168
hazard identification [59]. Recently, Arzuaga and collaborators [60], based on their
knowledge of the mechanisms by which chemicals cause reproductive toxicity, have
proposed a set of eight key characteristics of male reproductive toxicants that, in
combination with male-specific end points, can be applied for the evaluation of toxicological and mechanistic evidence for male reproductive hazard identification [60]
(Fig. 10.4).
Based on previous literature reviews and mechanistic analyses of toxicant- induced
adverse male reproduction effects, Arzuaga and collaborators [60] have described
each key characteristic in the context of mechanisms or pathways by which exposure
to male reproductive toxicants (e.g., environmental toxicants, pharmaceuticals, drugs
of abuse) can lead to adverse health effects. Examples of toxicants known to affect
male reproduction via mechanisms that fall under these eight key characteristics are
presented in Table 1. In support of an evaluation of a chemical for male reproductive
toxicity, this highly valuable initiative provides a structure for systematically identifying and organizing the relevant literature on mechanistic information.
10.5.4 Imaging Mass Spectrometry: A Powerful
Complementary Tool for Understanding
Toxicity Mechanisms
As defined by the OECD test guidelines, toxicokinetic studies must be conducted to
provide information on the absorption, distribution, metabolization and excretion
(ADME) of the tested molecule. Toxicokinetic studies are generally based on the
use of radiolabeled compounds and on the analysis of tissue homogenates or biological fluids by liquid chromatography-mass spectrometry (LC-MS), gas chromatography–mass spectrometry (GC–MS) and nuclear magnetic resonance (NMR).
Quantitative whole-body autoradiography (QWBA) is a commonly used reference
technique for distribution studies that involves the administration of the radiolabeled molecule, providing robust, sensitive and quantitative information. However,
as QWBA only monitors radioactivity, the parent molecule cannot be differentiated
from its metabolites - if any - or degradation products in situ. Therefore, metabolites
are generally identified from the analysis of tissue homogenates or biological fluids,
leading to the loss of information concerning their in situ localization. Since the last
decade, IMS [61] has appeared as a powerful alternative for distribution and metabolism studies of small molecules (<1 kDa) [62–65] and could be also useful for the
toxicological assessment of chemicals released into the environment. Lagarrigue
and coworkers have demonstrated that IMS could be used for the in situ absolute
quantification of chlordecone, an organochloride pesticide and known endocrine
disruptor, in the mouse liver [66]. Their quantification method combines the normalization by an internal standard added to the matrix solution, the correlation with
an orthogonal technique (e.g., GC), and the establishment of a correlation curve
between the data from IMS and GC, to achieve in situ absolute quantification
C. Pineau
hazard identification [59]. Recently, Arzuaga and collaborators [60], based on their
knowledge of the mechanisms by which chemicals cause reproductive toxicity, have
proposed a set of eight key characteristics of male reproductive toxicants that, in
combination with male-specific end points, can be applied for the evaluation of toxicological and mechanistic evidence for male reproductive hazard identification [60]
(Fig. 10.4).
Based on previous literature reviews and mechanistic analyses of toxicant- induced
adverse male reproduction effects, Arzuaga and collaborators [60] have described
each key characteristic in the context of mechanisms or pathways by which exposure
to male reproductive toxicants (e.g., environmental toxicants, pharmaceuticals, drugs
of abuse) can lead to adverse health effects. Examples of toxicants known to affect
male reproduction via mechanisms that fall under these eight key characteristics are
presented in Table 1. In support of an evaluation of a chemical for male reproductive
toxicity, this highly valuable initiative provides a structure for systematically identifying and organizing the relevant literature on mechanistic information.
10.5.4 Imaging Mass Spectrometry: A Powerful
Complementary Tool for Understanding
Toxicity Mechanisms
As defined by the OECD test guidelines, toxicokinetic studies must be conducted to
provide information on the absorption, distribution, metabolization and excretion
(ADME) of the tested molecule. Toxicokinetic studies are generally based on the
use of radiolabeled compounds and on the analysis of tissue homogenates or biological fluids by liquid chromatography-mass spectrometry (LC-MS), gas chromatography–mass spectrometry (GC–MS) and nuclear magnetic resonance (NMR).
Quantitative whole-body autoradiography (QWBA) is a commonly used reference
technique for distribution studies that involves the administration of the radiolabeled molecule, providing robust, sensitive and quantitative information. However,
as QWBA only monitors radioactivity, the parent molecule cannot be differentiated
from its metabolites - if any - or degradation products in situ. Therefore, metabolites
are generally identified from the analysis of tissue homogenates or biological fluids,
leading to the loss of information concerning their in situ localization. Since the last
decade, IMS [61] has appeared as a powerful alternative for distribution and metabolism studies of small molecules (<1 kDa) [62–65] and could be also useful for the
toxicological assessment of chemicals released into the environment. Lagarrigue
and coworkers have demonstrated that IMS could be used for the in situ absolute
quantification of chlordecone, an organochloride pesticide and known endocrine
disruptor, in the mouse liver [66]. Their quantification method combines the normalization by an internal standard added to the matrix solution, the correlation with
an orthogonal technique (e.g., GC), and the establishment of a correlation curve
between the data from IMS and GC, to achieve in situ absolute quantification
C. Pineau