Prenatal Lead Exposure and Schizophrenia: Further Evidence and More Neurobiological Connections

In 2004, Opler et al. published a study in Environmental Health Perspectives (EHP) suggesting an association between prenatal lead (Pb2+) exposure and schizophrenia (Opler et al. 2004). In the November 2008 issue of EHP, Opler et al. (2008) further supported this association using a different cohort of subjects. In a letter published in EHP in 2004 (Guilarte 2004), I indicated that a plausible neurobiological connection between prenatal Pb2+ exposure and schizophrenia may be that Pb2+ is a potent antagonist of the N-methyl d-aspartate (NMDA) receptor (NMDAR), and NMDAR hypofunction is thought to be involved in the pathophysiology of the disease. Since then, another plausible neurobiological connection has surfaced, and this relates to hippo campal neurogenesis. Neurogenesis occurs not only during development but is also prominent in the adult brain (Laplagne et al. 2006). A well-characterized neurogenic zone in the adult brain is the subgranular zone of the dentate gyrus (DG) in the hippocampus (Zhao et al. 2008). Although the significance of newly born neurons in the adult hippocampus is currently under investigation, the overwhelming evidence supports a role in hippocampus-dependent learning (Dupret et al. 2008; Imayoshi et al. 2008). 
 
Schizophrenia patients express cognitive deficits that may be related to hippocampal dysfunction (Gothelf et al. 2000; Sweatt 2004). So, what is the new neurobiological connection between Pb2+ exposure and schizophrenia? Recent evidence indicates that neurogenesis is decreased in schizophrenia patients, and this decrease may contribute to their cognitive dysfunction (Kempermann et al. 2008; Reif et al. 2006). In an animal model using the NMDAR antagonist phencyclidine (PCP) to induce schizophrenia-like symptoms in mice, Maeda et al. (2007) observed reduced DG neurogenesis that was reversed by the atypical anti-psychotic drug clozapine. Co-administration of d-serine and glycine also inhibited the PCP-induced decrease in neurogenesis. PCP, like Pb2+, is an NMDAR antagonist, and D-serine and glycine activate NMDAR; this suggests that chronic NMDAR hypofunction decreases neurogenesis in the hippo campus, an observation consistent with my comments in 2004 (Guilarte 2004). Models of developmental Pb2+ exposure have also shown decreased DG neurogenesis and are associated with deficits in learning (Jaako-Movits et al. 2005; Verina et al. 2007). Therefore, reduced DG neuro genesis appears to be a common factor in schizophrenia and in animal models of schizophrenia and developmental Pb2+ exposure. 
 
Schizophrenia is a neurodevelopmental disorder that is expressed later in life. Pb2+ is a neurotoxicant that is known to cause developmental abnormalities. Animal models of developmental Pb2+ exposure express a behavioral phenotype with features that overlap with those in animal models of schizophrenia, including increased spontaneous activity, decreased social interaction, and learning deficits (Moreira et al. 2001; Nihei et al. 2000). Also, some of the behavioral effects described in adolescents with early-life Pb2+ exposure are similar to those expressed in schizophrenia patients (Opler and Susser 2005). Thus, although the environmental causes of schizophrenia have not evaluated environmental toxicants, the emerging evidence from the human studies by Opler and colleagues and animal studies suggest that prenatal Pb2+ exposure may be an environmental risk factor for schizophrenia.

