Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 13, Number 29, 2007
Contents
Advances in Developmental and Reproductive Toxicology
Executive Editor: Gian Mario Tiboni
Editorial Pp. 2951
Interactive Endogenous Small Molecule (Gaseous) Signaling:
Implications for Teratogenesis Pp. 2952-2978
J.M. Fukuto and M.D. Collins
[Abstract]
New Proposals for Testing Drugs with-IKr Blocking
Activity to Determine Their Teratogenic Potential Pp.
2979-2988
M. Karlsson, B.R. Danielsson, M. Nilsson, C. Danielsson
and W.S. Webster
[Abstract]
The Effects of the Endocrine Disruptors Dithiocarbamates
on the Mammalian Ovary with Particular Regard to Mancozeb
Pp. 2989-3004
S. Cecconi, R. Paro, G. Rossi and G. Macchiarelli
[Abstract]
Reproductive Toxicology of Environmental Toxicants:
Emerging Issues and Concerns Pp. 3005-3019
E.V. Younglai, Y.J . Wu and W.G. Foster
[Abstract]
Prospective Teratology of Retinoic Acid Metabolic
Blocking Agents (RAMBAs) and Loss of CYP26 Activity
Pp. 3020-3037
P. McCaffery and C. Simons
[Abstract]
Multiligand Endocytosis and Congenital Defects: Roles
of Cubilin, Megalin and Amnionless Pp. 3038-3046
R. Kozyraki and F. Gofflot
[Abstract]
The Development of New Concepts for Assessing Reproductive
Toxicity Applicable to Large Scale Toxicological Programmes
Pp. 3047-3058
S. Bremer, C. Pellizzer, S. Hoffmann, T. Seidle and T.
Hartung
[Abstract]
Abstracts
[Back to top]
Editorial: Pharmacological Impact
of Snake Venom Compounds
The papers in this special issue of Current Pharmaceutical
Design cover a wide spectrum of relevant and fascinating topics
in the area of developmental and reproductive toxicology.
There is increasing evidence that small gaseous molecules,
such as dioxygen, carbon monoxide, nitric oxide and hydrogen
sulphide, serve important roles in modulating a variety of
physiological responses, including those involved in development.
The article from Fukuto and Collins [1], besides providing
an overview of the chemistry and biology of these soluble
gases, summarizes the information regarding the teratogenicity
of either excess or deficiency of gaseous signalling molecules.
Drugs blocking the potassium current IKr, are potential human
teratogens. The review from Karlsson et al. [2] supports
the contention that the conventional methodology used for
assessing drug teratogenicity, (based on repeated daily treatment
during the gestational period covering organogenesis) is not
optimal to characterize the teratogenic potential of agents
having IKr blocking properties. In this context, the potential
role of complementary teratology studies, including single
gestation day dosing and studies using embryo culture, is
discussed.
The manuscript authored by Cecconi et al. [3], concentrates
on the adverse effects of ethylenedithiocabamate, and with
special reference to fungicide mancozeb, on mammalian ovary.
The ability of mancozeb to induce spindle anomalies in meiotic
cells and ultrastructural changes in ovarian somatic cells
raises the possibility that mancozeb may also initiate cancerogenesis.
The article presented by Younglay et al. [4] focuses
on the potential negative impact of man-made environmental
toxicants, including polychlorinated biphenyls and dioxins,
organochlorines, phthalates, benzo-a-pyrene, synthetic polymers
and the fungicide vinclozolin, on human developmental and
reproductive function.
Retinoic Acid Metabolic Blocking Agents (RAMBAs) represent
a class of agent that have been designed to inhibit the CYP26
members of the cytochrome P450 family which regulates the
local levels of all-trans retinoic acid. The article
from McCaffery and Simons [5], besides describing the mechanism
of action of the RAMBAs, also discusses the potential teratogenic
potential of this class of agents.
Kozyraki and Gofflot [6] summarize recent data on the biological
function of the receptors cubilin, megalin and amnionless,
and focus on their implication in embryonic nutrition and
central nervous system malformations.
The last article from Bremer and co-workers [7], besides providing
a short overview on the current status of reproductive toxicity
testing, introduce new concepts for assessing reproductive
toxicity applicable to large scale toxicological programmes.
I would like to express my sincere appreciation to the contributors.
References
[1] Fukuto JM, Collins MD. Interactive Endogenous Small Molecule
(Gaseous) Signaling: Implications for Teratogenesis. Curr
Pharm Des 2007; 13(29): 2952-2978.
[2] Karlsson M, Danielsson BR, Nilsson M, Danielsson C, Webster
WS. New proposals for testing drugs with-IKr blocking activity
to determine their teratogenic potential. Curr Pharm Des 2007;
13(29): 2979-2988.
[3] Cecconi S, Paro R, Rossi G, Macchiarelli G. The effects
of the endocrine disruptors dithiocarbamates on the mammalian
ovary with particular regard to mancozeb. Curr Pharm Des 2007;
13(29): 2989-3004.
