent gender-related neurotoxic effects but failed to show whether exposed males were consistently more affected than females: inorganic mercury salts, methylmercury species, and certain endocrine disruptors (e.g., phthalates and BPA). The overall conclusion from the studies reviewed was that the brain in males is more vulnerable to many toxic exposures than it is in females. Evidence suggests that the reasons for the male brain being more vulnerable include:(1) greater glutathione availability in females; (2) greater sulfate-based detoxification capacity in females; (3) potentiating effects of co-exposure to neurotoxicants and testosterone; (4) greater neuroinflammatory response in males; (5) reduced vulnerability to oxidative stress in females; and (6) neuroprotective effects of female hormones (estrogen and progesterone), especially in the reduction of inflammation and oxidative stress.

Newborn vitamin D levels in relation to autism spectrum disorders and intellectual disability: A case–control study in california

“…An Australian study [Wilson et al, ] reported an interaction of fetal sex and gestational 25(OH)D on gestational diabetes mellitus, with female “pregnancies” showing an association in the unexpected direction, similar to our findings by sex. Other studies of environmental risk factors and ASD suggest sex‐specific effects [Kern et al, ; Lyall, Croen, Weiss, et al, ; Roberts et al, ; Schaafsma & Pfaff, ], but small numbers of affected females often limit the ability to study sex differences in ASD etiology.…”

Maternal inhalation of carbon black nanoparticles induces neurodevelopmental changes in mouse offspring

“…The statistical analysis did however show that gestationally exposed females mainly moved a longer distance, whereas males rummaged significantly more in the central maze zone. Sex differences in behaviour are often observed following changes in the intrauterine environment [ 82 ], and this is also the case following maternal exposure to particles [ 3 ]. At present the toxicological database does not suffice to evaluate whether this is a general issue for maternal particulate exposures.…”

Association of Low Lead Levels with Behavioral Problems and Executive Function Deficits in Schoolers from Montevideo, Uruguay

“…Therefore, it is important to study the potential moderation by sex in the association between BLL and behavior in settings where children are chronically exposed to contaminants. Interestingly, a recent review [25] concluded that lead exposure produces a consistent gender-specific neurotoxic effect in the cognitive domain, with males being more affected. On the other hand, the same review observed that the effect of BLL on behavior was similar for boys and girls.…”