Adverse Health Effects from Combustion-Derived Nanoparticles: The Relative Role of Intrinsic Particle Toxicity and Host Response doi:10.1289/ehp.0800218 It is widely accepted that airborne pollution causes adverse health effects in humans (Gauderman et al. 2007). In addition to the concentration of particulate matter (PM), these effects have been related to innate particle toxicity. Stoeger et al. (2009) recently showed that, with a slope that significantly depends on particle structure, surface, and organic carbon content, combustion-derived nanoparticles behave in a different manner in in vitro systems and when reacting with lung surface (i.e. after particle-lung interaction).
We have stressed that mechanistic linkages between PM and health effects should be investigated in more detail (Cetta et al. 2007(Cetta et al. , 2008. Here, we would like to comment on the role of the individual response in the occurrence of the clinically evident outcome, that is, how individual charac teris tics of the host, in the presence of the same (or similar) noxious agents, are responsible for or determine the type and the severity of the response.
Until now, toxicity has been considered mainly as an intrinsic property of each pollutant, depending on size, type, and composition of each particle. Stoeger et al. (2009) focused specifically on structure, BET (Brunauer, Emmett, and Teller) surface area, and oxidative potency. Interestingly, they stressed particle-lung interaction and the ability of some particles rich in organic content, namely, soot with high organic content, to determine a higher than expected inflammatory response due to increased cytochrome P450 1A1 induction; they also introduced a new parameter, inflammatory efficacy, in addition to oxidative potency.
In our opinion, this could be just the top of the iceberg. In fact, "oxidative stress" is a working hypothesis in the search for a common mechanistic linkage between particulate material and adverse health effects. But it is not unique. In particular, in a recent in vitro study in which different types of particles were used (PM < 2.5 or ≤ 10 µm in aero dynamic diameter, tire debris), the same concentration of different particles with the same exposure time elicited different effects on sperm cell function (motility, viability, rate of apoptosis) (Collodel G, Geminiani M, Cetta F, Camatini M, Bolzacchini E, Renieri T, unpublished data). However, variability of the observed effects was less than that elicited by changing the host, with lower adverse effects in New Zealand rabbit sperm, more evident effects in human sperm, and very severe effects in humans with previous impaired sperm function (e.g., varicocele). Sperm cell function is easy to quantify and compare not only among different pollutants but also among different host species or subgroups. These findings are in accordance with recent epidemiologic data showing more pronounced respiratory and cardiovascular effects in patients with previous respiratory and cardiovascular impairment or specific susceptibility, respectively (Gauderman et al. 2007).
The results of these studies will also have relevant implications for policy makers (Cetta et al. 2007). In fact, until now, contrast measures have mainly been directed to reduce PM concentration. Curent evidence suggests thatmore important than reducing the overall PM concentration-it is of paramount importance to reduce selectively the concentration of those pollutants that are more toxic or more strictly related with adverse health effects, such as traffic-related particles. In the future, because of the better knowledge of the host response and of the variability of individual susceptibility in the occurrence of these effects, a major goal for policy makers will be the proper and early recognition-by means of sensible and specific tests-of at-risk subpopulations.
This early recognition of at-risk sub popula tions could facilitate better prevention or reduction of negative effects of host-pollutant interactions.  (Opler et al. 2004). In the November 2008 issue of EHP, Opler et al. (2008) further supported this association using a different cohort of subjects. In a letter published in EHP in 2004 (Guilarte 2004), I indicated that a plausible neurobiological connection between prenatal Pb 2+ exposure and schizophrenia may be that Pb 2+ is a potent antagonist of the N-methyld-aspartate (NMDA) receptor (NMDAR), and NMDAR hypofunction is thought to be involved in the pathophysiology of the disease. Since then, another plausible neurobiological connection has surfaced, and this relates to hippo campal neuro genesis. Neurogenesis occurs not only during development but is also prominent in the adult brain (Laplagne et al. 2006). A well-characterized neurogenic zone in the adult brain is the subgranular zone of the dentate gyrus (DG) in the hippocampus (Zhao et al. 2008). Although the significance of newly born neurons in the adult hippo campus is currently under investigation, the overwhelming evidence supports a role in hippocampus-dependent learning (Dupret et al. 2008;Imayoshi et al. 2008).
Schizophrenia patients express cognitive deficits that may be related to hippo campal dysfunction (Gothelf et al. 2000;Sweatt 2004). So, what is the new neurobiological connection between Pb 2+ exposure and schizophrenia? Recent evidence indicates that neurogenesis is decreased in schizophrenia patients, and this decrease may contribute to their cognitive dysfunction (Kempermann et al. 2008;Reif et al. 2006). In an animal model using the NMDAR antagonist phencyclidine (PCP) to induce schizophrenia-like symptoms in mice, Maeda et al. (2007) observed reduced DG neurogenesis that was reversed by the atypical antipsychotic drug clozapine. Co-administration The correspondence section is a public forum and, as such, is not peer-reviewed. EHP is not responsible for the accuracy, currency, or reliability of personal opinion expressed herein; it is the sole responsibility of the authors. EHP neither endorses nor disputes their published commentary.