[4] Younglai EV, Wu YJ, Foster WG Reproductive Toxicology
of Environmental Toxicants: Emerging Issues and Concerns.
Curr Pharm Des 2007; 13(29): 3005-3019.
[5] McCaffery P, Simons C. Prospective teratology of retinoid
acid metabolic agents (RAMBAS) and loss of CYP26 activity.
Curr Pharm Des 2007; 13(29): 3020-3037.
[6] Kozyraki R, Gofflot F Multiligand endocytosis and congenital
defects: roles of cubilin, megalin and amnionless. Curr Pharm
Des 2007; 13(29): 3038-3046.
[7] Bremer S, Pellizzer C, Hoffmann S, Seidle T, Hartung T.
The development of new concepts for assessing reproductive
toxicity applicable to large scale toxicological programmes.
Curr Pharm Des 2007; 13(29): 3047-3058.
Gian Mario Tiboni
Ostetricia e Ginecologia
Dipartimento di Medicina e Scienze dell'Invecchiamento
Università "G. d'Annunzio" Chieti-Pescara
Presidio Ospedaliero "SS. Annunziata"
Via dei Vestini
66013 – Chieti
Italy
E-mail: tiboni@unich.it
[Back to top]
Interactive Endogenous Small Molecule (Gaseous) Signaling:
Implications for Teratogenesis
J.M. Fukuto and M.D. Collins
Dioxygen (O2) is an exogenously supplied gas with
a number of properties that make it valuable as a biological
source of energy and as a result much of life has become dependent
on this molecule. Nitric oxide (NO), carbon dioxide (CO) and
hydrogen sulfide (H2S) are small molecules that
are sometimes in a gaseous state and that can be either exogenously
or endogenously supplied. The chemistry of these four molecules
allows them to share some common biological targets and signal
transduction pathways as well as providing for unique aspects
to the biochemistry of each one. Dioxygen can be teratogenic
either in excess (hyperoxia) or in deficiency (hypoxia). Although
there is a great deal known about the chemistry and physiology
of dioxygen, the mechanisms by which it induces toxic endpoints,
such as teratogenesis, are unknown. This review examines some
fundamental concepts of these four signaling molecules and
considers some of the molecular targets and pathways by which
they interact. The information regarding the teratogenicity
of either excess or deficiency of the four gases is summarized.
Interaction information is generally unavailable for teratogenicity
endpoints with the four gases and also a mechanistic understanding
of the toxicodynamics of the compounds is lacking. Although
it could be theoretically predicted that certain interactions
would be additive, for example carbon monoxide and hypoxia,
based on the physiological role of these molecules, the data
is unavailable. Consequently, these small (gaseous) signaling
molecules have been demonstrated to interact with respect
to signaling pathways, but whether this indicates a similar
result for teratogenesis remains unevaluated.
[Back to top]
New Proposals for Testing Drugs with-IKr Blocking
Activity to Determine Their Teratogenic Potential
M. Karlsson, B.R. Danielsson, M. Nilsson, C. Danielsson
and W.S. Webster
Drugs blocking the potassium current IKr, either as an intended
pharmacologic effect (eg antiarrhythmics dofetilide and almokalant)
or as an unwanted side-effect (eg antihistamine astemizole,
propulsive drug cisapride, antidepressive drugs and macrolide
antibiotics) are potential human teratogens. It is the contention
of this paper that the existing repeat dose regimen used in
teratology studies to fulfil regulatory requirements, does
not properly identify the teratogenic risk of these drugs.
Results from conventional studies for dofetilide and almokalant
showed high rates of postimplantation embryonic death with
few malformed fetuses. For astemizole and cisapride only embryonic
death was seen. These latter results were not considered important
because they occurred either in the presence of maternal toxicity
and/or at high doses. Subsequent studies have shown that IKr-blockers
are highly teratogenic when administered on single gestational
days (GD) during a sensitive period of rat pregnancy (GD 10-14)
when they induce a high incidence of stage-specific malformations.
This teratogenic activity of astemizole and cisapride was
missed in the original teratology studies. Mechanistically
IKr-blockers cause bradycardia and arrhythmia of the embryonic
heart and while an embryo may be able to survive a single
day exposure to a teratogenic dose, repeat dosing often leads
to death of the embryo. With this review we suggest that new
drugs identified at the preclinical stage of development as
having IKr-blocking properties, should undergo more comprehensive
teratology testing including single GD dosing and studies
using embryo culture. This would further help identify and
characterise their teratogenic potential.