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Correspondence of d-serine and glycine also inhibited the PCPinduced decrease in neurogenesis. PCP, like Pb 2+ , is an NMDAR antagonist, and D-serine and glycine activate NMDAR; this suggests that chronic NMDAR hypo function decreases neuro genesis in the hippo campus, an observation consistent with my comments in 2004 (Guilarte 2004). Models of developmental Pb 2+ exposure have also shown decreased DG neurogenesis and are associated with deficits in learning (Jaako-Movits et al. 2005;Verina et al. 2007). Therefore, reduced DG neuro genesis appears to be a common factor in schizophrenia and in animal models of schizophrenia and developmental Pb 2+ exposure.
Schizophrenia is a neurodevelopmental disorder that is expressed later in life. Pb 2+ is a neurotoxicant that is known to cause developmental abnormalities. Animal models of developmental Pb 2+ exposure express a behavioral phenotype with features that overlap with those in animal models of schizo phrenia, including increased spontaneous activity, decreased social interaction, and learning deficits (Moreira et al. 2001;Nihei et al. 2000). Also, some of the behavioral effects described in adolescents with early-life Pb 2+ exposure are simi lar to those expressed in schizo phrenia patients (Opler and Susser 2005). Thus, although the environmental causes of schizophrenia have not evaluated environmental toxicants, the emerging evidence from the human studies by Opler and colleagues and animal studies suggest that prenatal Pb 2+ exposure may be an environmental risk factor for schizophrenia.
The author declares he has no competing financial interests. The recent article titled "Rising CO 2 , Climate Change, and Public Health: Exploring the Links to Plant Biology" (Ziska et al. 2009) is an interesting and useful commentary on this important topic. Although some aspects of the article have been considered in some detail previously, such as the impacts of climate change and elevated carbon dioxide on aerobiology (e.g., Beggs 2004;Confalonieri et al. 2007) and the human health implications of this (e.g., Beggs and Bambrick 2005;Shea et al. 2008), the broader review of links between climate change, plant biology, and human health, particularly the examination of toxicology and pharmacology, is timely and brings together a number of somewhat distinct areas of research.

Tomás R. Guilarte
In their article, Ziska et al. (2009) mentioned the potential impacts of elevated atmospheric CO 2 concentration on ragweed pollen allergenicity and poison ivy toxicity, and therefore considered respiratory allergies and contact dermatitis, respectively. Surprisingly, however, these authors did not recognize that there is a third major mecha nism for human contact with plant allergens: ingestion. In an article published in Air Quality, Atmosphere & Health, I (Beggs and Walczyk 2008) proposed, for the first time, a link between climate change and plant food allergens, such as peanut, and the rise of associated diseases. There is potential for such impacts in the future, but they may have already occurred (Beggs and Walczyk 2008).
I agree that the plant biology aspect of climate change and human health is underappreciated, and I also strongly support Ziska et al.'s (2009) highlighting of the many key questions that remain to be addressed and the urgent need to find answers to these questions. Studies should also investigate the impacts of climate change, particularly elevated CO 2 , on plant food allergens, especially their relative concentrations.
The author declares he has no competing financial interests.
Editor's note: In accordance with journal policy, Ziska et al. were asked whether they wanted to respond to this letter, but they chose not to do so.

ClarifiCation
On p. A155 of the April Focus article [Environ Health Perspect 117:A150-A156 (2009)], a statement reads, "The primary global impact of oil sands comes through the release of greenhouse gases created when about 800 million cubic feet of natural gas (approximately 10% of Canada's total natural gas consumption) is burned daily to create heat for extraction and upgrading, says Stringham." To clarify: This statement refers to the global impact of oil sands production. As noted in the preceding paragraph of the article, most of the greenhouse gas emissions related to oil sands overall come from burning the fuel derived from these reserves.