[Back to top]
The Effects of the Endocrine Disruptors Dithiocarbamates
on the Mammalian Ovary with Particular Regard to Mancozeb
S. Cecconi, R. Paro, G. Rossi and G. Macchiarelli
Many human-made chemicals are called endocrine disruptors
(EDs) because they have the potential to disrupt endocrine
functions in exposed organisms. Many EDs can disrupt hormonal
homeostasis by interfering with hormone receptor recognition,
binding and activation, while others act by still unknown
mechanisms. Among the EDs specifically affecting the female
reproductive system, those with steroidogenic/antisteroidogenic
effects have been extensively studied and the mechanisms of
toxicity clarified also at molecular level. For many others,
information is restricted to few epidemiological data and
in vivo/in vitro experiments with animal models. This
is the case of the dithiocarbamates, and in particular of
the fungicide mancozeb, an ethylenedithiocarbamate widely
used to protect fruit and vegetables, ginseng included, because
of its low acute toxicity in humans. Although the mechanism(s)
by which mancozeb may specifically act on female reproductive
organs are largely unknown, data on experimental animals in
vivo have demonstrated that the fungicide can induce
several disturbances on estrus cycle. When used in vitro
at concentrations considered too low to cause human health
injuries, the fungicide impairs mouse embryo development and
meiotic spindle assembly. The possibility that the female
germ cell (the oocyte) could be a specific target of mancozeb
suggests a role for this fungicide as probable inductor of
infertility also in exposed human populations.
[Back to top]
Reproductive Toxicology of Environmental Toxicants:
Emerging Issues and Concerns
E.V. Younglai, Y.J . Wu and W.G. Foster
Environmental toxicants comprise a number of man-made organic
chemicals which may resist metabolism or their metabolites
may persist in the environment and accumulate in the food
chain. Some of these persistent chemicals are carried over
long distances via the atmospheric transport and
can have biological effects in fish, wildlife and humans.
In this review the relationship between structure of these
chemicals, their mode of action and their possible roles in
adverse developmental and reproductive processes in humans
will be discussed. The focus will be on model polychlorinated
biphenyls and dioxins, organochlorines, phthalates, a constituent
of cigarette smoke (benzo-a-pyrene), synthetic polymers (polybrominated
diphenyl ethers and polyfluorinated compounds), and a fungicide
(vinclozolin).
[Back to top]
Prospective Teratology of Retinoic Acid Metabolic
Blocking Agents (RAMBAs) and Loss of CYP26 Activity
P. McCaffery and C. Simons
All-trans retinoic acid (atRA) is the transcriptionally
active product of vitamin A and induces gene expression via
specific receptors at nM concentrations. Essential enzymes
that regulate the local levels of atRA are the CYP26 members
of the cytochrome P450 family, which catabolize atRA. Compounds
that have been designed to inhibit these enzymes are known
as Retinoic Acid Metabolic Blocking Agents (RAMBAs). Treatment
with these compounds will raise endogenous atRA levels and
may be therapeutic for the treatment of diseases that respond
to high atRA concentrations, including several types of cancer
as well as skin conditions such as psoriasis and acne. This
review describes the mechanism of action of the RAMBAs and
discusses the potential side effects of these compounds. atRA
is highly teratogenic and the potential teratogenicity of
the RAMBAs is described by comparison with the abnormalities
resulting from null mutation of individual CYP26 genes. The
possible effects of RAMBAs on the adult brain are also described
that have the potential for harm but, in the right circumstances,
may also be beneficial.
[Back to top]
Multiligand Endocytosis and Congenital Defects: Roles
of Cubilin, Megalin and Amnionless
R. Kozyraki and F. Gofflot
Cubilin and megalin are multiligand receptors that mediate
uptake of extracellular ligands. Their function has extensively
been studied in the kidney where they play a key role in vitamin
B12 and vitamin D homeostasis. Amnionless is a plasma membrane
protein that binds to cubilin in various epithelia; the interaction
cubilin-amnionless in the gut is crucial for dietary vitamin
B12 uptake. Studies in patients with gene defects in these
receptors, and animal models with inactivated cubilin, megalin
or amnionless suggest an important role in embryonic development
and normal growth. In this review we will summarize recent
data on the biological function of these receptors and focus
on their implication in embryonic nutrition and central nervous
system malformations.
[Back to top]
The Development of New Concepts for Assessing Reproductive
Toxicity Applicable to Large Scale Toxicological Programmes
S. Bremer, C. Pellizzer, S. Hoffmann, T. Seidle and T.
Hartung
Large scale toxicological testing programmes which are currently
ongoing such as the new European chemical legislation REACH
require the development of new integrated testing strategies
rather than applying traditional testing schemes to thousands
of chemicals. The current practice of requiring in vivo
testing for every possible adverse effect endanger the success
of these programmes due (i) to limited testing facilities
and sufficient capacity of scientific/technical knowledge
for reproductive toxicity; (ii) an unacceptable number of
laboratory animals involved (iii) an intolerable number of
chemicals classified as false positive.
A key aspect of the implementation of new testing strategies
is the determination of prevalence of reproductive toxicity
in the universe of industrial chemicals. Prevalences are relevant
in order to be aware on the expected rate of false classification
during the toxicological testing and to implement appropriate
measures for their avoidance. Furthermore, a detailed understanding
on the subendpoints affected by reproductive toxicants and
the underlying mechanisms will lead to more science based
testing strategies integrating alternative methods without
compromising the protection of consumers.
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